Welcome, everyone, and thank you for joining us this morning for ImmunityBio's first KOL and Investor Day. We are here today to discuss the progress made over the past year since the launch of ANKTIVA in May of 2024. On the call today are Dr. Patrick Soon-Shiong, Executive Chairman and Global Chief Scientific and Medical Officer, and Rich Adcock, the company's President and Chief Executive Officer. Also joining us today are several key opinion leaders who will participate in today's call. The call is being broadcast live at www.immunitybio.com. A playback will be available for at least three months on ImmunityBio's website. Before I continue, I'd like to take a moment to read the company's Safe Harbor Statement. Certain statements contained in this Investor Day program that are not historical information contain forward-looking statements.
The forward-looking statements involve risks and uncertainties, and actual results may differ materially from those projected or implied. Further, certain forward-looking statements are based on assumptions of future events, which may not prove to be accurate. For details regarding factors that may impact such forward-looking statements and risks that may impact the company's business, please refer to the Risk Factors section of the company's Form 10-K filed with the Securities and Exchange Commission on March 3, 2025, and its subsequent filings made by the company with the SEC, as well as press releases. In a moment, Dr. Soon-Shiong and Rich will discuss the recent developments in ImmunityBio, including discussing the latest on ANKTIVA approved for BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ. They will also unveil and provide details on the Cancer BioShield.
During today's call, they will discuss a range of ongoing efforts at ImmunityBio with our panel of KOLs. Finally, they will provide an update on the company as a whole before we open the call for questions. With that said, I will now turn the call over to Dr. Soon-Shiong.
Thank you for the notes today, which I'm sure that will please you. If you could put the first slide on. Do I control it from the top here, or do you have? I just sort of control it there. Okay. I think today what we want to do is really waiting for the first slide. Okay, while we're waiting for the first slide. What we're going to do today is really, there's been such a groundswell of interest on this Cancer BioShield. It really was opportune that we had planned this Investor Day way in advance of this. We thought that this would be a real opportunity for me to expose work that's been going on for 20 years. This Cancer BioShield is such an important concept. I thought we would take this opportunity for most of this discussion.
First, I want to really thank the key opinion leaders who really traveled all the way here, and we'll meet them individually to really talk about the science behind the Cancer BioShield. You will hear a little bit about this concept of lymphocytes. When we talk to some of these KOLs and immuno-oncologists, this thing called absolute lymphocyte count is almost a foreign name or word, yet it's been looking, staring us in the face. We'll talk about NKs and T cells because that matters. We'll talk about how duration of complete response matters. We talk about how survival matters, and we'll talk about quality of life matters.
In a sense, that really is the vision that we've been pursuing almost for 25, 30 years now to say that we will think back a decade from now of how barbaric our standards of care have been with high-dose chemotherapy. Some of you may recall at one point for breast cancer patients, they wanted really intense high-dose chemotherapy. We will show you today how, sadly and inadvertently, that's actually killed the cancer bio shield. Let's start with that. The next slide, where I want to, as I said, introduce the, let me get away from the slide, the leadership that is present today. Obviously, time doesn't permit, but you will see and have a chance to meet with some of the leadership. I'm so proud that we have an amazing leadership team that will take this, what we think, to the next frontier.
Next slide. This is what we've been talking about today, very, very much so. When we did the IPO of a company called NantKwest many years ago, that this natural killer cell that is, and this is a real live sort of time-lapse of the natural killer cell touching a cancer cell. Those granules going in there are these cytotoxic granules. When I say we're going to immediately kill the cancer cell from the outside in rather than from the inside out, the revelation was that these, as you kill this cancer cell, it quite literally explodes and starts bringing to it the T cell. There is a very complex cross-talk between NK cells and T cells, which we'll show you as we go forward. Next slide. This was the idea that we put forth.
As I started recruiting oncologists and doctors to this team, and some of you know that right at the right-hand corner there, you will see this in 2016, January, where during the Vice President Biden time frame, I launched the Cancer Moonshot 2020. The concept here was for us to really explain this really, and we'll come back to this quantum effect. When I talk about quantum effect, it gets all lost. Every one of those little images is a cell. Next slide. This is quite literally an Oxford developed time lapse. This is what's happening in your body. These are real cells, natural killer cells that are quantumly trying to kill the cancer cell while the cancer cell is trying to hide and block.
This is where you have granules and you have T cells, and you need to train these T cells and the opportunity for them all to come together and kill. This complexity is not normally understood in the big pharma world, where you would try and develop one drug at a time. My question was, which drug, which cell do I not want? You have a T cell, a B cell, a dendritic cell, an NK cell, a memory T cell. They are all acting together in this battlefield. This is not a video. This is of a made-up video. This is what is going on in your body as you are all sitting here and we are speaking. This is your bio shield. This is what I mean by the cancer bio shield. Our job is to activate this.
Our job is to take your body and train your body to actually recognize, remember, expose, and kill. What would be the first way for us to pursue this? In my mind, and this is where another continuity of thought is, if we can catch the tumor as early as possible before it invades and create this thing called a NAND cancer vaccine, where I as a surgeon would not want to remove your tumor yet, but to leave the tumor in your body when it's a tiny kernel so that it acts as the vaccine to your bio shield, to use the tumor itself in your body, what we call the neoadjuvant, and then do the surgery, remove the tumor. Non-muscle-invasive bladder cancer, next slide, is the first opportunity to pursue the science.
Potentially change the care for patients with BCG-unresponsive bladder cancer, carcinoma in situ, plus or minus papillary disease. This is just the start. It may potentially change the way we treat other forms of bladder cancer in the future.
Here at Alpha, my whole focus has been on non-muscle-invasive bladder cancer and muscle-invasive bladder cancer. We have an NIH-funded research laboratory. When I first heard of ANKTIVA, I was a little, I don't want to say jealous, but everybody in the laboratory knew that this was going to be a game changer. We knew that this was going to have efficacy just based on the research that we had personally within our institution studying patients with BCG-unresponsive bladder cancer. We've identified pathways of importance, and one of the ones that we really think is pivotal for this is the innate immune system, specifically with the NK cells. This is where I think ANKTIVA is very important. Along with BCG, there's no surprises with efficacy and a durable response rate of approximately 60% in 12 months.
71% of patients respond at any time, either at the three-month mark or at the six-month mark. That's impressive. What makes it more impressive is the fact that only about 16% of those people ultimately need to get those bladders out.
As I followed the trajectory from the concept through the different phases and then finally to the FDA approval, showing in some patients that you have a durable response rate that goes up to 47 months or even more than 47 months, that was for me a, I want to almost say a proud moment because it's like, aha, this is exactly what we wanted.
In the case of bladder cancer, for the last 40 years, we've been using this bacterium called BCG. We give BCG into the bladder. It causes inflammation. It activates T cells. The cancer cell changes and pulls in its receptors so the T cell can't recognize it. Guess what? As soon as a cancer cell pulls in its receptor to T cell, that is the signal to the natural killer cell. Yes, a cell that's dangerous, go kill it.
What we understand from BCG-unresponsive bladder cancer is that as the cancer cells progress, you actually lose MHC class one. The ability for NK cells to come in and be the major dominant players is because of the ability to recognize a variety of different HLAs and so forth. With their communication with the dendritic cells and other cells within the tumor microenvironment, they can then identify and make those antigens and build that memory that can then be communicated to the T cells.
With ANKTIVA, we proliferate these natural killer cells. To reactivate the killing. In so doing, we also reactivate the T cells. In so doing, we also reactivate the dendritic cells and the memory T cells. For the first time now, we have a one-two punch that the tumor could not evade, we think, either the T cell or the natural killer cells. That is the difference that we have now brought to bed.
ANKTIVA allows me now to have a much more vivid and honest conversation with patients that we have a intravesical therapy that has a durable response. That gives me now a little bit more sense of hope where I do not necessarily have to push the more radical therapies on a lot of patients.
From a cancer standpoint, the best option we have available for patients who fail the procedure is surgical removal of the entire bladder. I think the use of ANKTIVA and BCG can potentially save patients from needing that operation.
My local doctor said, well, you know, I think you might have a tumor in your bladder. You know how you would kind of be worried a little bit. Oh, not now. No, I'm fine.
Over 20 years of practicing urology, I have not seen a clinical trial that has this durability for non-muscle-invasive bladder cancer. This is a unique space that we're in right now. When we reach that two-year all negative results, I'm out of the woods, now. I'm complete remission again.
I do think that maintenance therapy is an important part of the therapy. This is almost like getting your booster vaccine.
It's not as though their cancer is necessarily becoming less aggressive. It's just that the immune system is able to take care of the more aggressive tumors with high mutational burden. We're not seeing any systemic toxicity. That level of concern goes away when you're giving something locally and it doesn't get absorbed. N-803 is easy. You combine it with the BCG, and the urologist just instills the immunotherapeutic agent through a catheter. You take the catheter out, and the patient goes home. It's no different from a urologic standpoint than just giving BCG.
In a sense, ANKTIVA is for bladder cancer, the first NK cell treatment that has actually really shown efficacy in patients. Overall, I think that the biology speaks for itself. I think this is just the beginning of where we're going with the different types of therapies and how we're going to use ANKTIVA in the future.
The bar we are now setting is that you need not provide the patient with this high-dose chemotherapy. You can be kind to the patient's body. You can activate the patient's own immune system using this ANKTIVA to generate memory and long-term durable remission.
You begin to see these videos have been taken. I want to thank Caroline, who's been the most amazing videographer that's been outgoing and meeting with the patients and the impact that we make on patients. I think there's a lot of takeaways from that video. One, you talk about the toxicity. Actually, this is what you have in your body. We are giving you IL-15 that you have in your body. You talk about toxicity, but there isn't because what we're activating is a natural killer cell in your body, the T cell in your body. This is what we mean about really changing the entire paradigm. This is what we mean about the bio shield. For the next, let's see, I'm pretty well on time here, a few minutes.
Let me now go into the business details and the technical details and the scientific details of the results. As I said, we approach bladder cancer first, the first armamentarium with the first output of the bio shield. Your natural killer cell does not care whether it is a bladder cancer, a breast cancer, pancreatic cancer, liver cancer, because that is the cancers that all natural killer cells would kill. More importantly, it actually kills any infected cells. HBV, hepatitis, HIV, which we in trials, and even COVID. We will talk about that as we proceed. Let me start in a methodical way and go through bladder cancer. As investors, I think you focus very much on our very first approval and then how these really fall through the platform of the bio shield.
Now, just to set the stage, the bio shield of this NK cell, T cell can be given through this one shot, the jab, where you activate the NK cell. When I say one shot, I don't mean one single shot. I mean one shot, and you go home and you come back and you have a shot. That's what we call in vivo activation. We also need to activate your memory through a regular adenovirus, which we'll speak to. We can also, through an ex vivo, take your blood, grow these NK cells. There's different kinds of NK cells, INK T cells, NK T cells, and ex vivo infuse that. There's a whole component of this bio shield that we now, for the first time, have at our fingertips. Let's start with bladder cancer. Next slide, please.
In April 2024, this was the turning point for us, the first approval of ANKTIVA plus BCG. Many people did not understand why we would keep on using the BCG, because the BCG is an immunostimulating agent. You need to activate the body's immune system, and ANKTIVA is a proliferating agent of that immunostimulation. This is the first chemo free. If you look at those two boxes, there is no chemotherapy here. It does not mean we do not need to use chemotherapy, but we need to use it in a very different way. We need anything that would stimulate the tumor and wake it up and stress it, and in this case, it was BCG. In another case, it could be some other therapy, which we will discuss. Next slide. Here are the results.
I mean, the take-home message here is we've now updated this, and we're presenting some of this at the AUA, upcoming AUA. The remarkable nature, we went from 77, which the FDA reviewed, to 100 patients, and we completed it. The data is consistent. We now have, in these 100 patients, 71% complete remission. This is not a response. This is a complete remission. What's inciting is the duration of this complete remission is now 53 months and ongoing. This bio shield, so to speak, not only is important, but I think the next most important part of that slide is the avoidance of removing the bladder. The cystectomy free rate at 12 months is 95%, 90% at 24 months, 84% at 36 months, with an overall survival of 93% of these patients. What we've done, in my mind, we've changed the course of bladder cancer.
Next slide. Here is a graphical example of exactly what we talked about. For us now to be able to say with a high level of probability that there's a long-term overall survival and complete response duration. Next slide. Which then takes us to, as I said, there are two types of bladder cancer. There is the cyst, which has got approved, and now papillary. I think my level of frustration, it's heads and tails of the same coin. We published this data in 2022. Now, one may think theoretically, you should get both approvals simultaneously. We did not. We have now submitted that as a supplement to the FDA that existed before. Hopefully, the new administration will recognize the urgent need. More importantly, rather than the urgent need, let me show you the science. Next slide. Here are the results on papillary.
Again, the cystectomy avoidance rate, 92% at 12 months, 81% at 36 months. The overall survival rate is 91% at 36 months. That means patients with papillary disease, which by the way, is the larger number of the bladder cancers, 80,000 bladder cancer patients a year, and then the prevalence of these, who resort sadly to chemotherapy, to anything to avoid having their bladder removed. Unfortunately, chemotherapy is very toxic to the bladder. Chemotherapy does not allow the bladder to heal, the pain and suffering from a patient receiving chemotherapy. Worst of all, chemotherapy kills the bio shield. Let's talk about the results of the comparison. Next slide. Before I go there, we took the cysts and the papillary and combined them in terms of safety. Here now we have 180 patients. Look at all the zeros.
That's remarkable for a treatment that gives you complete remission without any toxicity. It's biologically rational because this is what your body has. The 3% is consistent with just the BCG alone. Next slide. If you combine that toxicity and safety and you look at these two issues, this is what I mean by the heads and tails. Cysts with or without papillary is approved. Papillary alone, which is just the heads without cysts, is not approved. I scratch my head about that. I think I'm now at the stage where I do need to speak out. I do need to speak out on behalf of patients because all we do is follow the science. I want to show you the science in the next slide. On the left is the approval.
If you look at 36 months on the left, 93% overall survival and 84% saving the bladder. On the right, papillary, 82%, 92%. Same bladder disease, same therapy, same treatment. On the far right, when you combine the two, the safety is no different. In fact, it is combined. I am very hopeful that on behalf of patients, this current FDA recognizes the inconsistency of why you approve one and do not approve the other yet. This is what we call a supplemental BLA. We have just announced today that we have submitted it to the FDA. It is sitting in their hands. We submitted it. We talked about it in 2022 when the paper got published. Now it is 2025. We submitted it again after a January meeting where finally we convinced some of the leadership that this does not make any sense.
They said, "Go ahead and submit it," which we did. Now it's sitting there. Look, I had a long talk for the first time in my career with a non-scientific, long, what do you call, podcast discussion with Tucker Carlson. That received remarkable responses from the general public. I'm not here, and this is not the right audience to talk about what goes on behind the scenes, how people make decisions, on what basis they make decisions. I do need, again, I suppose, at some level of risk to the academia, and I'm an academic. I was a professor at UCLA of how decisions are made at what we call the NCCN. NCCN provides guidelines for drugs that are not approved but should be made medically accessible. Obviously, papillary is not approved by us. Papillary is not approved by Merck.
Papillary is not approved by Afferent. Let me show you the next slide. Here we have the NCCN guidelines. If you look at the data for papillary, cystectomy free rate of Afferent is 86%. For Merck's pembro, 76%. For ANKTIVA, 92%. If you look at the treatment-related AEs, which is the toxicity, 3.8%, 14%, 3% with no immune-related. All three of us are not FDA approved. To our knowledge, both Afferent and Merck have not filed a BLA. Obviously, I say unknown because I do not really know. To our knowledge, it is not. We are the only ones who submitted the BLA. The NCCN, the chairman, vice chairman, and the committee met last year after the New England Journal of Medicine paper, 2022. It was already published on papillary. Those guidelines said papillary is okay for Afferent and Merck, but not for ImmunityBio.
We asked this question, why? To this day, I don't have an answer. I leave that as it may be of how decisions are made and what's behind some of these decisions. I think this is a struggle. We are here to talk and speak on behalf of, one, science, and two, the patients. We recognize this struggle, and we will take it on. I think as long as we present good science with good results that really help the patients, we'll continue speaking out now. I've kept this really quiet for a year and a half, but I don't think we can afford not to speak out when there's no basis for this kind of inconsistent policy. Next slide. Let's talk about the next level. What we just presented to you was the BCG unresponsive.
Really, we want to get to patients at the earliest stage, meaning once they're diagnosed with bladder cancer, which we call BCG naive, they never received BCG yet. The current standard of care to these patients is to get BCG. As we'll discuss this with some of our key opinion leaders at the fireside chat about BCG, we've initiated a trial with BCG naive. I'll show you some data today, which I've spent, I don't know, three other scientific episodes presenting that data. Yet, at the European meeting, our competitors said, "There's no data presented yet on the naive." I scratched my head and I said, "Maybe I should just present it yet again." Let me do that yet again. Not only there is data, it's published data.
Here, the patients with BCG naive published that received our drug, whether it be papillary or cyst. In this publication, six years, complete remission. We then went to the FDA and said, "We want to follow this up." Now nine years, as we sit here today, and you'll see some videos, complete remission. I worry very much about the misinformation that our competitors are willing to say. It's not a criticism in terms of, "We hold you to now." I understand competition is good. It is important for us to really present truthful scientific information. I've been asked to give several keynotes at the AUA. I'll probably stir a lot of noise by saying, "Here's the truth." Here we are. Next slide. Most importantly, the FDA, next slide, asked us to give an interim analysis.
This is what I presented multiple times. Now, when you do this trial, which is ongoing, it's a randomized trial. It's BCG alone versus BCG plus ANKTIVA. The goal, obviously, is to beat BCG because in 40%-50% of cases, BCG fails. That's what you call BCG unresponsive. The FDA made an unusual request to say, "Unblind," even though you don't normally unblind a randomized trial. We said, "Fine, we'll unblind if you ask us to." I wonder internally whether they didn't really believe that ANKTIVA could really change the course of cancer therapy because they asked us to do this, because they asked what they call the contribution of effect. Let me show you the results. We unblinded. Next slide. Here it is. By nine months, the response with N-803 plus BCG, ANKTIVA plus BCG, 85%, 85%, 84%.
BCG already began to fail. At the statistical level, P 0.045, it was already statistically significant with a small number of patients unblinded at the request of the FDA. What bothers me a lot is when our competitors go out to large plenary sessions and say, "We don't have any data on naive," when this data has been presented at many conferences. More importantly, look at the value of what we can now, in this form of a bio shield, bring to patients. Therefore, the randomized trial is now enrolling rapidly, as you could speak, in U.S.A, India, and South Africa. One of the problems, however, was availability of BCG, which then took us to the next step because Merck was making the BCG. As some of you may know, the shortages of BCG.
The way they were making BCG, believe it or not, is growing it in potatoes. I know that sounds crazy, but that's how the BCG is currently manufactured. Next slide. That said we needed to address that, which brought us then to this recombinant BCG. We met with the Serum Institute of India and said, "We want to address the shortage." Next slide. Most importantly, what was really exciting to me was this recombinant BCG was engineered so that it would activate the CD4, CD8 T cells, exactly the cells that I wanted that cross-talk to the NK cells, exactly what we just showed you. Not only is it a BCG that would be available now to the world, thousands and thousands of vials could be made very rapidly. More importantly, it would appear to have a higher immunogenic effect.
Most importantly, it appeared to have a higher tolerability than the current BCG. To me, here was this combination that I think we're now going to reveal at the upcoming AUA. Next slide. When they did the trial in Europe, just with BCG alone, remarkably, they had this four-year duration of 42%. I've not seen a BCG do that. What's exciting is that imagine then that combination, which we're now instituting of that BCG with our ANKTIVA. That trial is now ongoing. You'll hear some thought leaders here to speak a little bit to that. Next slide. We went to the FDA and said, "Look, we really have the shortage. We need to address the shortage." Thank goodness, in February 2025, the FDA authorized what we call this access to BCG, which is through the expanded access. Next slide.
The first dose, and again, one of the thought leaders are here today to speak to how the first dose was given, how we activated the 60 sites. You'll hear a little bit about the response and reaction to that. I think this is an important point, is when the FDA needs to move, they can move. We filed for that request for that expanded access, and within weeks, it was granted. I think we face the same issue now for the supplemental BLA. Why would we not allow the bladder cancer patients to receive the same drug that's already approved for cysts with and without papillary? Then papillary with and without cysts, it doesn't make any sense. That is where we stand with regard to the bladder cancer. Next slide. Which then says, "Am I ahead of time?" It's amazing.
Which then says, "We're going to really have an opportunity to talk about," and I want to really introduce Dr. Pieczonka, if you could come up to the fireside here. Dr. Reddy, if you're in the audience, I'm not sure where he is. There he is. You could have a seat. We can just have a chat a little bit about your experience with recombinant BCG. I don't know what the next slide would be. Dr. Pieczonka, first of all, thank you for joining us. If you don't mind giving introduction to yourself and your background.
That's a much younger version of myself up there. Apart from that, as by way of introduction, we've had an opportunity to work in the bladder cancer space in clinical research for the last 10 years or so.
My company is part of a larger private equity-based platform called U.S. Urology Partners that recently had an investment from a company called General Atlantic. They have really done a yeoman's job of supporting our research endeavors within our organization. To that end, I am the Chief Executive Officer of our practice in Syracuse, New York, but serve as the corporate research director for all of U.S. Urology Partners. That is how I became introduced to Dr. Soon-Shiong and Dr. Reddy, probably 12 to 18 months ago. We were not part of the original clinical studies that were presented on the TV, but are actively engaged in participating in the ongoing clinical studies now, including having one of our sites be the first place to actually use the recombinant BCG.
Thank you very much.
What I'd like to do is combine this discussion with a commercial launch discussion. If I could put up the next slide and invite Richard Hancock, the CEO, and Matt Hillman. Then I'll moderate from here. Please have a seat. We'll moderate the commercial launch discussion and get into that. Maybe a few slides first about where we are on the commercial launch.
Thanksgiving Day. Didn't go to bed at all. Went to one local hospital, the doctor put a catheter in me, and they did a scope for surgery. It was 14, 15, 16. I was the first time I was at it. The surgeon spoke to me. I think there's a possibility you're going to lose your bladder. I didn't know how to react. My wife was sitting with me too.
The biopsies came back non-vessel invasive, so that's good. He started me on the BCG treatment. Waited a couple of months. Tumors again. It did not work. Okay, let's take the tumors out again. Another surgery. Fourth time. BCG again. Six weeks, same thing. Tumors came. I decided I can't just keep doing this. It's got to be something else. The clinical trial option opened up. The new doctor still did the BCG for around two years. I tried. Already failed. They thought it's going to enhance it to work better than BCG alone. For some reason, the positivity really returned. Everyone's going to work. When the first results came back, no more tumors, urine cytology was negative. It was cheers and happy times again. It just kept getting better and better and better news. All of my lab results were negative.
What a wonderful feeling overcame me again when we reached that two-year of negative results. Now the woods now. I'm complete remission again. I learned that the N-803 combination with the BCG therapy was giving a boost to the NK and T cells, which are cancer-fighting cells. That was eliminating the growth of the tumor cells in my bladder. My friends say, "How far do you run?" I said, "On good days, I can do six miles, seven miles." You're 70 years old. You shouldn't be able to do that. I said, "I will do this until I can't do it anymore. I'm not going to stop." Everything was wonderful. Until we see the cytology. That's the proof. The single cell that may have escaped, we can't see. That's negative. You can go party again, be happy.
I'm looking forward to looking at yesterday's results now. I haven't seen it. No cancer cells in the urine cytology. Woo-hoo. Scan looks good. Everything's good.
The wonderful news is that he's now nine years. Maybe Rich, you want to then take on this discussion, the commercial launch.
Certainly. First of all, I just want to thank everybody for being here. For those that are online listening as well, I think if you look at ANKTIVA and there's one message you get, it's duration matters. This slide here really talks about it. While this was not a head-to-head study, it tells you the results of A versus B versus C. Dr. Soon-Shiong has talked about this as to the why. It was the original design.
You heard from physicians that are online, that duration of 47 months, and as he announced in the prior one, we had previously announced, at the end of 154 months of ongoing duration is what really sets ANKTIVA apart, not in just bladder cancer, but across all cancer types. Next slide. As we started with ANKTIVA, and this one, and many of you have seen this before, I think what matters most in this one is that we've progressively, and I was just having this conversation with somebody at the back of the room, been checking off checkboxes one at a time. We got it approved. We got it launched. And we had our initial sales going. That was good. It was really the J‑code that was needed. You saw with today's announcement, the rapid increase in sales that happened.
It was really the physicians that needed this, that J‑code that allowed them to have that confidence of permanent billing. That allowed them to see that. We saw 129% revenue, 150% increase, quarter over quarter of our sales on those. Now Q1, we really started to see these. We are also incredibly excited about the submission and the work that we are doing with Europe. We are the first, to our knowledge, and only that have submitted to Europe for that one for both U.K. as well as EMA. We are in the process of that review right now. Next slide. One of the things that I always try to identify for folks, and for those of you that know my background, I am not a physician. I have worked in helping to enable physicians my entire career, working building very large practices of those.
I had a group of doctors that I was presented to, and they said, "You kind of almost Amazoned the drug delivery to us because we order it, and you ship it direct to us in one day. There's no middleman that we have to go through. We can order through our normal distribution, but everything comes directly from you." We have 36 months of shelf life. It's a normal refrigerated product. You take it out of the refrigerator. For some reason, the patient shows up with a fever, UTI, you just put it back in the refrigerator as opposed to another product that you actually may not be able to do that with. It is very different. In Dr. Pieczonka, I would ask you to talk about this as well, maybe. There's no change in the BCG workflow.
Maybe you wouldn't mind talking about what does that mean to you guys in your practice?
That's a big deal. The reality is, in our practice, we struggle with keeping our staff employed just like any other different industry within the country. In particular, the nursing staff and the medical assistant staff is a fairly high turnover staff. Keeping things as simple as possible is very important. We've had the opportunity of participating with several of your competitors' clinical studies. Suffice to say, the usage of ANKTIVA and BCG is easy. The usage of some of the other medicines is not easy, just relative to procedures, physician time. The freezer thing is actually a real issue. Where I practice, we have a catchment of patients that may drive from three to four hours away.
Taking something out of a freezer and then having the patient not show up because of weather, literally, or some other thing is a real problem for us logistically. As a business, we can't be on the wrong end of wasting any medicine. The practical aspect of this, independent of the science and the benefit, makes it a lot easier for us to operationalize in our clinic. We've been able to successfully do that. The J‑code thing was an important thing at the beginning of the year. Since that's happened, that's been a pretty easy thing for us to operationalize.
Dr. Reddy and I were with a large group of physicians. They were smart because they actually brought the BCG nurses with them. As we were talking and Dr.
Reddy was explaining, "Here's how it works." Pretty soon, one of the BCG nurses, she raised her hand. She said, "So you mean exactly what I do today, I do tomorrow with ANKTIVA, except I just add mix it?" Dr. Reddy said, "That's exactly right." She goes, "Okay. I love that."
I think there's another component on here that we need to look at. As easy as it is for the staff, it's easier for the patient. An ANKTIVA patient can come in, and I've personally given ANKTIVA and BCG to patients. It takes exactly 90 seconds. The patient comes in, they check in, and then they leave. Some of the other things that are on the horizon are not that at all. Hours of patient time.
Independent of that particular product, there are other products that require instrumentation by the urologist. Part of the problem on that is the logistics for the patient in terms of cost. One of the dirty realities of just the way that the Medicare system is, Medicare is now making it near impossible for urologists to be able to do cystoscopies in an in-office setting. There is a continued push to decrease the reimbursement. In Medicare's infinite wisdom, that's going to shunt patients to surgical centers. Surgical centers are a much higher cost for the patient. With some of the other medicines that are going to potentially be coming out, the cost toxicity for the patient is going to go way up relative to the procedural aspect of it. I think there is a social thing for the patient time.
There is a real concern about additional cost toxicity for some of the other things that are going to require procedures as they go in and out of the patient's urethra.
Thank you. Dr. Pieczonka, could I just ask you, I think I hear about the costs, and I hear about the logistics, and I hear about the ease. What concerns me as a physician and a scientist is the toxicity. While we do not really want to compare ourselves to any competitors, what big pharma seems to be wanting to do is go back to chemotherapy. There is now a molecule that is put into a little pretzel device that actually releases this chemotherapy. You will hear through the course of today that chemotherapy kills these natural killer cells. Chemotherapy kills the T cells, which does not make actually rational scientific sense.
Could I ask you your experience or your knowledge of this? Not yet approved. I get that. It's in clinical trials. They'll have massive marketing power of trying to induce patients to receive chemotherapy rather than this natural product. Could you share with us some of your experience with regard to that?
I think that this is a real concern for patient care because part of it is how does the patient's bladder feel. Anecdotally, I can tell you in a couple of handfuls of patients that we have that the tolerability of ANKTIVA plus BCG, a lot of patients report that it's better than BCG alone. That's one aspect. That's not quite what you asked.
The thing that I think that you're getting at is, are we making these patients' bladders effectively crippled bladders that the bladder simply can't work, store urine, be able to have an opportunity to go to a movie, go watch whatever the new Disney movie is coming out, not have to go to the bathroom midway through it? The sheer fact of chemotherapy effectively being somewhat indiscriminate in terms of how it destroys both cancer cells as well as the collateral damage to the bladder is a real concern. I think what's going to be really interesting to look long-term as some of these chemotherapeutic options actually potentially become to market is what the side effect profile on that's going to be and the tolerability for the patient on a minute-to-minute day-to-day basis.
I think the other thing that's important on that is the durability that we have with some of the data that you're showing is really intriguing. We don't have that near any of the other studies that are out there. I get concerned about long-term what the quality of life will be for the bladder for patients who may be successfully responding to chemotherapy, but what's the downstream implications for that in year two or year three or even year four?
Spoken like a real urologist, I look at the patient. He looks at the bladder. What's wonderful, it's the first time I heard from a healthy bladder to a crippled bladder to removed bladder. If you look at it that way in a realistic sense, what we try to give is a healthy bladder.
You just see these patients' quality of life where you can run for six miles, which makes me jealous, to a crippled bladder when you get chemotherapy, to removed bladder when you have no duration. You put that in the context of a whole human being, when we get to pancreatic cancer, lung cancer, breast cancer, triple-negative cancer, you'll sort of see the same effect. What we're actually seeing is truly this paradigm change of how we really need to think. Our struggle is going to be to actually educate both scientists, and thank you for being here as a doctor that's not involved in the trials, but now seeing experience in the real world with your patients, that it's intriguing.
We're now hearing reports after reports that when you give ANKTIVA plus BCG, it's better than BCG alone because we know that this modulating effect of your immune system, and as you have this BCG and it gets inflamed, but you have a modulating effect of the NK cells, is a very exciting phenomenon which we will continue to study. I think the other exciting phenomenon is that this BCG you were still using was Thai BCG. You've now used the first recombinant BCG. If you may want to speak to that.
I think that I always get concerned with, well, first of all, on the BCG shortage front, we have offices in five different states. And one of our states actually cannot get BCG. And as a consequence for that, we have something that we call a BCG tracker.
Our physicians in that office have to review and literally ration care because there's not BCG available. That's just a horrible thing to be told as a patient. You simply can't get medicine even though the doctor wants to give it to you. That's one aspect for it. The second aspect is I always worry about the variability that you get with I didn't know actually BCG was made in potatoes until you said that earlier. I mean, when I look at potatoes, I think that there are nice-looking potatoes and ugly-looking potatoes. My concern would be is there variability with the BCG based on how cute the potato looks compared to the ugly potato. The recombinant aspect takes that completely out of the equation and makes that very serene and calm in terms of the BCG effect, I believe.
In terms of the dosing and what you expect to get out of the BCG should be consistent based on it being made in a very controlled setting where there's quality control rather than coming from a potato.
Yeah, more than the potato. It's actually made in potatoes and then in roller bottles, quite literally roller bottles that has to roll a long way. Anyway, I think that really speaks really not only to the science, but to quality of life. This is what's really important to us as a means to buy. I understand that investors look at revenue, and I think revenue is going to be important. The purpose of our revenue and our growth is not to spend from the sake of spending.
Some of you had the ability to do a tour this morning with Rich Adcock and really see the enormous amount of investment we have made in capacity building. I often say that when companies fail because they plan for failure, they really fail because they do not plan for success. Meaning that once you actually have this breakthrough and the knowledge of the breakthrough, I think it would be immoral not to have patients who really deserve it to have access. We have invested for success. Some of you have seen not only the clinic, but also the manufacturing facilities. With that, I will ask Rich to go to the next slide to speak to what has happened since the J‑code.
Yeah. Maybe actually I will turn this one over to Matt first.
If you want to talk about what's really happening, Matt Hillman heads up our entire commercial operation.
Sure. Hi, everybody.
You can clearly see that where we received our J‑code was the true catalyst for us. There were a couple of other things that were kind of really important that we speak to. I think we had a course correction in recognizing that the sales team be brought in-house. I had a strategy with Rich. We decided to bring everybody because at first, we started with a contract sales organization. Recognized senior leadership decided to invest and bring everybody in-house. That allowed us to bring in a different kind of talent. That continued sales momentum. You can clearly see January the receipt of the J‑code when that kind of was brought to life. How about the chart went completely up.
I will tell you the most important thing. When we train these new representatives, a lot of people have had the ability to speak to a complete response that Dr. Chung and Rich spoke to. The complete response is super important. We have never had that ability to tell someone. When you tell someone they are in complete response, they will be there for up to four years. Plus, remember, we have not been our duration yet based on our package answer. That is what resonates the most. That is why duration matters. It is messages like that that will allow us to see the success that you see on the chart to take away because nothing else can do that. That is something we are really proud of. That is what the sales force means.
The other one I would add in here, this sales growth is using all Thais.
None of this was with the recombinant BCG. While we're not selling the recombinant BCG, we're now able to deliver that. As Patrick said, we've had our first centers and first patients. We actually have almost 90 centers that are in process of being signed up. There are many, many more that are going through those. It's a pretty light process to get going on those, but it takes just a minute to work through that process. I think that's what I'm most hopeful for in Q2, but really Q3 and Q4 is that now there are no encumbrances. The J‑code's fully in place. BCG, we effectively have an unlimited supply of. It gives us the ability to truly meet patients where they are. Doctors don't have to rationalize care.
They don't have to make a trade-off to say, "This one gets it and this one doesn't get it," or, "This one gets a partial dose. And this one will be able to deliver it for everybody." The other one I would add to that is it's not just the BCG, but the diluent. If you remember in October of this last year, in 2024, there was a hurricane that hit, took the largest sterile saline plant offline for the United States. Now not only in October and November and December, where is there a BCG shortage, now there was a saline shortage. One of the things, and Dr. Soon-Shiong has always emphasized this, we have to control every element of the supply chain. If we don't do that, then we're incumbent upon somebody else.
As we sit here today, we have the ability to produce an immense number of ANKTIVA. We have more that is available than all of sales across all of ours that are needed. We have the BCG, but we also have the diluent. And that's a very strong feeling. Couple that with the J‑code, and you see this chart that's headed straight up. We believe it's going to continue that way.
Thank you for that. I think the supply chain, look, I learned my lesson. Some of you may know or not know that I ran a company called American Pharmaceutical Partners in 2001 for about 10 years. In 2008, there were 87 deaths in the United States from heparin. The show came on at Nightline. We were the only company in the United States that controls the supply chain of safe heparin.
Heparin comes from the intestine of pigs. We were able to actually monitor and make sure that we had all the way from the pigs to the intestines to the heparin in our hands. That is what really changed the ability for patients to have heparin. Otherwise, literally 100,000 patients a day require heparin in the United States. That was a lessons learned that we said would not happen here. The massive amount of investment that ImmunityBio has made is to ensure that we have access to the entire supply chain. When we knew that Merck had this issue with regard to BCG shortage, not only did we want to control that supply chain, we wanted to make sure that patients would have access to this therapy that would give them this long duration. With that, I want to thank this group. Okay.
Amazingly, I'm literally by the minute on time, which really gives us time now to talk about this. I really want to introduce this concept, which is crazy that I have to introduce, called lymphopenia. What lymphopenia means is that you lose your NK cells and T cells, the very cells that are necessary to kill cancer. Again, I went to the FDA in January and presented the concept that, look, we have a therapy that could change the course of cancer forever. A test I do and one of our thought leaders I did this test on, if you speak to your oncologist today, they will say, "When you do a CBC, which is a complete blood count, you measure for anemia." Because we know that when you get chemotherapy, you get anemic because we have a drug called Epogen.
That is made by Amgen. We give that. Red blood cells do not kill cancer cells. We have a treatment for that. The next thing you measure is platelets because platelets drop when you give chemotherapy. We have a treatment for that because we can give you a platelet transfusion. The next thing we measure is called neutrophils. That is called ANC. Neutrophils prevent infection. We have a treatment for that because we call Neupogen for Amgen. You ask 90% of the oncologists, "Do you measure the thing called absolute lymphocyte count or ALC?" They would say, "No. What is that?" That happens to be the only cells in that CBC that actually kills cancer, i.e., the natural killer cells and the T cell. That has been staring us in the face for 15 years.
I would challenge you to go to PubMed or Google and hit the word lymphopenia and overall survival in all cancers. It makes rational sense. If you have no NK cells and no T cells in your body, you have a reduced overall survival. That is what I want to introduce today. In January, I had the privilege to be able to be invited to the FDA to meet with the leadership there. We had a two-hour session, no minutes, just presenting the science of how we could change the course of cancer by giving patients the ability to overcome lymphopenia and prolong overall survival. Today is the opportunity for me to present the data before the fireside chat. I think I am going to present the data and speak to this lymphopenia reversal or treatment.
Before I do that, let me show you what we're activating. You will see soon, I'll put up a video soon of a video that we put together, oh, maybe 10 years ago. Think about that, in which we had a breast cancer cell that we could light up as a green cell. And then we would have our natural killer cell and our T cells kill this breast cancer cell. We'd watch it die, and it would go blue. We showed this video around, and it was a sort of nice video, except that was the paradigm change that we've been pursuing. If I may show that video. What you're seeing, the red cells, and look at the blue cells happening, dying, and the green cells of the breast cancer cells. The attack is enormous. These are your lymphocytes.
This is what our chemotherapy kills. Imagine that. You give chemotherapy, you destroy those exact cells that are fighting so hard. You give radiation, you destroy those cells that are fighting so hard. You give steroids when you give docetaxel, and with chemotherapy, you destroy those cells that are fighting so hard. You give checkpoint inhibitors, you actually destroy those cells that are fighting so hard. That makes no rational sense. For me, as a surgeon from UCLA saying, "I want to create cancer into a surgical disease so I can capture it as early as possible so we do not actually destroy these cells," which we now call, thank you for Tucker Carlson who says, "Do not call it the vaccine. We call it the cancer BioShield," which it really is. It is your bioshield.
Every one of you sitting here today have a cell that's about to transform because you're having stem cells that's growing. Every one of you. And every one of you have these cells in your body that's killing those transformed cells so you don't have cancer. You are in equilibrium because of these cells that's happening now called lymphocytes. The fact that I have to now introduce this concept of lymphopenia, and it is independent of tumor type, and the ability to create this bioshield is the next slide. There's what I call this missing link.
I now really have to go on an educational campaign, but it's really been staring us in the face that after many, many years of spending literally millions, maybe tens of millions, actually hundreds of millions of dollars on genome sequencing and of the largest genome sequencing lab and having a genome test to look at your mutations that cost thousands of dollars, we are reduced to a $20 test called a CBC. If I show you the next slide, all of you have this test called a CBC. The single blood test, on the one hand, measures your anemia, which a doctor gives you Epogen, measures this thing called ANC, absolute neutrophil count. Everybody understands ANC. It gives you neutropenia.
If you ask 99%, and some of you should go away and ask your oncologist, "Do you measure or look at the same test that gives you this thing called ALC or absolute lymphocyte count?" If it is less than 1,000 lymphocytes per microliter, it is called lymphopenia. If it is between 1,000-4,000, you have normal lymphocytes. In most cases, and this is not a disparagement to the doctors, by the way, the reason they largely ignore it is because there was no treatment. That is why they largely ignored this, because there was no treatment available to overcome lymphopenia. There was treatment called Epogen and Neupogen. Next slide. There was this missing link. I want to show you now the fact that this missing link has now been filled. I call this a missing link.
I said to Tucker Carlson a little bit, "It's like finding the lost ark." These are the only cells in our body that kill cancer. We can now measure that. If you go into the literature, as I said, and type in lymphopenia or type in absolute lymphocyte count or type in a thing called neutrophil lymphocyte ratio, you will begin to see that no matter what cancer you pick up, is that in the presence of lymphopenia, you have a reduced overall survival. It makes rational sense. This missing link, next slide, is the ability for us to really understand what we're doing with our standard of care. This is why you will hear from some support leaders today. I won't name him until I bring him up, who I called and said, "You do radiation. Would you mind looking at your patients?
Please de-identify them for the next first 20 patients that you've done radiation on and look at the ALC. The question is, "What is ALC?" No, the lymphocyte count, not the neutrophil count. You'll see that discussion when we get to the fireside chat, when we talk about not only radiation but chemotherapy, steroids. This is a difficult conversation, actually, because what it actually implies inadvertently, and I must say it's inadvertent, there's no bad—I believe 99.999% of doctors want to do the best thing for their patients. It's this educational need, not only to the medical community, the thought leaders, the Sloan Ketterings, the MD Andersons, the UCLAs, the Cedars-Sinai, and Johns Hopkins of the world, to say, "Wait a minute, should we really rethink if we kill the NK cells and T cells and we get a lower median overall survival, which is logical?
Should we be doing something differently? Is that why we've not won the war on cancer? Is it because we win the battle but lose the war? What's crazy is this information of lymphopenia has been in the literature for 10 years, 12 years, 15 years, 20 years. I'll show you a few papers or just select papers. Next slide. Guess what? Lymphocytes is a new organ at risk. Can you imagine? It's not a new organ at risk. It is the only cells in our body that protect us from cancer. We've put it at risk. That, again, is a very, very difficult conversation because we'll be accused of all kinds of stuff, non-science, hype, whatever. This is the science, not from me, but from papers I'll begin to show you. We couldn't stop finding these papers when we did the search.
10s, 20s, 30s, 40s, 50s of these papers from different parts of the world. Next slide. They even have Kaplan-Meier plots in these papers. That is exactly how it is in this paper, meaning not lymphopenic and lymphopenic. The red line shows the overall survival reduced statistically. Next slide. This is even with checkpoint inhibitors. It is remarkable that this has been the biggest breakthrough, and rightly so, that T cells and checkpoint inhibitors have generated billions and billions of revenue for pharma companies that followed each other, whether it be Merck, Bristol-Myers, AstraZeneca, Roche. They all followed each other because it was a large revenue generator, except this is what you are getting.
In 2017, I presented myself to the FDA and said, "Listen, there's no question in my mind that checkpoint inhibitors are good, but they're going to fail because we're actually inducing what we call, you heard from the doctors on the video, that the T cells pull in their receptors." Think about that. If you have no T cells, the checkpoints are supposed to accelerate T cells. If you have no T cells, I'm not sure what you're accelerating. We spend billions of dollars in patients where we take a checkpoint and we combine another checkpoint on top of that checkpoint to see if it actually would work, and they all failed, etc. The idea of following rational science oops, looks like somebody decided they don't like that slide.
The idea of following rational science was so difficult that we just had to pursue this on our own. That is why if you ask why the cancer moonshot did not progress, none of the big pharmas really wanted to participate. We will get into that at some other time. Next slide. This was the most telling slide. On the right-hand side are the references in the blue of all different papers. On the left-hand side, just look at them. Every cancer you can think of. If you look on the middle side of lymphopenia, look at them. All lymphopenic. If you look at the statistics and overall survival, they are all decreased. How old is this paper? 2019. What we are revealing today is not some revelation. It has been staring us in the face.
The way they now present this is a prognostic factor back then that if you have lymphopenia, we know you're going to have a lower survival. This was really prescient. I don't know these authors. This is for combination with cytokines. It turns out that every lymphocyte has a receptor on it called IL-15. That's what ANKTIVA does. It actually binds to that receptor, next slide, and kills it and proliferates it. Here's the lung cancer. We'll speak to lung cancer today because we took patients who failed this, failed their checkpoint, progressed on the checkpoint, gave them nothing more, plus the same checkpoint, plus ANKTIVA. You'll see the overall survival because we reversed lymphopenia.
This became sort of incredulous both to a large group called SWOG, again, thought leaders, the biggest thought leaders of lung cancer, who, again, it is not pejorative, did not understand the science that what we are trying to drive is prolonged overall survival. Think about that. You have a patient on a checkpoint inhibitor or who has had chemotherapy, radiation, second line, third line, fourth line, for which there is no treatment left. These patients die, sadly, within seven months. That is the duration. They get docetaxel as their standard of care afterwards, which is very toxic. It turns out that docetaxel has to be given with steroids. Both docetaxel and steroids wipe out your lymphocytes. Now you have a checkpoint failure. Think about this in a logical way. I will walk it through in a logical way.
I tried at multiple meetings to explain it, but it did not sound scientifically reasonable that if you are going to give a patient a checkpoint, trying to accelerate the T cells, and it works, and then it fails. The reason it fails is because there are no more T cells. Giving back that same checkpoint should not work. The truth is it should not unless you reactivate those T cells. That is why the treatment of lymphopenia. That is the bio-shield. Our treatment then was to combine that checkpoint. By the way, you will hear today from Beijing, a representative, because we are agnostic to the checkpoint, any checkpoint, because it is a biological activation of that T cell.
If you proliferate your NK cells and T cells with this IL-15 stimulant or superagonist or the bio-shield, whatever you want to call it, you now have the reactivation of these checkpoints, and you prolong the survival. I will show you data for the first time today. I will show you data for that, not only for lung cancer. I will show you data for that for pancreatic cancer. I'll show you data for that in let me see what I've got in this list here. For all tumor types, actually. We've never shown this data. I'm in the process of putting it together as a paper. I hope it doesn't jeopardize the paper. I think it's important for this to be exposed now.
With that, if I can show the next slide, I really want us to now go into this bio-shield and talk about why lymphocytes matter. This is the first introduction. All you see have the little buttons of the cancer bio-shield, why NK and T cells matter. You will hear from some thought leaders coming here today to talk about NK and INK T cells, why duration matters, as you just heard, in our bladder cancer patients and, more importantly, in our lung cancer patients, pancreatic cancer patients, why survival matters, but most importantly, why quality of life matters. Because all of this therapy is given as an outpatient. Some of you who visited the clinic this morning know or have seen. It's all given as an outpatient. That's the remarkable basis of this and why all of this matters in this cancer bio-shield.
I think we're on track still for me to go through this now for the next 30 minutes. Okay. Let's go to the next slide. This is the missing link. I apologize for getting technical. I can't help myself, but I have to. On the left-hand side, you will see that on the top of that, every cell that is a lymphocyte, whether it be NK cell, CD4, CD8, and T cell, has a receptor called the IL-15 receptor. That's the key. That receptor is what has been waiting for some molecule to come into your body and activate that receptor. This is called the IL-15 superagonist down below. This IL-15 is in your body. It's not an unnatural product, but it only lasts for two minutes. It does that because that's how your body works. It needs to give you a balance.
That's what eluded the scientists, even the NIH, for 15 years. They could not create a system where not only it could last for more than 15 minutes or 2 minutes, but it could bind with great strength to that receptor called the beta receptor and proliferate on the right-hand side in natural killer cells, the T cells, and with the adenovirus or by itself generate the dendritic cells and the memory T cells. This is what we call a new class of immunotherapy called a lymphocyte-stimulating agent. For the first time, we are now nominating this as a new class of immunotherapy called LSA. This lymphocyte-stimulating agent is what we've put in front of the FDA as we speak. We have shared with the FDA in January the importance of this molecule. It's already approved. We've received thousands, literally thousands.
The most painful thing about the Tucker Carlson interview is the pain and the suffering that's out there. We received literally thousands of requests for what they call the bio-shield. We can't do that because we needed to get what we call emergency or expedited or expanded access. We filed that with the FDA as we've just announced for the first time today. I'm awaiting a response. I'm not sure what the response would be, but I'm hopeful it is next slide for the opportunity for them to understand that for the first time, and it's more than 50 years, radiation was done 100 years. That next slide, a link is available for patients. This drug is now approved for bladder cancer.
We chose bladder cancer early on because it was what we call non-muscle invasive, as early as you can, even though it had failed BCG. Now the goal in my mind is to find patients or to treat patients the moment they're diagnosed, whether you have pancreatic cancer, brain cancer, lung cancer, the moment they're diagnosed, and be able to actually institute what I call the new adjuvant therapy. There are patients, sadly, that have gone through the ravages of every treatment today, and they can still be rescued. That's what I'm going to show you now, the next slide. The first thing I needed to do was to actually prove to ourselves that this ANKTIVA actually stimulates NK cells and T cells in normal human beings. In 2022, this trial was done in healthy volunteers.
Again, I'm not going to go too technical, but it's published now. Next slide. Here it is. On the top right in column A is the absolute lymphocyte count with two different doses. You begin to sort of see it actually able to actually stimulate and maintain. In C, you will see the NK cells, CD4, CD8 T cells. In F, you'll see how it peaks at day seven. In D, you'll see how at the end of the treatment, it's maintained. The exciting thing is not only can we stimulate it, proliferate it, and maintain it, but it's also safe because it doesn't go beyond what your normal levels are. You don't get what we call lymphocytosis. I know this sounds a little crazy, but it's not. This could even be involved with aging, what we call senescence.
When you age, these NK cells and T cells all deteriorate. There is a possibility—and I say that as a possibility because we've not done this trial—that this has an effect on aging. Why I'm so excited about this in healthy volunteers is because we have been chosen to be the first trial using this molecule in patients without cancer called Lynch syndrome. You'll hear about that in the fireside chat, where you will see that patients who have Lynch syndrome, which is 1 in 280 Americans, have this thing called Lynch syndrome, a genetic disposition to cancer, and an 80% increased risk of colon cancer, breast cancer, and lung cancer.
We have now recruited this nationally across the country like wildfire, in which these patients are getting a shot of this ANKTIVA, this BioShield, plus an adenovirus to generate the memory and T cells, which you'll hear today from some of our keynote speakers. The proof that it actually works in healthy volunteers—next slide—is emphasized by this very detailed analysis, what they call the flow cytometry on the right-hand side, where all these cells proliferate. Next slide. As I said, at the end of the cycle, it maintained. What was really disturbing, I listened to a talk at the European Urology Association given by either the thought leader or competitor who said there was no clinical evidence of ANKTIVA actually proliferating in NK and T cells. I don't know how to react to that when you actually have this all published.
This is what I worry about. As I said, competition is fantastic. Competition is good, but misinformation is bad, especially for patients. This is the data that is out here. This is, again, I will be presenting at the AUA to correct some of these statements that actually pervade for whatever purpose. Next slide. This is the missing link that would then take us, if you can go to the next slide, to what I want to now show is that this—I now call this a lymphocyte-stimulating agent or the bio-shield or LSA—it not only treats lymphopenia, but it prolongs overall survival across all tumor types. Nobody's seen this data. We submitted this data to the FDA. We submitted the data as part of the expanded access request.
We will be submitting this data as part of whether it be a supplemental BLA or RMAT discussion. We got the RMAT authorization, which is very rare, which is regenerative medicine advanced therapy. This is the work of this QUILT trials, and QUILT was this quantum oncotherapeutics of this discussion I had across second-line non-small lung cancer patients that failed everything. These patients, the only chance today would be docetaxel or something else and some other molecule. Third-line patients and fourth-line patients for which there's no treatment. Their overall survival in every time you do a docetaxel, there's hundreds of docetaxel patients that receive docetaxel in tons of clinical trials where it's been approved I think 20 years, 40 years ago, in which the median overall survival is seven months. We'll show you data of how we change that when we rescue lymphopenia.
We have renal cell carcinoma, hepatic cell carcinoma, and some of the thought leaders here speaking to some of that: colon cancer, breast cancer, etc., what I call multiple tumor types. I call that tumor agnostic. That makes biological sense because this natural killer cell was not a surgeon and did not get surgical training, so it does not know whether it is a breast cancer or lung cancer. It actually works wherever you have cancer. Finally, a cancer that I spent my life trying to overcome, i.e., metastatic pancreatic cancer. If we can get that cancer early on before it has a tumor burden, we think we can change the course even of pancreatic cancer. Let me now show you this data. I am going to show you very snapshots of it.
I'm not able to show you the full, holy glory of it because otherwise I wouldn't be able to get this paper published. I'm in the process of drafting it. Here it is. In these patients, where on the left-hand side you see the docetaxel median overall survival, I understand that's a historical data, but it's not changed five to seven months. When we're able to reverse lymphopenia in some patients beyond severe, we get 11 months. When you're really able to get them into this 1,500 range, which is closer to your normal, what I call mild lymphopenia, you get 21 months. The probability of these patients living five years is 20% for which there's no other treatment. These patients, all they received was a checkpoint plus our ANKTIVA. This speaks to the spire shield.
I hope both academia, NCCN, the regulatory bodies, the FDA recognize why this is a paradigm change. There's no chemotherapy in these patients. Next slide. When we did the same in the same trial, which is called a basket trial, we had 147 patients, including these lung cancer patients. So it's not a small trial. 21 months, regardless of its tumor type. These patients, in order to be eligible for the trial, must have failed everything. Imagine if we got them before they failed everything. This is what I mean about why this is so exciting because it is tumor agnostic. Next slide. Finally, we were only allowed to do these in pancreatic cancer patients at a third line, fourth line, fifth line, sixth line. Think about that. That literally would have weeks left.
When we actually be able to capture even these patients at fifth, sixth line, not only do we give them not weeks, we gave them months and 6.6 months. For those who understand the tumor burden, think or CA19-9, the normal level is about 30 in our lab, 40. The median, not even the range in these patients, was 3,000. Huge tumor burden. Yet with that huge tumor burden, we were able to get this. Next slide. On that basis, we went to the FDA, and it's still sitting there, and we'll see where that goes, to ask for this RMAT, which we got granted. We now wanted to get also the request for emergency use while we're getting this RMAT designation BLA filed because that has to go through the process, rightly so.
But I don't know how our single unit can manage 2,500 patients just in the last few weeks' requests. We need to make this available to the entire country where every doctor could actually give the shot if needed before they get radiation, before they get chemotherapy, before they get steroids, before they get docetaxel, before whatever the standard of care. That is the EU designation that we put through. On that basis, if you could show me the next slide, I'm not sure where we are now. Before we go to the fireside chats, which I think we're going to take a little break for lunch, we are quite literally a half an hour early, right? I'm happy to take questions, and then we can take a break, and then we can continue with the fireside chats with all the rest. Please.
There are microphones on either side of the hallway, or if you can put the microphone in the center, maybe, somebody, and we can have people have the chats. If you're on either side of the so we can all hear you.
Hi. I'm Heath Cunningham. Thank you for having us. Before you submit the BLA for lymphopenia, will you have to do additional trials?
The trials are done.
So no.
That's what I just showed you. The results are those three trials. We did the trial in healthy volunteers, as you could see. We did the trial in first-line randomized control in first-line lung cancer, where we did ANKTIVA alone versus ANKTIVA plus checkpoints and looked at the results of that to show that we can in fact change it. We did this in third-line lung cancer. We did this in multiple tumor types. We did this in metastatic pancreatic cancer. The trials are done. The results are we literally have to now put all this massive amount of data into the BLA. We just completed what we call a briefing book and submitted to the FDA yesterday, actually. No, actually tomorrow. Tomorrow, I think, is the date in which we have a physical meeting with the FDA in May. Any other questions?
Right here.
Hello. My name is Dr. Gregory Howard. I was wondering if you had combined ANKTIVA with histotripsy or high-intensity focused ultrasound. For those of you that do not know, high-intensity focused ultrasound was just FDA approved last October. It breaks up the tumor, and the fragments can be seen as foreign. In about 20% of the patients, the cancer goes away and never comes back because the body will continue to see it as foreign. I did this 15 years ago on my dad, and he lived to age 90 after advanced lung cancer.
Thank you for that question, you have now basically enunciated what we've been trying to say. This is how it works. If you took, for example, those patients with high-intensity ultrasound, whether it be high-intensity ultrasound or whether it be a small dose of radiation, what that does is it exposes the tumor to the body's natural killer cells and T cells. The tumor has this amazing capability of hiding. In order to expose it to the receptors of your body, you need to disrupt it slightly. That is what we call immunogenic cell death. By disrupting it slightly, you release a thing called DAMPs. Now, I'm getting very technical, but you asked a question, so that allows me the opportunity to give you some really technical, which DAMPs means damage-associated molecular patterns.
When you give high-intensity ultrasound or even a tiny dose of SBRT or even a tiny dose of even a chemo, I call these immunomodulators. That exposes the tumor. The moment you expose the tumor, that little slide that I showed you of all these cells coming in and says, "I found you. I'm going to kill you." Because it disrupts the tumor, it also disrupts the antigens. It becomes its own vaccine to create memory T cells and now remember you. That's why you have patients now free of disease. It's not complicated. It's really the biology of the human process of why all of you are in equilibrium without cancer because that's how the body works. We just needed to be enlightened enough to understand it and, more importantly, activate it.
These pre-activation molecules or immunomodulators that induce or expose the tumor could be anything. It could be a little bit of SBRT. It could be a little bit of radiation, which we'll talk about. It could be literally what we call a metronomic low-dose touch of chemo, not to hurt the patient and hurt the immune system, but to expose the tumor. It's a different way of thinking. The answer is yes. All these opportunities now, even in lung cancer, now where they have these nodules and patients now can be able to give directly towards the tumor the ability to stimulate and expose that tumor. The answer is absolutely. That is why all these treatments that we've created have not gone to waste for the last 40 years.
We just need to rethink how to use them and then, with that concept, create this missing link, the spire shield, to activate the cells that are already in your body. That's why I said I want to convert cancer to a surgical disease or interventional radiological disease, meaning that you could use a tumor in your body as the vaccine so that you can kill it with your own cells. It is tumor agnostic. When I say the word, "We need to treat the host rather than the disease," it goes sort of over the head because you're not sure what you're talking about. What we're trying to do by treating the host is to activate the patient's tumor system, the immune system, and use a tumor itself as the bioshield of the vaccine, whatever you want to call it, and create memory.
We get a complete response. We've seen this in bladder cancer. We've seen this now. We should be able to see this in all cancers as long as we capture them early. The sad news is our standards of care now see this tumor once a sort of short-term satisfactory effect by giving high-dose chemotherapy, high-dose radiation, checkpoint inhibitors. You see a tiny reduction, and then you see a response. You see a failure. If you think about it, our regulatory bodies now, again, I don't want to disparage the FDA. It's a dangerous thing for me to do. Our first opportunity was response rate. Now, what's a response rate? A response rate is merely a short-term effect. The next endpoint that the FDA gave us was progression-free survival, PFS, it's called. You think about that.
It means that we are accepting at the regulatory body that you will have progression. It does not make any sense to me. I said progression-free survival is not the right endpoint. There is another thing that the FDA asked us to do in phase I, which is what we call maximum tolerated dose, MTD. What that means is, let's give you enough chemo that does not kill you but kills a tumor to get the response rate and progression-free survival. That is what we have pursued for 50 years. If I put that logic out to you and you say, "That's craziness," and we keep on doing the same thing, and then President Nixon says, "We're going to win the war against cancer," and you do not because you wiped out the very cells that killed cancer, and you are surprised. I am not sure why you are surprised.
A long answer to your question of should we use high-dose ultrasound? Should we use SBRT? Should we use low-dose chemotherapy? Should we use anything? You will soon see there's another molecule called, it's even got worse than that, epigenetic modulation. Where the cancer hides through its genes, it actually prevents you itself from being exposed. We can now outtrick that by exposing those genes and making them express the receptors so we can see the T cells. We hear that from a thought leader that you'll speak to today. You gave me an opportunity to give you a long answer to a question. The next question.
We have online questions, so I'm going to pick two here. The first one is, "Some providers believe the neutrophil-to-lymphocyte ratio is more important. Can you explain why that could be misleading?
Thank you. We're getting questions from, obviously, the viewers listening into this. Here's another unexpected effect. You have in your body called neutrophils, and we have a drug called GMCSF that is given to upregulate these neutrophils. What we haven't realized is that because is the cat alive? Is the cat dead? It has a dynamic effect. These neutrophils could be killers, and immediately they could change to become suppressors. This thing called myelo-derived suppressor cells is stimulated by the very drug that we give to upregulate the neutrophils called GMCSF.
When you have high suppressors, which is the neutrophil, and low killers, which is the lymphocytes, and you put then the ANC, which is the neutrophil count, divided by the ALC, which is the lymphocyte count, and you have a double whammy of high suppressors, a high ANC, and low ALC, you have a high neutrophil-lymphocyte ratio, and now you're in trouble. That is why if you go into the literature and look at neutrophil-lymphocyte ratio, you will see in pancreatic cancer, any other cancers, when you have this high ratio, you have a lower survival. Again, it is such logical science. Why are we giving GMCSF to patients? Why are we upregulating the suppressor cells? Because you're going to end up with a lower survival. Sadly, these molecules are out there.
There's like an IL-2 that stimulates these Treg cells, and there's now soon be another bladder cancer gene therapy that is tied to upregulating GMCSF, i.e., these suppressor cells. You watch the industry doing things that it makes no biological sense, but it makes marketing sense. This is why I think we have to exist as ImmunityBio to keep on fighting the fight and talk about the science on behalf of the patients and then show how the science has major impact on the longevity of patients with cancer.
We have one more online. This one is, "Can BioShield be given as a preventative, especially in past cancer patients who are in remission but have gone through radiation and/or chemotherapy?
I didn't hear you.
Can Cancer BioShield be given as a preventative, especially in past cancer patients who are in remission but who have gone through radiation and/or chemotherapy?
The answer is, could we give it for patients who are in remission? It depends on your ALC count. We haven't looked at that in terms of long-term. I can tell you that if your ALC count is in the lymphopenic range, we can help you get it out of that range. I think that's going to be important. You will see a few slides soon on the patients with prostate cancer and patients with ovarian cancer, how we've done that before they had surgery. If you are in remission, what I worry about today, and we'll talk about that when you talk about long COVID, is that long COVID is immunosuppressive.
If you have your low lymphocyte count and you have immunosuppression from this virus, would you then end up with a very rapid recurrence of your cancer when you've been in remission for a long time? Would ANKTIVA help? That's something we have to actually explore now very urgently.
Patrick, we got a couple more questions here.
Hi. I'm Joel Shapiro. I'm trying to wrap my—hi, Patrick. I'm trying to wrap my head around autoimmune disease as a back or mirror image of the cancer and looking at maybe if ALC is too high, is that perhaps an inducement to an increase in autoimmune, of course, in diabetes and other considerations?
That's a good question. You have a balance in your body called the yin and the yang. The Chinese have taken this for thousands and thousands of years because it's a basis of truth. While on the one side, the NK cells and the T cells activate to go kill, on the other side, if they overreact and you have what we call autoantibodies, they will then actually kill self. This is when you start getting these autoimmune diseases. I always believe that type 1 diabetes was autoimmune disease. I think even Alzheimer's is an autoimmune disease. You begin to sort of see then how do you then go to the other side? How do you then induce suppressors? Now you could see when you people with psoriasis, et cetera, there's these drugs out there.
What it's doing, it's inducing the opposite side, these suppressors. You have to be careful. As you induce the suppressors, do you actually activate the, do you induce then the cancers? There's this balance. It's a great question, Joel. The idea would be, is there the opposite to IL-15, which is called IL-2, that stimulates these suppressor cells? That's not what we're doing at this point in time. I think there's one more question.
Hi. I'm Dr. Michelle Howard.
There's a mic right behind you.
I was wondering if you had ever looked at measuring the circulating tumor cells before and after giving ANKTIVA.
That's a great question. You'll see one of our patients with ovarian cancer that we're now measuring the circulating tumor cells beforehand and then giving the ANKTIVA and measuring circulating tumor cells after, and there's none left after that. The beauty is that we now have really these early diagnostic markers of these circulating tumor cells, cell-free DNA, and now even, believe it or not, a simple CBC that'll measure lymphocyte count. The answer is, yeah. Now we can actually capture what we call minimal residual disease and really truly drive what I've been trying to say. The earlier you catch the lower the tumor burden, the more maximum activity of your immune system we can actually drive towards. I call this long-term complete remission. I don't want to say the word cure because it would be slapped about.
I do believe we are on this path. Any questions?
Thank you. You spoke about scratching your head on why the FDA approved ANKTIVA for the carcinoma in situ, but not for the papillary alone. You showed some of the data for the naive, BCG naive. The results look similar. Are you similarly scratching your head there? Can you give us some sense of specificity of timeline for when you expect that FDA might approve ANKTIVA for BCG naive? Similarly for the lymphopenia, the results seem great. Is there any sense of when the timeline might be for when the data might be strong enough to get an approval in that sense?
I can see you want to get me into trouble, but I have been scratching my head for the last four years, almost to the point I've got bald. Seriously, you're absolutely right, right? I think when you end up in some level of bureaucracy where you have a checkbox and I don't want to be political, but the last four years has been horrific for us, where for no unknown reason, whether you talk about COVID, let me speak a little bit about that, where we had a T cell vaccine completed phase I, and then we were told by the FDA to stop. We have cyst plus papillary approved, but papillary without cyst with the same results or not. You begin to ask yourself why. I sit on Tucker Carlson's show.
It's not a conspiracy if it's true, but there are some things going on behind the scenes that we're not privy to. I am really hopeful that by having this investor day and showing the science in a very public way, that both on behalf of the patients as well as the scientists and the investors—I know this is called investor day, and I'm cognizant of that fact—but more importantly for the regulators to stop, to really just adopt what you just said, common sense. Not common sense without data. Now we have data with hazard ratios of 0.3. Some of those were statistical, P 0.001, 0.0001. I don't know how much more significant you can get with regard to that. We're showing this over and over and over again. I am just hopeful that this current administration, this current FDA recognizes that.
I do understand there's now a patient groundswell on behalf of patients that may take that up. Maybe that's what should happen anyway if this doesn't go forward. I'm really encouraged and hopeful that common sense will now prevail. I hope I didn't get into trouble.
Not answering.
Any other questions? Okay. I think we should take a break a little bit.
Yeah. The restrooms are all the way at the end of the hallway over here. They're setting up lunch now. You'll be able to grab that, and then we'll start back shortly. Thank you all. We do have about 1,000-plus people that are online.
What time should we start back? Just so I'm clear, it's 12:00. What time are we starting back, Rich? It's 12:00. Should we start back at 12:30?
12:30.
Just so everybody, we will start back at 12:30.
We'll start back at 12:30.
There is nothing that I want to, but I think I'm starting to strain. Have I done something to hurt you? 'Cause it's not been feeling the same. Maybe I've been seeing salt in the sand. I should know it's all in my head. A question I know I have to ask: Are we in the hands of borrowed time? Borrowed time. Where do we stand while deep in the hands of borrowed time? If you ever were to leave me, would you come back lonely someday? If I fell apart completely, would you still come running my way? Maybe I've been seeing salt in the sand. I should know it's all in my head. A question I know I have to ask: Are we in the hands of borrowed time? Borrowed time.
Where do we stand while deep in the hands of borrowed time? Are we in the hands of borrowed time? Borrowed time. Where do we stand while deep in the hands of borrowed time? My all, I'll make it, make it right this time. You can say, say, say all you want to me, 'cause I know I can take it through hell and not come back a second time. You can't play your tricks on me anymore. My mind will let me overcome this. This just an exit. In that's a trick. This just an exit. In that's a trick. This just an exit. In that's a trick. This just an exit. Everybody, everybody, put it, put it off. Put your game, game, game just work. On me. If there's something between us, I've been going off for way too long.
Now it's time that we just let it go. My mind will let me overcome this. This just an exit. In that's a trick. This just an exit. In that's a trick. This just an exit. In that's a trick. This just an exit. In that's a trick. This just an exit. This just an exit. This just an exit. This just an exit. This just an exit. This just an exit. I never got a chance to see him. Never heard nothing but bad things about him. Now my arms are depending on you to tell me the truth. I never got a chance to see him. Never heard nothing but bad things about him. Now my arms are depending on you to tell me the truth. I never got a chance to see him. Never heard nothing but bad things about him.
Now my arms are depending on you to tell me the truth. I never got a chance to see him. Never heard nothing but bad things about him. Now my arms are depending on you to tell me the truth. I never got a chance to see him. Never heard nothing but bad things about him. Now my arms are depending on you to tell me the truth. I never got a chance to see him. Never heard nothing but bad things about him. Now my arms are depending on you to tell me the truth. To tell me the truth. To tell me the truth. Just come home. Run away from all your curse from all. You are my love. You are my love. You never say this feels right. We're talking in circles all night. Can we see the light before both blinded? You are my love.
There's only love for you. When you're not all gone, you're all I see. When the lights go down, it's all I need. When you're not all gone, you're all I see. When the lights go down, it's all I need. When you're not all gone, you're all I see. When the lights go down, it's all I need. When the lights go down, you're all I need. When the lights go down, it's all I need. I should have told you I don't have to fight. Just let me try to guide you. I should have offered you my space. I've been all over the place since I met you. I was better off alone. I've been having bad dreams. I'm stuck in elevators. I've been having worries, my friend. Let's not pretend. We are not, oh yes, we are more than friends. Let's not pretend. More than friends.
We are not, oh yes, we are more than friends. Let's not pretend. We are not, oh yes, we are more than friends. Let's not pretend. Let's not pretend. More than friends. Oh yes, we are more than friends. Let's not pretend. Let's not pretend. We are not, oh yes, we are more than friends. Let's not pretend. We are not, oh yes, we are more than friends. Let's not pretend. More than friends. We are not, oh yes, we are more than friends. More than friends. Let's not pretend. It's a fantasy. In our own reality. We are more than friends. It's a fantasy. Let's not pretend. More than friends. Let's not pretend.
Hi everyone. Are you ready? Okay. I'm going to get him and have us start.
If I can have everyone go ahead and take their chairs, we're going to get started here in the next minute or two. Good. Okay. Are you guys ready? You're ready for online? Huh? You're ready for online? Yeah. Hello everyone. Can we take seats now? We're going to restart the program. Thank you. Are you ready? Please. She was up front. No, sir. Go ahead and tell everybody to grab their chairs and—I don't think you're on. Rich.
Am I on now?
There you are.
You know, I tell a lot of people, you got to read the instruction book. The first thing is you got to plug it in. The second thing you have to do is turn it on.
First of all, what we're going to do, I want to really, again, thank the—these are really amazing key opinion leaders that have said they would want to participate in this. I'll be bringing them up and having a chat where we'll speak to the science, but really talk about, in my mind, I really wanted outside scientists who are really esteemed in their work to speak about the science that will affect all of us today. It really is important because the subjects will be covering things like what happens when we get our standard of care? How do we know what happens to our immune system? Things like what happens if you have a genetic disease which affects 1 in 280 Americans? Things like what happens when you get COVID? Things like why do we have long COVID?
Most concerning, I wanted to do that today because last year I was invited to Washington by the Henry Jackson Foundation to speak to the CEO, thinking that I'd have a meeting with just a CEO and in a room bigger than this, maybe twice the size of this. He puts me up on the stage, and there's about 20 people in the room. The head of NIAID, the Walter Reed Institute, all the thought leaders. I had no slides, and the time frame was unlimited. We spoke about two hours, three hours maybe. I decided it was time. I shared my concern. My concern was, is this virus or was this virus something we never anticipated? Could it act like HPV? Some of you may know about HPV. Is it oncogenic?
When I brought that up, the first response by one of the members in the audience, "That's impossible." At the end of three and a half hours, he said, "This is so important. You have to publish it." We have the science and the information, and I was fearful of publishing it because I did not want to create panic in the country. However, we now have a glimmer of an opportunity to treat it, to face it. Because we have an opportunity to treat it, you needed to first understand how and why it occurs. That is why we are going to have some of these KOLs speaking today about long COVID and what I call the oncogenic potential of it. It is not to scare us, but as a nation and as a humanity, we have to be prepared.
This thing about countermeasures and how do you prepare ourselves against radiation exposure, not from a nuclear war, but radiation exposure that we're getting as treatment. How do we prepare ourselves against long COVID? How do we prepare ourselves from 5-10 years from now to address why are we seeing cancers in younger people? Today, I have a colon of a 21-year-old that had a recurrence. As I shared with on the interview, an 8-year-old, 10-year-old with colon cancer. How's that possible? A 13-year-old with metastatic pancreatic cancer. How's that possible? We can't put our head in the sand. I have taken this opportunity to have these key opinion leaders come and share not only the experience, but their unvarnished opinion based on science so that not only it could be exposed, but you could ask them.
Feel free to ask them any question you want. There are, as I said, microphones on either side, and maybe you want to put a microphone in the center so that the audience and online audience can really interrogate this in a very transparent way. I think one of the important opportunities now for us as scientists and as biotech and pharma is to be as transparent as possible about the knowledge we learn in real time so that you can really adapt to it, accept it or not. I got in big trouble with the early times when I said, "I want to create a bias meter." We have that. It is not a bias meter. It is perspectives of your opinion. I do not think science is about opinion. I think science is about data.
If you have data that is validated, then you really need to accept it. This data we talked about, this lymphopenia, was staring us in the face for 30 years. It was in literature for 25 years, but nobody did anything about it. With that, if I could look at my list of fireside chatters, I think it is Dr. Steven Finkelstein. Phil, if you could put this slide on. Let's talk about the platform maybe first, if I may, the Bioshield platform. Before I bring the—if I can have the next slide, please. This next slide. Is there on the Bioshield platform? There we go. There we go. I think you've got—there we go. Thank you. What you saw this morning is ANKTIVA. By ANKTIVA, we mean we either give it into the bladder or we give it subcutaneously.
It literally is a jab or an infusion through the catheter. That is what we call a fusion protein. It is what we call in vivo lymphocyte rescue by activating the NK and T cells. We need to train your human body to have a T cell that is specific to the cancer or specific to COVID or specific to the protein that the tumor is putting out. That is what we have created. You will hear from Beth this next generation adenovirus that has been tested now extensively by the National Cancer Institute to be very safe, injected, and more importantly, teach your T cells the memory they need so that you can have long-term memory. This is the T cell vaccine that I was talking about from COVID. We will talk a little bit about that.
You will hear these words when you see a CEA, MARC1, BRCA U, PSA, HPV. These are all the proteins that the tumor expresses. If we teach a T cell how to do that, how to go after that tumor and then activate it with ANKTIVA, you now have a combination of the fusion protein and the DNA vaccine as what we call in vivo stimulation. One jab, two jabs. That's it. That's the treatment. Two subcutaneous injections. On the other hand, you have in your body NK cells. You have in your body T cells. We can pull out of your body these NK cells. We have developed an off-the-shelf NK cell that we can target to the tumor. Here is a PD-L1 CD19 NK cell that is targeted, that is infused in 30 minutes as an outpatient.
Now you have what we call a CAR NK cell. And that's already in clinical trials. The final one where we can have these cells, and now we're getting very technical, a cell called an NK cell and a cell called an INK T cell. That is both an NK cell and a T cell. You all have that in your body. By the way, what's exciting about that, we can extract that from your body and give it to somebody else. There's no blood matching needed because it's universal. The ability—well, you got something on the slide there. Dr. Yang, I think. The idea is on the left is the in vivo, and on the—thank you. On the right is the ex vivo.
With that, this fireside chat is going to try and go through these and explain to the audience what we call this Cancer BioShield. It's more than the Cancer BioShield, by the way. I believe it's also infectious disease BioShield. We are very much deep into clinical trials for HIV. We're in clinical trials for HPV cancers. We hope soon to be in clinical trials. We are beginning, and one of the doctors is here for the treatment of long COVID. With that, I'm not sure what the next slide is for, if there's a next slide. With that, let me start the fireside chats. Dr. Steven Finkelstein and Ellen Patella, if you could both come up and introduce yourselves. I'll sit down with you. Have a seat, Ellen. Good seeing you. Where's Dr. Finkelstein? Oh. Oh, yeah. Do you have a seat? Okay.
I'll sit out here so you don't strain your neck. Let me ask first, if you don't mind introducing yourself, Dr. Finkelstein.
Hi. It's a pleasure. I'm Dr. Steven Eric Finkelstein. I'm the National Director of Radiation Oncology for U.S. Urology Partners and the Chair of Radiation Oncology for A&P in Syracuse, New York. It's been an interesting journey. As I talk today about our fireside chat, I think for me, it's personally, how did I get in front of all these nice folks? It's about Steve Rosenberg taught me three patients, three patients who've gotten me to sit here today to be with you and with you as we've talked before. My background is my grandmother had colon cancer, node-positive colon cancer when I was about 12 years old. She was treated with surgery and high-dose chemotherapy.
She was cured of that, but the chemotherapy impaired her life to such a degree that she never lived the quality of life that she had before. For me, it was a trigger for me to want to do something different. Building a difference is pretty much what I think we will talk about for the remainder of the hour about trying to help patients to get better therapies that were different than we were currently doing. I ended up becoming a surgeon because I knew that the chemotherapy was not what I really wanted to do for a living. I wanted to be a surgeon and find a better way to do surgery to solve the problem.
I did my fellowship at the National Cancer Institute with Steve Rosenberg, who taught me about the immune system and all of the intricacies that I could know at that time, and won the presidential award for that from what you guys now know as Society for Immunotherapy of Cancer, SITC. Ultimately, I found in my lab as a surgeon and an immunotherapist that radiation was cool and radiation could trigger immune responses against cancer. I went back to school after 10 years of a career in surgery and immunotherapy to take national leadership roles, of which I have several in the United States.
But it's been a pleasure to join U.S. Urology Partners in the last six months to be partnered with Chris Pieczonka, who you met earlier today, who's a dear friend, as we're building new therapies for cancer to help patients to physically see new exciting therapies occur.
Thank you, Steve. Ellen, do you want to just introduce yourself briefly, and then we'll get into the discussion?
Ellen, I'm a prostate cancer survivor. And definitely, I'm very honored to be here. I'm cancer-free thanks to the ANKTIVA vaccine.
Before we start, again, I think Steven just reminded me about Dr. Rosenberg and the amazing work that he did at the NCI. As you all know, he pioneered cell therapy and the growth of the CAR-T and the T cells that you worked with. Let me take you down this path.
Even with the most amazing scientists and science at the NCI, that if we sort of create an assumption that gets locked in to a drug called IL-2, in order to do that, you use IL-2 to stimulate the T cells, grow the T cells. This is where it gets confusing and difficult for many to understand. The IL-2 is a protein just like the IL-15 in our body. It happens to exceed the exact same receptor on T cells as IL-15 does. Except IL-2, when it goes onto the T cells, causes suppressor cells. It induces the suppressor cells. IL-15, when it goes to the T cells, induces the killer cells. For years and years and years, people are pursuing IL-2 in proliferation of T cells. There was even a drug approved for IL-2, which itself has toxicity.
I'm not fully—and there's not, again, a disparaging thing about anybody. It's just how science works. Because this is so confusing, it's called the IL-2 receptor that actually sees IL-15. By not fully understanding and having enlightenment, that actually what we're doing is going in favor of the tumor by creating the suppressor T cells. Even today, there's a company that just got approved for the first pill, which is a tumor-infiltrated lymphocytes, and using IL-2 to proliferate them. This is why science is complex. This is why we really need to go deep, deep, deep, deep into the receptor level and truly, truly understand it and then develop drugs in that vein.
That was just a sidebar that I'm not sure we were going to plan to discuss, but I wanted to just show that if you have IL-2 and you have GMCSF, very important molecules approved, both drive one on the one hand to a neutrophil that is suppressor and the other one to a T cell that is a suppressor. As Steven just shared, a chemotherapy that wipes out all the killers. If you're going to war, and before you start the fight, all your killers are gone and all your suppressors are there, I think no wonder we're losing the war.
With that, Steven, maybe you want to record the conversation, and then you called me back on the call while I was driving and said, "You're going to make me really happy." This conversation we had about, "Steven, do you mind looking at what happens with radiation?"
Yeah. How did I get from a surgeon like Patrick got from being a surgeon to being a radiation oncologist, right? Because surgeons are cool, right? Oka y.
You notice I didn't say anything because there's a lot of MDs in the room.
Yeah. Yeah. All right. My grandmother gets cancer. I knew I wanted to do something different. I was in medical school at 16, like some people I know, to do surgery before I could drink legally. I'm at the National Cancer Institute, and we're playing with using ways to try to stimulate the immune system.
We had, as Patrick said, IL-2. I started playing with radiation in my lab as a way to trigger those kinds of immune responses. In doing so, I found that, first of all, I think for the audience and those who are watching outside, when we think about radiation, you can't just think about the word radiation. It's kind of like if you're doing surgery, the difference between taking a little mole off and Patrick doing a Whipple is completely different, right? Everybody would say that those two things are generally a small thing and a big thing. With radiation therapy, I could be doing a little radiation to a small spot, or I could be radiating the entire person to be trying to get them preconditioned for bone marrow transplants. It's very different.
When we use the word radiation, we have to put words in that clarify what is it you're actually radiating, what is the size of it, how much energy you're getting. There are all these nuances. Radiation, does it work? Maybe, but it has to be the right kind of nuanced thing, as Patrick has discussed previously. From my standpoint, I was working in the lab with radiation therapy. One of the things that was striking to me in animal models was we spent 15 years of three fellows at NCI working on to create a mouse that could make a cell that could go after a specific cancer. We injected that animal after 15 years of three people's hard work, and that was the last five years of it.
The cancer grew in that mouse where every single T cell would know to go after that cancer. That was kind of a bummer, right? We realized that if we were able to give certain medications, IL-2, IL-15, and couple that with radiation therapy for the first time in a very, very, very, very, very long time, in vivo, in animals, we were able to impact those tumors. We always wanted to take that to humans, but we never could because no one had an IL-15 construct that could give to humans until now. With that, I was interested in something that was in the textbook. In the textbook, when I converted from being a surgeon to a radiation oncologist, the first thing was radiation is immunosuppressive. Yes.
If we drop an atomic bomb on someone and you're right next to it, that's probably very bad. If we radiate an entire person, right, that's going to be tremendously immunosuppressive. What would happen if you radiated specific things, specific small things? Would it be immunosuppressive? Would there be lymphopenia? That was, early in my career, something we went after.
I think we have slides to talk about that next. I called Steven three weeks ago, two weeks ago, when I said, "Steven, you published this paper how long ago? 12 years ago?"
It was in 2015.
I said, "Steven, after you radiate, what happens to these patients?" They're fine. He said, "The ANC doesn't change." I said, "No, no, no. I'm not talking about ANC, which is the neutrophils.
Tell me what happens to the ALC." He said, "What's that?" We went back into the paper, which we will show you today. This is not a disparaging of Steven. This is what's happened with the entire industry because it was not a treatment, as you said, and people did not look at ALC. We went back into the paper to look at that paper. The ALC did drop. Let me just show a few slides, and I'll ask Steven to react to them. Here it is. What he talks about, and we will talk about that when we speak to Ellen, is that could you combine immunotherapy and radiation? The answer is absolutely.
You need to understand how to combine it because we would know in the next slide what radiation does in terms of, as Steven said, if you're a neonatom or you get radiation, that's probably not a good thing. This is what happens because it basically kills your cells. Next slide. We asked Steven, "This is your paper," to look at ALC. If you look at the slide, lo and behold, the median when he started is 1,700. On day one, it dropped to 970. I think that was a surprise because nobody had looked at it. That paper was published 12 years ago.
Yeah. When we thought about this in 2015, think about the world. When I went back to school, I was told that there was no role for immunotherapy in cancer.
When I said I was going to go to the NCI, my friends all said, "That is one of the stupidest ideas you've ever had," right? Because immune things don't have anything to do with cancer. Twenty years later, everything that this audience might know about checkpoint inhibitors and things of other nature, right? When we did this, there was just the creation of ProVenge, right? What we were looking for was ALC counts that were able to potentially support harvesting lymphocytes to some degree. When we looked at it, we said, "It goes down, but there are some lymphocytes." This is very specific. This was a specific form of radiation therapy given to a very, very, very small area, just to prostate in low and intermediate-risk patients.
This was not the kind of things that Patrick and I are talking about today. This was talking about, could you radiate very, very small targets? As Patrick was right, and I was wrong in my interpretation, the lymphocyte counts fall. They do not fall as dramatically as we are about to see, but they do fall in a way that you could harvest T cells and other things if you needed to, but they fall in a way that is probably not great for taking care of your cancer.
Just to explain what Steven just shared with us here, this was his very important experiment to test whether you do SBRT, very localized shot, as you said, without invading the lymph nodes in the pelvic area around. I think to his surprise, even with a single shot locally, it goes from 1,700 to 970.
Look what happens. After one year, it never gets back. It's 1,350. What's happening here is what people do not realize is that no matter where you radiate, the circulatory events of the systemic event of this lymphopenia occurs. You can protect that. You can protect that by actually making sure that you have an activator and recover that. I then went to the next step and said, "Steven, would you do me a favor?" This was two weeks ago. "Would you go into your database and get the IRB approval to de-identify?" Because I know this was done just with a localized. What if you actually exposed to the pelvis in different areas? I think you looked at that. Y eah.
When we are talking about radiating high-risk patients, classically, what we do is we radiate the prostate and we rate the regional lymph nodes.
Now, God did not put the lymph nodes on the planet for me to radiate them, right? What would you imagine would happen with your lymphocytes? That data is from a very, very small target. I think we're just going to see on the next slide. Here's what happens for the same number of patients if you actually radiate the prostate and what we would think important in high-risk patients, significant prostate cancers, the kind of people that we need to cure in the world. You can see it's a significant drop.
I got this call from Steven as I was driving, and he said, "It's very exciting. You're going to be happy for it." I said, "I'm not happy about it because this is exactly why, Steven, I need you to educate us or educate radiologists, radiotherapists, that that drop can be prevented.
More importantly, it could change the course of treatment." Which then turns me to Ellen because Ellen was a CEO of one of my companies. He had then moved to another company and basically was going to retire. I got a call. Ellen said, "Patrick, I have a—" he is allowing me, by the way, very openly to share his history, and I'll ask him to share himself directly. This was in December last year. "I'm about to go for radiation because my prostate cancer has recurred." Knowing what I know, I said, "Ellen, please stop.
Before you do that, I want to give you ANKTIVA Plus and Adenovirus, the educational tool to educate your body about the T cell and prevent this from happening. He spoke to his radiotherapist, and I think I'll ask Ellen herself to share with you what these radiologists or radiotherapists said. In most cases, when you give radiation to these patients who recur high risk, the PSA drops six months over time. Maybe, Ellen, you can then react by sharing. This is, I think, normal now. What did your radiation oncologist say that we're going to do beforehand, or should we or should we not? Maybe you get your reaction.
Perfect. Thank you. Thank you, Patrick. After my radical prostatectomy and biochemical recurrence, the oncologist at UCSD Medical Center recommended that we watch over time and see if it was going to increase significantly.
Every month, actually, it was increasing by 20%, my PSA. I reached very quickly what is the 0.2 number where you have to start radiation. At the time, they recommended radiation and hormone therapy. Of course, they told me to do both at the same time and the hormone therapy for six months. I mentioned that I did not want to go through the standard treatment for hormone therapy. But yes, I will do the radiation. That's when I called Patrick. Immediately, the thing that the radiologist mentioned is that my PSA was not going to drop for a while if I was just doing the radiation. I started the treatment a few days before the radiation. Within five days pre-radiation, my PSA dropped from 0.2 to 0.16. In 12 weeks, it went completely undetected.
What was the reaction of your radiotherapist or your oncologist?
First, they told me not to do this and that there is absolutely no role of immunotherapy in prostate cancer. Since I started going through the radiation, every week, I had a team at UCSD that met with me every Wednesday just to see what was happening to me. They did a number of blood tests to see how this was dropping. They are amazed. They are amazed. They said this was a miracle. The last day of my radiation, when you ring the bell, I was like a movie star, and I did not realize I was going to be doing this.
I think it is not a miracle. I think it is actually just what God gave us, right? If you look at the next slide. This is Ellen. Thank you, Ellen.
Ellen produced a slide for me. He did some of those magnificent slide productions where if you look at the left-hand side, you see January 3, 2024. As he says, all of a sudden, his PSA started rising, rising, rising, rising. I said, "Stop." At that point, he got the ANKTIVA plus this adenovirus vaccine. That is March. He had the radiation. As you said, within weeks, his PSA started to drop. By March 10, I think, is that 10/3? I read things differently. The English way, 10 to me is October, but that is the 10th of March, right? His PSA was basically undetectable. By the time he is finished, it is undetectable at the end. You see the dotted line. He now has trained memory T cells.
This is the promise of radiation immunotherapy and the opportunity for us now to take this into clinical trials, which we've now initiated, about to initiate with Dr. Finkelstein at U.S. Urology and other places in the country, is overcoming this barrier of insight that, in fact, you can train your immune system. It's not a miracle. What we see here is basically the biology that exists. I worry when people said, "We're going to remove your lymph nodes in surgery." As you said, the lymph nodes were there because that's where your memory T cells reside. Imagine now you're given chemotherapy, knocked out your NK cells, knocked out your T cells. You're given radiation. You've got yourself in lymphopenia. You go to surgery and you remove the lymph nodes.
You ask yourself all these little steps, do they make logical sense when you have this particular insight? The next slide is the protocol that we're about to institute now in prostate cancer. The opportunity to take what we call high-risk patients. I think also the question is, can you avoid hormone therapy, which you see? Maybe, Steven, you can speak to this a little bit.
I said at the beginning that this is very personal. It's about patients who have guided my thing. This is my dad. My dad had high-risk prostate cancer. When he was, the average age of showing up is like 69. He was about that age. He basically had two choices. He could have radiation therapy or he could have surgery. Those are felt to be equivalent.
As you get older, a lot more men, based on American Cancer Society statistics, get radiation about 300% more, but they're equal in outcome. You had a choice between what we see on this slide and what we'll see on the next slide. This is, if you look behind me, to have surgery.
Oh, sorry. Yep. There we are. We could do the surgery one first. Can you go back one? I don't think we have the data.
This is the radiation. We'll talk about the radiation one. For me, what I do personally now is the radiation piece, which is basically we would normally offer someone radiation therapy to the prostate. Before that, they would usually get androgen deprivation therapy as an option to go along with it. What if we could actually use the immune system to do the heavy lifting?
What this does is add innovative immunotherapy before getting their radiation therapy and then afterwards. Something that if my father had been alive to get back 12 years before, I would have told him that this was something that was rational and reasonable, but it did not exist. My dad got radiation therapy the way that is described on here. He lived 12 years before he ended up passing away of COVID. Today is 2025. I think if we could add innovative immunotherapy to both approaches in high-risk prostate cancer, a disease which one out of every three patients, despite our best work in surgery or radiation therapy, will have to come back, would be a huge blow for freedom.
What this does is does all the usual what we do to classify the stage of the patient, imaging, blood work, all of those things beforehand. Patients get, as Patrick can talk about, the innovative BioShield approach, and then get their radiation therapy and then see how they do, and then get more BioShield out back as a boost.
Thank you, Steven. That is what we are trying to do to get what we call this emergency use access because we cannot, as I said, address this across the country now. The only way we can think about it is get the FDA to give us this emergency access. I am announcing we were willing to provide this drug free, literally to anybody about to get radiation if the doctor wants to use it until we get this approved as a lymphopenia rescue agent.
I want to thank you. Maybe are there any questions before I let Ellen and Steve go? I want to thank you, Ellen, for sharing your story with us. Are there any questions? If not, a re there questions?
It looked like from your slide, you gave 33 treatments of radiation. Is that right?
We're talking about in this trial here?
Mm-hmm.
This trial is innovative in it. When we think about radiation therapy, that classically is this much energy broken up into small pieces. Why do we do that? Because we've always done that. Every time we've tried or wanted to try changing the way we do radiation therapy, it comes back to what we have standardly done with radiation, doing the heavy lifting to deal with the problem. What if you didn't? What if you used innovative radiation therapy?
As Patrick talks about, exposing a tumor, which it's in you. It's you. Cancer is you, and yet it grows in you. What if you could use it to expose, as Patrick said in the interview with Tucker Carlson, expose the truth, expose things where the immunotherapy gets to do the heavy lifting, and I don't have to do as much to potentially cause side effects? For that trial, it can be done with standard fractionation if patients wanted to go this way we've done it for 60 years, or they could use stereotactic body radiation therapy, the new hot kid on the block for radiation therapy. I think that allows some innovative approaches to radiation that we've never been able to do before.
I think one of the most important, if you look at the total gray in the standard of care, what's the total when I go gray? Just 300.
For high-risk prostate cancer, that would be 81 gray for years. We have shortened it to about 28 treatments based on some work that was done within the cooperative groups. We are able to do it in as fast as five days. We have lowered the dose to what's called 40 gray, but the biologic effectiveness we think is equal to doing 81 gray. It is complicated, right? The point is that radiation is not all radiation. If I do something a certain way to radiate just this target, or if I am radiating this plus the entirety of the lymph nodes, that has got to be somewhat different, right?
In this way, people can get radiation just to the prostate without radiating all the lymphocytes, potentially in the lymph nodes that go all the way up to the pelvis. It's a great question you ask. It basically sets the tone that when you say, "Hear the word radiation," ask, "How am I going to get radiated?" Not, "I got radiation."
Let me explain the difficulty for you. You hear 80 gray. Some people with other forms of radiation go to 100 gray, 200 gray, huge numbers. The gray, by the way, is the amount of exposure to radiation. Just to give you some idea what that means.
For Senator Reid, we said, "We're going to give you 30 gray who had pancreatic cancer over the course, not over five days, once a week." Because the idea is not to kill the tumor or kill your NK cells or T cells. It's to really stress the tumor, what I call cytostress. If you look at that little wiggly map that I did in 2016, the word cytostress, stress the innards of the tumor so it exposes outside. That is such a revolutionary idea that when I said to Steven, "Steven, can we go put that in the protocol?" He says, "No, we will do that, number one. Two, you'll never get reimbursed, number two." I said, "Oh my God, how do we break through this?" Your question was a perfect question that not only do we have to break through dogma.
I see Marty McCarry wrote this book on blind spots. We have a lot of blind spots in medicine. The blind spots are biologically rational. Why the heck are you radiating so much? Why the heck are you radiating this large area? Why the heck are you radiating lymph nodes? Why the heck are you killing NK cells when all you really want is to expose the tumor? That's why I said all these therapies that we've created don't go to waste. We just have to figure out how to use them as immunomodulators and unblind the blind spot. That's going to be the challenge for us. I get it. There you see that trial. It says 40 gray. We negotiated. If some of you wanted to know how I got to the dose of Abraxane, it would blow your mind.
When Taxol was approved, it was 240 mg, 260 mg high dose. We completed a study at MD Anderson. It showed it could be given at MTD, what FDA wants, maximum tolerated dose at 360. Finished the phase I, I said to MD Anderson, "We now want to do phase II at 100." They said, "If you don't do it at 360, we're going to ask you to leave." I said, "I'm leaving." We left. I then went to Northwestern, Dr. Bill Gradashaw, and I said, "Listen, can we negotiate?" He said, "Fine, let's take 100 off." That's how we negotiated. It became 260. That was the dose. Think about this empiric craziness. It took me five years finally to get the dose to 100, which it is now of Abraxane for pancreatic cancer.
It is this kind of blind spot that is not understood of why we have to do what we're doing. This conference today, I think, is the first time I'm speaking out this publicly. I've been railing like this quietly with my academic friends for 10 years. Your question is so pertinent about why are we giving what dose we're giving. Thank you.
Yeah. That was my point. I think it's just dogma that we're giving so much radiation. Dr. Finkelstein, I think that we've talked in the past, by the way, and I've read some of your articles. To achieve the abscopal effect, I think you were talking about using much less radiation. Is that right? I think there's so much undiscovered country. As a radiation oncologist, I'm not encouraging that anybody just go out and do radiation whatever dose they want.
When they're allowed for the ability to work in synergy with immunotherapy, it creates the ability to start doing things we've never really been able to do before, which is start to change the fields and change the amount of dose that we give because the immune system is probably what can do the heavy lifting. It's not just on me. If there's no other possibility, surgery can't solve the patient, and Patrick isn't here, there's no such thing as immunotherapy. As a radiation oncologist, we're going to cover where the cancer is and treat the cancer. That's not what we're talking about today. What we're talking about today is, what if we could combine the benefits of the immune system with the benefits of radiation and figure out what that right place is? I don't think we're there yet.
I think we've built history based on radiation by itself, but never been able to build history because these drugs didn't exist before.
Just so for the audience, when you heard this abscopal effect, what he's talking about is when you give radiation to, let's say, one spot in the thigh, just making that up, and you have a cancer in your lung, and you're not radiated alone, that lung cancer disappears. That's called the abscopal effect. It turns out that that effect is based on your natural killer cell. If you wiped out your natural killer cell, you will not get an abscopal effect. Cancer is a systemic disease. It's not a localized disease. That is why this is so important, what's been brought up here.
The lower the radiation dose, believe it or not, counterintuitively, the better because you do not want to wipe out your natural killer cells. Question.
Yeah. Kelly Shi from Jefferies. Curious, across various tumor types, how does lymphocyte count vary at the baseline in patients? If we think in the future, when ANKTIVA moving to frontline treatment, would you prioritize certain tumor types for patients to achieve the best benefit, or you'd rather think this is more like a universal mechanism of action for lymphocyte reversal? Thank you.
Good. Thank you for that question. And a great analyst question. You're right. It's very complicated because your lymphocyte counts, whether you're healthy or with cancer, varies depending on your age. The younger you are, the different lymphocyte count, and the older you get, the different lymphocyte count. Cancer itself reduces the lymphocyte count.
Cancer has figured out a way to reduce the lymphocyte count. Worse than that is your chemotherapy reduces the lymphocyte radiation, and all the things we do reduce the lymphocyte count. There is a definition of a cutoff that we've seen from all the data that when you go below 1,000, you're really in trouble. If you get to 1,500, you're a little better. You get greater than 1,500, you're in great shape. There is a normal range from 1,000 to 4,000. Crazy as it may sound, it depends on which lab you are. Some labs say 700 is a normal range when it's not. Some labs say 1,000. We have then taken what we call the median. We've taken the pancreas and looked at the entire population and looked at a level. The median is usually around 1,000 because they've all had this sad chemotherapy.
You see that median that Steven's patients has 20 patients. That was just literally pulled out the first 20 patients. It is quasi-universal, sadly, that all cancer patients, whether de novo or more importantly, after whatever has happened to them treatment-wise, they end up with lower than 1,000. We use a cutoff as a primary endpoint of less than 1,000, and we want to hope to capture all these patients and get them above. What we have shown and we provided in our meeting package yesterday is that it is linear. When you get to 1,000, you beat 1,000, you get this kind of survival. You beat 1,200, you get this survival. 1,400, you get a longer survival. 1,500 and greater, you get even a longer survival. Your lymphocytes matter. When I say lymphocytes matter, your count matters, survival matters, duration matters, and quality of life matters.
These aren't just soundbites. These are biologically intentional to really explain in soundbites why this is all important. It is universal, and we will use an ALC count of 1,000, which, by the way, is a $20 test now. As I said, ironically, after years and years of hundreds of millions of dollars of genomic analysis, all you need is a CBC and look at your lymphocyte count.
Hi. My name is Leola Oliver, and I had no intention of speaking tonight. I'm not a medical professional. My question has to do with being that this chat centers on immune disease, I should say immunocompromised disease, and the bioshield. I'm wondering if there has been any thought given to conditions like myasthenia gravis in that regard, and would this type of immuno disease be a good candidate for the bioshield?
It's a complicated question.
It is very much like what we talked about, and we may be talking about when we get to cell therapy on myasthenia gravis and even lupus, where there are treatments at the NK cell therapy. It has to be very targeted under those circumstances because each of these, I consider with immune disease, have a specific error in one of the cell types, which we can correct, or the cells themselves in your body has an error. We will get into that when we talk about the NK cell therapy. Okay. Thank you very much, Steven and Alex.
Thank you.
Thank you for coming. Okay. I hope I am still on time. I think we are good. This time, I have asked Dr. David Kerr and Dr. Gabitzsch to come up, and we are going to talk. I do not know if Dr. Mark Lanasa is on. Okay.
Dr. Lanasa is going to remote, and please have a seat. Good seeing you, David. I can't tell you how honored we are to have David here with us, and we'll introduce Beth. David is one of the most foremost oncologists in the world, and I mean that. He is ahead at Oxford, and he is considered such a thought leader that is invited by literally every country I know of to not only give advice but give his opinion. David, thank you fo r coming, being with us. Beth and I have known each other now for years and years and years and decades. Beth used to be at one of the government facilities, which she will share. Red has been the innovator of pursuing what we call this next-generation adenovirus that will train all our T cells.
We will sort of explain that. Beth is now the head of our cell therapy adenovirus program and science program and process science program at ImmunityBio. With that, maybe, David, you may want to introduce yourself and your background. We will start from there.
No, no. Thank you, Patrick. I am professor of cancer medicine at Oxford. Warm words of welcome from the dreaming spire. Still a practicing physician. I mean, given the tenor of the discussion this morning, I probably should say, "I'm David. I use chemotherapy." Hide my head in shame. There is a sort of balance to be made. I think the one other thing is, as I say, still busy in the clinic and so on. In terms of what Steven was saying, I think we are forming an elderly uncle brat pack.
I think I went to university when I was 16 also. I think there's a sort of small group of us describing that phenotype. Delighted to be here. Of course, contributing to this fantastic seminar, to seeing what we can do to explain the basis of immunotherapy, but perhaps most importantly, its future and where we're going n ext.
Hi. I'm Beth Gabitzsch. My background, I was trained in microbiology and focused on virology, where I actually served a tenure at the Center for Disease Control researching different viral vectors to be used against primarily first infectious disease. Over the last couple of decades, especially working with Patrick, really taken advantage of this T cell-inducing technology against cancers.
Oh, and there's Dr. Mark Lanasa. Can we expose a little more than that little thumbnail? That's it, huh?
He's a—maybe Mark, thank you for being here. Mark was at AstraZeneca. He's now in BeiGene. One of the most important things that we're going to need to partner is a combination with a checkpoint. As I said, the checkpoint inhibitors upregulate the T cells. If we can actually proliferate T cells and upregulate them and then train them with best technology and expose the tumor with what David will share with us. I'm so grateful for BeiGene, or Bay1 now, for agreeing to partner with us as we provide—they will provide the checkpoint inhibitor throughout the course of these trials that we will be undertaking. Mark, if you don't mind just introducing yourself.
Sure. Thank you very much for the introduction. Very glad to be here this afternoon. My name is Mark Lanasa. Also a physician, a medical oncologist by training.
I went to school at the University of Pittsburgh. Subsequently, went to Duke, where I was on faculty, took care of patients with acute and chronic leukemias, decided to move to industry so I could stop giving chemotherapy and really focus on targeted therapies that would be better tolerated for patients. As Patrick kindly mentioned, I was at AstraZeneca for the best part of a decade. My current role is that I'm the Chief Medical Officer for solid tumors at BeiGene, now B1 Medicines. Again, very glad to be here today.
Thank you, Mark. With that, maybe do we have a few slides for us to talk about? If you look at what we're talking about in this session of the fireside chat, we spent the morning on ANKTIVA. Imagine the combination of the fusion protein plus the DNA vaccine.
Those are both with two jabs giving you lymphocyte rescue and one component of the bioshield. David will speak a little bit deeper because, as you could see soon, these tumors hide. He has found a way to expose them with yet another molecule. With that, we're going to spend some time now. I'm not sure which slide you got coming up next. On the end of—Beth, maybe we can speak to your adenovirus, where we've done this clinical trial where you combine the IL-15 plus the adenovirus with the HADCA mark 1 and BRCA URI. We have the Lynch syndrome, but maybe you can give a little background before the Lynch syndrome. This was—are we coming to the colon cancer slides after this? Just to speak to this a little bit, this is a trial to prevent colon cancer. Think about that.
This is a first trial now in patients who do not have cancer. These patients have the thing called adenomatous polyps in their colon and an 80% increased risk of getting colon cancer. They are born with this genetic defect, so to speak, that allows, frankly, the body not to protect itself against cancer. If we can actually create this bioshield, so to speak, train the body to see what they call CEA-specific T cells or MUC1-specific T cells or BRCA URI-specific T cells and go after these cancerous cells before they become cancer, that's the goal. So far, as of today, 101 subjects have been enrolled. If you look at the logo, what I'm grateful about is the entire country, whether it be MD Anderson, Mayo Clinic, UCSF, Northwestern, Fox Chase, Dana-Farber, are in this fight together to prevent cancer.
I'm really privileged and honored to say that the only two treatments for these patients that they are trying now are these ANKTIVA plus the adenovirus. Maybe Beth, you can speak a little bit about the adenovirus.
Absolutely. I've been working on this specific platform for a couple of decades. You'd say I'm a believer, but really, it comes down to the power of the T cell. This agent, we're kind of dancing around the word vaccine. It's gotten a negative connotation. I'd like to use the word specific T cell-inducing agent here.
What you are doing here is using this virus, which is a very common cold and flu virus that most of us have encountered while we were children, to actually use that as a very elegant delivery system that we have co-evolved with for centuries, millions of years, and essentially deliver a payload to your immune system, to your T cells, to specifically educate them against your protein of choice. What you see listed here on the screen, such as MUC1, BRCA, URI, CEA, these are our antigens of choice. A very common one that I think a lot of us have been exposed to is PSA, or prostate-specific antigen, that we just spoke about.
In the context of that vaccine or T cell-inducing agent, we are presenting that protein to your immune system to now allow the education of your T cells to go and destroy cells that are expressing this protein, so prostate-specific antigen that's specific to prostate cancers. We have been working with the National Cancer Institute on these targets for about 15 years. That's where some of our more unique targets, such as BRCA URI, which is actually a cancer stem cell target, come in. When your cancer is metastasizing and moving through your body, it will display or express BRCA URI. If we have pre-trained your T cells to see that target and recognize it as a foreign, as an invader, or something to clear, we now have that army of white blood cells that's circulating through your blood that will seek and destroy those cells.
It is a very important part of this overall bioshield. It is one of these extremely powerful killers that you need to actually go in and destroy a cell, that being a tumor cell or an infectious disease-riddled cell, so a cell that is producing more virus. It is a very powerful technology, which we have harnessed and now been able to apply to multiple oncology as well as infectious disease indications to essentially train those T cells to go out and do their job and kill its target.
I think, as I said, the sequence of events is to expose the tumor. We just talked about that. Then you need to find and kill. You cannot just find and kill where we have the NK cell. Imagine you have had an educated T cell that could actually seek out and be targeted to kill.
This is exactly what we did. Beth has not spoken about that, but she'll see that we have actually treated patients with not in the animal models as well as patients where it's lesser fever, all infectious diseases, HIV, and as well as cancer. These trials have been done in cancer patients. If you look, see Jeffrey Schlom, the last author, and I want to give him credit. He's been at the National Cancer Institute for decades pursuing the cancer vaccine or cancer immunotherapy. If you look at the date of this slide, it's 2015. Think about that, a decade ago. This has been a decade in the making. When COVID came around, not only were we already in patients, safely in patients, but we had generated these T cells.
When you get into this paper, you will see that the investigators drew the blood of these patients after having given them these vaccines. There were specific T cells to each of these targets, which meant that if we created a T cell to the nuclear capsule of the COVID, it would kill the COVID virus and clear the virus. We actually showed we did that. We'll get to that when we speak to long COVID. That's what I mean by a T cell vaccine. On that basis, this became the basis of the Lynch syndrome trial. It is now in colon cancer trials. We're about to start. If you may want to talk a little bit about that, maybe David will speak to that.
I think the Lynch study is incredibly important to have these agents, which are so safe that we can give them to fit healthy people. I mean, as Patrick has said, these are individuals who are at an exceptionally high risk of developing colon cancer. It's a genetic time bomb and a possibility yet to be proven in the trial that we can intervene with these very safe agents, which are targeted specifically on the genesis of those early stages of colorectal cancer. It's a remarkable step ahead. It really is. It just shows the genesis of how safe the agents that Beth developed is. It makes a real difference. One of the things that we've done—colorectal cancer is a difficult disease to treat with immunotherapy. It's traditionally a rather cold tumor.
It tends not to be very well recognized by the immune system. We have talked this morning and so far about what we can do to stimulate, to arm, to improve the activity of the body's own T cells, NK cells, and so on. The approach that we have taken is to see what we can do to make the tumor cell a more attractive target for the body for immune recognition and destruction. I guess one of the things that Patrick has done, I think, is to assemble a toolkit. Those of us who are active in individual areas, he has had the vision and oversight to see how if we bring these together in a combinatorial way, we will see what we call synergy: 1 + 1 = 3 . We have used then what we call an epigenetic regulator.
We regulate the genes of the tumor cells themselves to turn a cold tumor hot. What do I mean by that? The flags or targets that the immune cell recognizes are called antigens, which are shown and presented at the cell surface of the tumor. It is literally a flag sitting on the surface of the tumor, which is part of the important recognition element for the body's own immune cells. The machinery of getting the antigen from inside the tumor cell to the surface is called the HLA system. In many tumors, they close that machinery down. This is as if the factory has been literally closed down. Even if the cell is making antigens, there is no way that they can get to the surface and are therefore invisible to the cells of the immune system.
By using an epigenetic regulator, we can restore the activity of the factory. We can restore the machinery that then plants the flags on the cell surface that, in a way, the stimulated immune system that Patrick, that Beth, and the team have worked on to activate can now fully engage with these attractive, juicy, hot cancer cells and do their best to destroy them. If we then add ANKTIVA to the mixture with our epigenetic regulator, we're seeing 1 + 1 = 11 when we've looked at the mouse experiments that we've sort of put together in this way. We're incredibly excited to take the lessons learned here and to build in these with colorectal cancer, both treating patients with advanced disease and in a setting of which we call the adjuvant system.
If we resect the main tumor type, there may be tiny microscopic metastases, lumps of tumor left behind, so small we cannot detect them using conventional CT, MRI scanning. In that disease setting in which there is a high likelihood of the tumor relapsing, we think that would be an excellent clinical target with minimal residual disease that would allow us to target and to give the immune system the best chance it has of overcoming and eradicating any residual tiny microscopic deposits. This can only come through this multidisciplinary approach. We have heard from Steven, from other colleagues who are willing clinically to put novel innovative designs, but to put trust in the sort of therapeutic values, the therapeutic agents that Patrick and the team have assembled, and that we will be able to bring in, I think, sensibly into clinical trial. It is an exciting time.
Thank you, David. I'm so glad I brought scientists into the room because it allows—I'm sure all of you understood that, not because he's Scottish, but I may be able to help with that. The work, what David has just exposed, is so significant. Maybe I'll try and put that in English. I'm glad your 1.1 is 11. Let me just explain what he just said, right? I think it's so important. When you look at all the drugs on the market today, the checkpoint inhibitors, etc., going after colon cancer, believe it or not, it's only up to 20% of the colon cancers because they are only going after the colon cancers that they call hot, what they call MSI high in technical jargon. The other 80%, they can't treat because those colon cancers—so think about it.
Our therapies today for 50 years treat 20% of colon cancers. I don't think the public recognizes that. What has happened is David and his team at Oxford have discovered why they are cold, not hot, because at the genetic level, these tumors hide, meaning they don't express the proteins on the surface to allow even the T cells to recognize them. Let's call MHC I to get more technical. He has developed a molecule that is oral, that can be taken, that tells this tumor, "Stop hiding and expose yourself to become now not just 20%, 100% of colon cancers are exposed to the T cells." That molecule is called sabotinistat, which I'll share with you in the next slide.
More importantly, what David and his team have done is there's yet another molecule which we won't go into, is that they've been able to find the secret that the tumor is hiding and create a peptide that can actually find the T cell in the patient's own body. That is this elusive T cell that has already been educated. That's the future of T cell therapy. We'll get to that when we get to T cell therapy. The revolution is happening. This has been work now 10 years, 15 years? 20 years. 20 years.
Yeah. Boy and man. No, it's a really clever point. You're right with our other drug. What we can do is we can make hot tumors hotter. We've discovered a new source of antigen.
We can mine the tumor's own genome to make more antigens to be presented at the cell surface in that way. Again, once we've known that mechanism, we can use that. We can put it into Beth's adenoviruses. This is rather a love match that we're building on even as we speak. By building in those pathways, I hadn't thought of that, make a hot tumor hotter. Clearly, we need to make it hottest. Maybe that's when we come back next year and talk then.
Until you go on the red carpet. Now you begin to see the synergies. This is why it's difficult for us to explain this to Wall Street and even to academia and our analysts, because there's no one magic bullet. We keep on fighting this chess game.
We really fight playing chess and trying to understand what is this tumor doing. It's the smartest machine, as I said. The fact that the tumor hides and this DNA that we called before junk DNA, it's technically non-long coding DNA or RNA, they've been able to expose. By actually exposing that, we can now get deep into the heart of the tumor. By doing so, we can find peptides that nobody has ever found before that the tumor itself is expressing that then Beth can put into an adenovirus and now teach the T cells, or we can go fish it from the patient, grow them together with the NK cells. You begin to notice there's no chemotherapy here. This is all basic immunology at the most basic fundamental level. Folks think at the investor level that we're just spending money like crazy. We're not.
What we're doing is trying to interrogate to a level where we can cure a patient and give the highest quality of life. Having said that, we test all these theories, not only amongst ourselves, but also with Jeffrey Schlomm at the NCI and in very sophisticated models. If you could show the next slide where 1 + 1 = 11 . This is for you, David. This is your slide. Or is it? No, this is Jeffrey's slide. We collaborate so beautifully that we've been doing this for six to eight years together with Jeffrey Schlomm and his team. We really don't care whose slide it is, whose work it is, because it's all our work together. Just to give you an idea, this CT26 is a colon cancer cell line. On the left-hand side is where you see the tumor volume.
You grow the tumors, and you could see on the left-hand side, the tumors grow in size. Then the legend of PBSZ, NA23, PD1, Z plus NA23, sabotinistat, NA23 plus anti-PD1. When you do all three, let me explain that to you. Z is sabotinistat. Look at the survival, the days post tumor implant. Look at the top line. It's 100%. No, that's a mouse. Everybody can cure a mouse. I get that. The other mice, look how they fall off. If you add ANKTIVA to that, look what happens to that. You add anti-PD1, and that is why we needed Mark from Beijing. If you look on the right, five out of eight of these cancers in this triplet, that's what David means. One plus one plus one is eleven. Imagine, however, if you also put the adenovirus into it.
This may sound ridiculous, but Beth did a clinical trial with colon cancer, phase I and phase II, just with the adenovirus. In third line, with no treatment, and prolonged the survival to the extent that the FDA said, "Go ahead and do the trial of the single agent." Maybe you can talk about that.
Absolutely. I think the data that Patrick just spoke to, and that is published, really demonstrates the power of even just one of these tools by itself. In this study, we actually were working with Duke University and treating really late-stage failed Alcurin therapy colon cancer patients. By just administering subcutaneously this adenoviral vector expressing CEA, or carcinoma embryonic antigen, which is your protein, your flag, overexpressed on colon cells as well as many other cancers, we were able to actually really extend the lives of these patients.
I think that's a big difference between immunotherapies and chemotherapies. That's very important is that really chemotherapies are administered until toxicity, until you have to stop for the patient. When you see the tumor come back, it regrows at the same growth rate. Now with immunotherapies, by just applying that immune pressure on the tumors, you actually change the growth kinetics of the tumors. You actually slow down the tumor growth. What you see with that is an actual extension of life. It's different in chemotherapy where you might see an immediate reduction, but then it comes roaring back. With these immunotherapies, even single agent, you're altering that tumor growth and allowing for these long tails of extension of life to be provided. That's what you saw in several of the other slides earlier.
If you imagine the power of the T cells alone, and now you come in with these other agents, such as the ZABA, which cranks up that expression, like the PD1, like Patrick said, if you hold back the PD1 or the regulatory T cells of PD1, but you don't have the activated T cells, there's nothing to actually affect the cancer. That's the beauty of marrying these agents together, that you're now conducting that symphony within the human body to bring on the effectors, hold back the suppressors, and the timeliness of that. You're now able to hold that beautiful concert for the host and allow their own system to overcome the disease.
That's what we do talk about. I think it is an orchestration of a concert. It really is a concert. It's a concert happening dynamically in real time.
When Beth showed me that data, just a single agent, adenoCEA, giving this prolongation of life, it really reaffirmed that this concert that we need to do, which meant that at the end of the day, we want to reactivate the T cell. That's why a checkpoint inhibitor, and Mark may want to speak to that, because we tried with every other Merck, Bristol-Myers, etc., said, "Will you share with us your checkpoint?" There's lots of reticence, whatever that may be for whatever reason. When we went to BeiGene and John Oyler, the CEO, that was not only open arms, but to me, I believe it's one of the best checkpoints. I don't have any financial relationship with BeiGene whatsoever. Scientifically, I think it's one of the best checkpoints. Maybe Mark, you could speak to that if you don't mind.
Yeah.
Thank you very much for that. As I've been reflecting on your comments today about the importance of the lymphocyte compartment, just to say a few things about this Lismab and how it's different. Everyone in the audience will be familiar with PD1s and how they work, that basically they bind an inhibitory receptor and an inhibitory protein on the surface of lymphocytes, which in turn then leads to T cell activation. What might be less familiar is that there are other white blood cells in the tumor microenvironments called monocytes or macrophages. When they find these lymphocytes that are decorated with antibodies, it's their job to actually destroy those lymphocytes, to kill the lymphocytes, because they shouldn't have antibodies on them. They're sick in some way. Maybe they're infected by a virus or something like that.
The body did not evolve in this context of receiving therapeutic monoclonal antibodies. It turns out that the monocytes or macrophages recognize those antibodies through what is called the FC gamma receptor. Tislelizumab was uniquely designed to not have binding to FC gamma receptors. Or to put it more simply, Tislelizumab was uniquely designed to avoid evasion and ultimately preserve the lymphocytes that have been activated to fight the cancer. We think that this is a very exciting combination, Patrick, to the point you were just making about synergies or rational combinations to take a lymphocyte, a molecule that expands and activates the lymphocyte compartment combined with a PD1 that was designed to be lymphocyte protecting, we think makes all the sense in the world.
I will just say that for tislelizumab, for those of you who aren't familiar with it, this is not just theoretical that we're approved for three indications here in the United States. We are approved for at least one indication in 40 countries worldwide with more submissions underway. We are very excited about the opportunity. When I reflect upon the amazing Kaplan-Meier plot that you showed earlier today, of course, the data in the patients with a high lymphocyte count is so striking. Even in the patients with a lower lymphocyte count, they substantially overperformed the historical control of docetaxel, as you mentioned. We are hopeful that this combination can bring patients with PD-1 progressed non-small cell lung cancer a lot of benefit, particularly in light of the unmet need for those patients.
Thank you, Mark.
I think it's not a fair fight when you think about it. Here you have a checkpoint inhibitor that actually protects lymphocytes, and you're having ANKTIVA that actually stimulates and proliferates lymphocytes versus docetaxel that kills the lymphocytes and steroids that kill the lymphocytes. You're asking to compare the two. To be honest, I think it's a ridiculous trial that we should even do. We are going to go to the FDA with the data that we really have, where we've done ANKTIVA plus nivo and the data I showed you, ANKTIVA plus nivo pembro, that got us 21 months. You follow regulations, and the regulation says, "Do a confirmatory trial, so be it." This trial is in motion. As I said, we know what the data is going to show for docetaxel. It's going to be 7-10 months.
There's just nothing's going to change. We know what docetaxel is going to do to the patient. Interestingly enough, one of the difficulties we're going to have is be able to recruit patients in the United States, because now American patients are smart enough to say, "We don't want docetaxel." We are bringing this, sadly, to a global trial. That is why the help of BeiGene is going to be so helpful, because they're all around the world. It's very frustrating to us to have to even do this trial, because you ask yourself, if you're the patient that's actually allocated the docetaxel, is that even ethical? I just leave it out there. I'm already in enough trouble, so I'll just leave it. Mark, maybe I'll ask you and David to react to that.
I mean, what do you think about a trial like this in terms of we can almost predict the outcome?
It is a challenge. To be clear, tislelizumab is not approved in second-line non-small cell lung cancer. I do not want to convey the wrong message. We have run studies in second-line non-small cell lung cancer. It is operationally difficult to enroll patients to docetaxel monotherapy. It is, shall we say, formally a regulatory standard of care, but it is not a commonly administered molecule. The other problem is that we really rely upon randomization to have scientific integrity in the study, but you cannot effectively blind this type of study. The side effect profiles, the drugs are so different. The patients will know what they have received.
That in and of itself presents its own set of challenges to the integrity of the study, keeping patients in the study, keeping them motivated and engaged. Yes, there are real challenges with delivering this type of design. Again, as you say, the regulations are what they are, and certainly we aspire to meet the expectations of regulatory authorities in terms of the dat a package.
David, do you want to comment?
No, no. Well said. I mean, I agree with Mark. I mean, we're here in Hollywood, and my little boy watches The Mandalorian who says, "This is the way." For those of you who are similarly aged children, and we're just sort of caught up, aren't we, in this sort of groupthink and this sort of very traditional way that we have of doing things. Now, there may be an opportunity.
You're knocking at the door. I know that you and Rich are knocking at the door and doing your best to see what you can do to sort of bring some of the pillars down. I think for the time being, the trial, as is, will give the answer that all of us predict, and it will meet the needs of the regulatory authorities and so on. I agree with you that there will be casualties along the way, and those will be with patients, not with us.
Right. I can tell you from the outset, David, it is not possible for me to know of any patient that's in third-line lung cancer that has a 20% opportunity to have a five-year survival with docetaxel alone. We've shown that with a hazard ratio of 0.3, which then says, "Why?" You're right.
I am knocking on the door. I may be able to try and kick the door. I'm not sure what I'll do to the door. The opportunity to have common sense now with, hopefully, the new FDA to ask this question, "Why do we want to do this to patients? What box do we want to check and why?" Especially since ANKTIVA's approved, Tislelizumab's approved, and dose is approved. If I showed you the pictures of the horrific side effects which we have, which I want to spare you, which was presented at ASCO 2024, the horrific pictures of the side effects of docetaxel, you will ask yourself, "How dare we put patients at risk by giving them this trial?" Yet we're forced to. That's what I'm going to try and knock on the door, kick the door, scream.
I'm hopeful that common sense will prevail with this new administration at the FDA. Any other questions before we close this session? Any questions for anybody? We'll talk a little bit about another checkpoint when we get to the cell therapy, but we'll talk about that. Thank you. Okay. The next one is going to be a treat, Dr. Jennifer Buell and Dr. Lenny Sender. I know you can see him. I'll ask them both to introduce themselves, but maybe, Phil, if you put the next slide up in terms of where we are in this bio shield. Now we move towards the cell side.
Somebody asked this morning, "Could you actually take your cells from your body and grow them?" The answer is, "Absolutely." You will see some interesting things today where we are going to show you something at the end of this session that I think Jennifer is going to see for the first time as well. Thank you, Jennifer, for coming, Dr. Buell. She is one of the most amazing scientists whenever we speak. When you talk about oncology, that is not immunology. You talk about virology, that is virology and not immunology. You talk about radiotherapy. Therefore, these disciplines do not really talk to each other, except when I speak to Jennifer, she talks all these languages in an amazing way. Dr. Sender, you will hear his introductions with us on cell therapy from UC Irvine.
Jennifer, maybe you want to introduce yourself, and thank you for coming.
Thank you so much for those kind words. It's an honor and privilege to be here. I have to first say, congratulations to you and your team for the progress that you have all made. I mean, you're pathbreaking in changing a paradigm in the treatment of oncology that is not only so necessary, but their potential is limitless. I'm just really humbled to be a part of it. I'm Jennifer Buell. I'm the president and CEO of MiNK Therapeutics. For those who do not know MiNK Therapeutics, we have been focused on the development and scalability and delivery of an invariant natural killer T cell. Up on the slide you just saw, the INKT, Dr.
Soon-Shiong mentioned earlier, this is a very unique and powerful, one of the most highly conserved cells in immunity. We've known about it really for the longest period of time. What has challenged the industry is the isolation and scalability of this cell type. We've been able to tackle that through a specific proprietary technology that allows us to not only take the cells from a donor, but then to isolate, purify, and scale these cells to levels that allow us to distribute them and make cell therapy really quite accessible, both in oncology as well as in other diseases of the immune system. What's so spectacular about these cells and the discussions that we've been having together is we have seen firsthand the power of what IL-15 can do with some of the most important cells that were in the immune system.
Not only can they enable the cells to naturally proliferate in vivo, but also the durability and persistence that you see in vivo, actually in a human, actually allows us to see persistence beyond what any available or conventional T cell therapy or NK cell therapy or other therapy can do when you add in the potential of IL-15. We've taken technology to actually leverage this very important cytokine and engineer it to armor our CAR-iNKT cell therapy. It sets ImmunityBio up with this portfolio to actually do some pathbreaking things beyond what you're seeing already. To take a cell, armor it, and have not only the tumor-killing potential, but then also the natural within-human proliferation and persistence beyond six months is something that we have not yet seen before in this space. It's such a pleasure, really, to be here.
Thank you for the opportunity.
Thanks, Jennifer. And thank you all. Thank you, Patrick. I joined Patrick nine years ago. I sort of found my soulmate. I'm from South Africa originally. I did the first transplant as an intern in Johannesburg, South Africa. I fell in love with cell therapy. As a transplanter, we were using horrendous doses of radiation and chemotherapy. I always wanted to get down to less therapy and understood it was the cell. When we talk of immunotherapy, we talk about cells and what can we do. With Patrick and what ImmunityBio is doing, we've learned that we can manipulate all the cells that are necessary for that immunotherapy approach. We can make CARs. We can make memory-like NK cells. We can make some of the newer cells which maybe Patrick will talk about.
We have been able to do this, and we did it at scale. When I joined Patrick, he said to me, "That's a project in someone's lab making one patient dose per week." He says, "You've got to be able to make it to scale because there are thousands and tens of thousands of patients. And how do we do it?" The magic glue was ANKTIVA. We have something really magical. When you add ANKTIVA to cell therapy, we do something that no one else can do with any other type of therapy.
Thank you so much, Lenny. Let's break this down for those. If you look at this cell therapy board here on the left-hand side, this is how we started off with this NK cell line. It's like having a healer cell line. Think about that.
In 1992, there was a patient with a cancer of NK cells, which we then pulled out, and it grew like weeds. We figured out, would the FDA ever allow us to put that into the patient because we could engineer that and grow that, radiate it so it does not become cancerous and inject it? That is what we have done with PD-L1 THANC and CD19 THANC, both in clinical trials. The PD-L1 THANC is really important when it is at PD-L1. It is basically going after a myelo derived suppressor cell. For the first time, not only activating on the left-hand side the killer cells, we had to suppress the suppressor cells. That was the purpose of that combination. That was what we put in pancreatic cancer.
When you see a pancreatic cancer patient, somebody asked early on about the neutrophil-lymphocyte ratio, where the neutrophils are high because they're actually suppressors. We need to go after them with the PD-L1 THANC and kill them. Then the lymphocytes are low. That's why we had to give the ANKTIVA. That combination got a complete response in Senator Reed. We just published now in Oncology, five-year complete free of disease in patients with metastatic pancreatic cancer. She's still around. I want you to understand that this biology works on the left-hand side. It doesn't persist, as Jennifer mentioned. There's this unique cell that has been around for millions of years. I say sometimes 500 million years, 100 million years. If a cell has been around for that long, it's doing something really important. That's the INKT cell.
That INKT cell is a combination of a T cell and an NK cell. That what we call invariant NK T cell can be given to anybody. The opportunity to actually grow that, but it requires IL-15 to stimulate that, here we go again. Finally, you'll see up here a memory NK cell. At the end of the day, the fight of cancer is actually between two cytokines. If you look at the two major antagonists and protagonists, on the one hand is interferon gamma, and the other one is TGF beta. Now I'm getting real technical. If you reduce everything down to TGF beta and gamma interferon, and if you can outweigh TGF beta, which is a suppressor, by upregulating gamma interferon, which is a killer, you win. That's what these NK cells do.
They stimulate gamma interferon and actually upregulate the exposure in the tumor cell and kill. Next slide. When we started this program, the opportunity to create through a single apheresis. This is a very technical slide. I don't expect you to get it. You can pull out this amazing cell in your body called a gamma delta T cell. That is Superman of T cells. You can pull out this amazing NK cell called INKT cell. That's a Superman of NK cells. Then you can manipulate that NK cell to create a memory NK cell. We are doing all three at ImmunityBio, the opportunity to work with our collaborators and do all three through a single apheresis.
However, I said to Lenny, "This is a process, not a product." I said, "We need to convert this into a product." Meaning when I say a product, a vial that you can cryopreserve and keep forever and hang for 30 minutes as an outpatient. Some of you who visit the clinic say, "We've done hundreds of patients like that." Next slide. This is a real picture of what we're doing and how we did it. Now you'll sort of see the improvement of the process. Next slide. Before you get to the video, which we'll hold off, this is all hand-manufactured. Next slide. As you can see, these are your NK cells that were produced from the apheresis. Next slide. Then they're hung as a blood transfusion.
The opportunity for us to create what I call the American Red Cross of cancer, quite literally, cryopreserve thousands of those, either T cells or NK cells. Jennifer was a little more modest about her work. I'm going to ask her to speak to a little bit about what they've done with kids with colon cancer and how they've seen some amazing responses when they combine it with their checkpoint. Maybe you can speak a little bit to that.
Thank you very much. Certainly, as you've heard, colon cancer is a growing disease. We're seeing a substantial increase in incidence, particularly in younger individuals. And we've personally seen very young individuals under 18, 8, 11, 15 coming in through the young onset clinic and requiring intervention. For the majority of these colon cancer tumors, the majority are something called microsatellite stable, the most difficult to treat.
You see that not only are these so difficult, they also are really pervasive. They're highly metastatic, and they typically go to areas that are immune privileged, metastasizing in the liver. What we have established is a combination therapy that's been really quite active. That is taking the invariant natural killer T cells. You can administer them as just a single administration. What we observe biologically, immunologically, through immunohistochemistry, you could see that sort of an immune cold tumor, an immune desert tumor on the slides, becomes substantially infiltrated. You can see that the INKT cells will help to chaperone CD8 T cells across the stroma. They can start to help eliminate the tumor. We combine this with checkpoint modulating antibodies. There are two antibodies that we're working with most often.
That's a standard PD-1 called valstilimab, as well as an FC engineered CTLA4 called botensilimab. The combination of these agents allows you not only to modulate the tumor microenvironment. When you administer the INKT cells, you see the proliferation. You see the trafficking of CD8 T cells into the tumor. You see the activation and improvement of T cell clones, essentially the diversity of your immune repertoire. By increasing that immune infiltration and changing the dynamics of the immune system, you armor essentially your fighter cells to eliminate the disease. We're seeing a substantial amount just by way of numbers. Currently available chemotherapy will give tumor shrinkage in 2% of patients, 2-5% of patients, and disease elimination in 0% of patients. It's a uniformly fatal disease, MSS colorectal cancer.
What we're observing is that more than 25% of the patients actually see their tumor shrink. We now have more than half of the patients alive at 18 months, over 65% of the patients alive at 18 months. We're going to continue to push. Dr. Soon-Shiong made some very provocative statements that I very much agree with, that our regulators really do need to be more open in order to drive innovation in this country. I think with the continued push and the inexhaustible push that the ImmunityBio team is doing, I have a sense that we're going to start to see movement in DC and an openness to getting some of these non-toxic immune therapies to patients as opposed to the chemotherapies that they're getting now. The tolerability profile that the team mentioned earlier is very similar to what we're observing. Patients maintain their quality of life.
There are very limited tox associated, no grade 3 tox associated with the INKT cells. We do see some colitis associated with the FC engineered CTLA4. It is reversible and preventable with TNF alpha predosing. There is an enormous opportunity here. The concept of then addressing lymphopenia in this population will expand the number of responders dramatically, I believe.
Thank you, Jennifer. Before we end the session, I am now going to surprise you with a video. One of the challenges that I really think we cannot afford, we cannot afford a million-dollar CAR-T cell therapy. There is no way that patients who could benefit from it go bankrupt from a million-dollar CAR-T cell therapy. What we have done is begun a very quiet process of roboticizing this technology, which has never been done. Together with Dr. Lenny Sender and myself, we initiated and begun this process.
You know, when you look at Starlink, the little things that you put on top of your roof is now about $200, $300 versus a couple of thousand. Because 100% of that manufactures is through robots. The opportunity to take this very time-difficult manual process of cell therapy, but you could actually software train robots. Let me now show you a video that is in process. The first big robot is about to enter. On the right-hand side is the human. This is the robot pulling out the syringe. You'll begin to see on the right-hand side is what we do with our bioreactors. That's what the robot can do. From a biologist syringe, there's a full robotic operational now. The opportunity to pull out that and train.
All the software will come from us, all the knowledge of how this robot should learn and be taught and have 24/7 and not have a lunch break. You begin to see these are real images of real robots in action. We are connecting bags to machines that currently exist, which really take a long manual process. This is how you do the manual. This is how you do this by the robot. This is how you do the aspiration. There are errors sometimes. Now the robot actually does that directly. This is how we do the operation. You push it in. You look. You wait. The robot does that automatically with results in minutes.
The opportunity for us to democratize now cell therapy and CAR-T cell therapy and NK cell therapy and bring it down the cost, some affordable cost that can actually be actually distributed to the rest of the world is very, very, very real. As I said, the opportunity for our country to become as a foreign policy to bring health to the rest of the world is a real opportunity. I'm really proud that you're all part of that. Thank you.
Thank you so much.
Thank you so much.
The next, I think this call is going to be on the call. Okay. Okay. Next is a little change in direction, Tim, where we're going to talk about something that, if you don't mind, Tim, I'm afraid it's just you and I now. There's no callers.
No, I'm here. I'm here.
There yo u go. There we go. Fantastic callers. If you have a seat, you can see me.
Yep.
It's a talk about long COVID. And this has been percolating, unfortunately, with us at ImmunityBio since the onset of COVID. Let me give you a little bit of perspective and history. What's happening? Okay. Whatever. The history is that when COVID occurred, it was around November 2019. I recognize it by understanding this virus. As I said, it was a very painful moment because it was exactly around the time that Kobe Bryant passed away. We had a funeral session where thousands of people were together. I was standing next to, sitting next to Gavin Newsom. I said, "I'm worried about this virus because it's different. It's not a respiratory virus. It's a systemic virus.
It's a virus that actually has, at the tip of its spear, the ability to go into every blood vessel. It has at the tip of its spear to go into your brain or the blood vessels of the brain. Carlos and I looked at each other and we said, "We have to write a paper." We did. We published a paper together. Dr. Cordon-Cardo, which I'll have him introduce himself soon, and Dr. Tim Henrich soon, that COVID is cancer and cancer is COVID, what does that mean? That if we make ourself aware to understand COVID, that it would penetrate every blood vessel and it's a systemic disease, we need to think of it differently. Most vaccines are given in vaccinology as an antibody-based vaccine. The antibodies block it, but doesn't clear it.
The key to everything was clearing the virus from your human body because the hallmarks of a bad virus is its persistence. We will talk about that with Dr. Henrich. If it persists and does other things, which is scary by acting like HPV or hepatitis, there are only seven viruses that cause cancer. The way they do that is you and I, we all have in our body a thing called P53. If it knocks out P53, it knocks out your protection for cancer. There is a thing called RB. It does the same. There is a thing called MHC-1. If it knocks out these three things, it is a hallmark. This is not a downer call because we have harbored this for four or five years quietly between myself and then PolyBio and Amy Proel and Tim and the team.
Because unless there's a therapy, potential therapy to overcome that, we would create such an alarm that there'd be panic. As I said, when we went to Henry Jackson Foundation and the thought leaders of the country said I should publish it, we still haven't published it. We will soon. I wanted to use this opportunity to expose this from science that we haven't done. It's somebody else's science. That's what this session's going to be. Tim, if you may want to introduce yourself and thank you for coming.
Sure. Thank you so much for the invitation to come and have us talk about our work. I should mention I'm a professor of medicine at University of California, San Francisco, just up north. Just as an aside, I'm also a physician scientist.
I take care of people with cancer who develop severe infections in the setting of chemotherapies, radiation therapy, etc. Profound cytopenias, including lymphopenias, can lead to very, very pervasive systemic infections, viral infections, fungal infections. My team is not the team that a cancer patient wants to see when you're in the hospital. This means that there is a problem because of the treatment for cancer. That is just an aside off that. In my day job, I'm a virologist and a viral immunologist. I have been studying for about 20 years now how chronic viral infections impact immune health, impact human health, and how we can harness the immune system to really clear out and resolve chronic viral infections. As Dr. Soon-Shiong was saying, there is a tight axis between chronic infection, tumor risk, and cancers.
A lot of cancers are actually viral related. That is something that we are very interested in looking at going forward.
I met Tim when I was introduced to Dr. Amy Proel. She runs a PolyBio non-for-profit institute that we support to really ask this question. I got into the first Zoom call with everybody and amazing scientists that you support across the country. My heart sank when I started hearing your talk about two years ago, which now just got published. I want to ask Tim maybe to present some of those slides today, the implications of those that has now got published. The implications of what you have then found and your colleagues also found of what happens with NK cells in that circumstance. Tim, could you take it away with the first slide?
Before we do that, let me introduce Dr. Carlos Cordon-Cardo, who's som ewhere. There we go.
I'm here. I'm here. I'm just following. I have been here almost all of the time. Congratulations on a wonderful, high-energy positive way.
Dr. Cordon-Cardo, Carlos, could you just maybe introduce yourself, what you do, and where you are? First and foremost, pathologist at Mount Sinai.
Yes. I'm Carlos Cordon-Cardo. I'm the chairman of the Department of Pathology for the System of Mount Sinai Health, which is one of the largest in the East Coast. Before that, I was the vice chair and the associate director of the cancer center at Columbia University. Before that, I spent over 20 years between Cornell and Memorial Sloan Kettering, where we essentially were one of the groups that founded what we call molecular pathology.
At Sinai, during COVID, we were pretty much at the epicenter of the disease. We were able to very rapidly produce detection methods as well as stratifying the disease. We have been very worried about what we have been finding and how we are following our patients. We will probably talk more about that during this dialogue. Thank you.
Thank you, Carlos. We will ask both Tim and Carlos to present the data. We will have a discussion about what happens next. Tim, over you go.
Sure. Just the background, we were studying mostly chronic HIV infection and how people living with HIV have immune dysfunction chronically.
What we were noticing in people that were recovering from long COVID, and we actually started this cohort back in March of 2020, when we saw the initial cases from outside the United States, was that this infection, so COVID-19 or SARS-CoV-2, is not your standard RNA virus respiratory infection. It was profound lymphopenias, profound immune dysregulation, and obviously quite a bit of morbidity and mortality in folks that have immunocompromise or immunosenescence and advanced age. We thought that there was definitely going to be something about this virus that was not just going to resolve quickly, that there had to be some type of long-term implications of having SARS-CoV-2. What we noticed is actually back in April, May of 2020, we had participants that we had enrolled right after acute infection, so two to three weeks later, but they were not getting better.
Three, four months later, even up to five months later, we had people that were Division I collegiate athletes that could hardly walk up a flight of stairs without getting winded or just profound fatigue. We had people with neurocognitive issues, with GI issues, with cardiopulmonary symptoms, with orthostatic hypotension, and you name it, just a lot of different types of symptoms. We started to say, "What's going on with the immune system here in people with long COVID?" We took a deep dive. We started to identify that people that had these symptoms had elevations of chronic inflammation, things like IL-6 or other cytokines that really suggest that there's some kind of chronic persistent trigger of that immune system over time. Not only were people revved up and inflamed, but they also had a dysregulated immune system.
The T cells, for example, the cytotoxic T cells were exhausted. It was dysregulated with antibody production and the helper CD4 T cells. They just were not working together in concert. That told us, "Okay. The T cells do not seem to be normal." This was even six, seven, eight months later in people who had mild to modest infection, did not require hospitalization over time. We said, "What about the NK cells as well?" Because we know that NK cells are really this, as you are saying, this first-line defense or shield, this immuno shield for the person.
We noticed that certain types of NK cells—so this is the phenotype or type of NK cell that is cytotoxic, that it's able to go and to kill these cancer cells, to kill viral-infected cells—were actually significantly lower in people that had long COVID versus those that had full recovery and even lower than what we saw before the pandemic as well. That actually seemed to be worse. They even had lower levels, the more symptoms and the more symptomatic a person was at that time. That gave us a lot of concern that if you have an infection that now leads to chronic immune dysregulation, T cell exhaustion, and low cytotoxic NK cell function, what's going on and what could be the implications for human health?
I can also say that there are certain signatures that we see in viral-related cancers, which include chronic inflammation and immune dysregulation that can actually allow cancers to persist and to metastasize and to grow. Unfortunately, we are starting to see a bit of the signature in our immune system that we would see in some of these viral-related cancers as well. Again, I do not want to be cause of alarm, but I think this is something that we need to be aware of and we need to study. That is exactly what we are doing at Deep Dive.
If you look at the hallmarks of this oncogenic virus, persistence is one of them.
That is right.
Replication, persistence, loss of RB, loss of P53, loss of HLA-1. Let us talk about your findings on persistence.
Sure.
One thing that we also noticed over time was that people were not able to clear the virus from their immune system. When we started looking before, five, six months, up to two years after initial infection, this is in a cohort before we saw a lot of reinfection, which we're now seeing as well. This is for people infected early on and then, say, two years later. We were actually seeing in, for example, the gut immune cells, so myeloid immune cells in the gut, dendritic cells or macrophages, we were seeing actual viral persistence. Not just virus itself, but we were seeing some of the RNAs that are made during replications, these double-stranded RNAs of the virus itself. It was not everybody, but it certainly was in some people up to two years after their initial infection were still in persistence as well.
Are there any of these slides filmed that you could speak to maybe?
Yeah. What we're seeing here is that if we look at, for example, different types of T cell sets, this is a lot of science up here on this slide, so it's difficult to distill down. I think what we're seeing normally is that cell types that are lower include different types of T cells that are either trafficking to tissues, for example, where they're needed to have antiviral effect, or they express immune checkpoints. These are exhausted T cells. Why do T cells become exhausted in the setting of infection? You need to have chronic antigen persistence that drives those cells to try to proliferate over time. Over time, they just get exhausted. They become dysfunctional.
That to us is a clue that there is also ongoing viral presentation in some of these participants as well. That's a lot of detail for that one summary right there.
The final slide I think we have here. I think what you're basically saying then is there's not only persistence. You actually can image them. You've actually biopsied them. You've biopsied not the tumors. You've biopsied the colon.
That's right.
You've seen it replicate. It's not on the surface of the colon. It's what we call the lamina propria deep inside the colon. Deep inside, yes. I think, and the good news from the perspective of where we go next, it's clearly important to go clear those cells, to move those cells from your body that are infected.
They can be recognized by NK cells if the NK cells were actually active rather than dysfunctional.
That's right.
Is that a fair statement?
Yes. What we've been finding in our, for example, our gut tissue studies is that where virus persists, there's actually exclusion of these cytotoxic cells, whether they're NK cells, cytotoxic T cells, or at least the indication that they are. We're seeing genes being transcribed from the host immune response that actually allows virus to potentially escape some of this cytotoxic killing. What this does is creates, at least our hypothesis is, a downward spiral. You have an infection that causes chronic inflammation. At the same time, it's also evading immune clearance by these cytotoxic cells, the NK cells and these cytotoxic T cells.
Onctiva was the natural next extension: "Why don't we rev up those cells or reactivate the cells that we need to finally clear out chronic viral persistence within these deeper tissues throughout the body?" That is just starting now.
What you just described as a virologist sounds like a cancer doctor, actually. When you say, "That's what we mean by COVID is cancer, cancer is COVID," because cancers behave the exact same way. You have these cancerous cells that have found amazing ways to immunosuppress the surrounding cells, even though they exist, your NK and T cells, which means there's a lot of TGF-β around myelodyrex suppressor cells, which, by the way, is the hallmark of well-established science. That's what the COVID virus does. The COVID virus has found a way to stimulate immunosuppression. You agree with that?
I would agree with that 100%, yes.
Okay. Now we have an agreement between a cancer doctor and an immunologist and a virologist. Let me ask you, what would the pathologist find? If I can then turn to this, "If it walks like a duck and quacks like a duck, is it a duck?" The question is, if it persists, it immunosuppresses and replicates. The next question, if I go to the next slide, is, does it block or inhibit the production of your P53, which is your protective gene from cancer? I read somewhere, I don't know if it's true, but I think it is, that elephants don't get cancer because they have eight P53s in them. Imagine if you have zero P53s in a virus that immunosuppresses and protects and persists. This is where Dr.
Cordon-Cardo and I have been working quietly, not only in patients with long COVID, but also in the autopsies, what you call warm autopsies, where you try to find and extract out the COVID virus across all the tissues. More importantly now, discovering COVID virus in cancer tissues. I wanted Dr. Cordon-Cardo, we have not published this. We are in the process of putting together the paper. I think it was so important that we had this opportunity for Dr. Cordon-Cardo to now present this.
Yes. Thank you, Patrick. Thank you all for allowing me to be here today. The reality is that, as Patrick was mentioning, COVID has a lot of the landmarks of cancer. When we think about and we talk about metastasis, we think about tumor cells. As we teach medical students, the term metastasis means a colonizing at distance.
That's what some bacteria and viruses do. They may enter into your nose, into your larynx, but then they go into your lungs. In the case of SARS-CoV-2, travels through the blood vessels, can colonize even the blood vessels, and go into different organs and produce systemic disease. In that context, together with Patrick, we published a paper in Cancer Cell, doing the staging and talking about the similarities between COVID and cancer. May I have the next slide? Over the study of many autopsies, we were one of the first groups that published the largest series of autopsies during COVID, over 100 autopsies. We learned a lot.
We were the first to identify the virus both by electron microscopy and a special technologist in different tissues, including the endothelial cells of many organs, including the endothelial cells of the brain, which can explain for the brain fog that patients have and that, unfortunately, some of the long-haulers also complain. Interestingly enough, in some of the autopsies of COVID and post-acute syndrome of patients, we are seeing by bulk RNA sequencing on tissues from these rapid autopsies, as Patrick was revealing, the presence of viral RNA across many different organs.
Not only that, the sequences are present, but in some of the instances, the amount of high viral RNA that maps into some of these organs reminds us of some of what we have seen in the very acute response of some of the patients when we were able to do even quantitative assays, such as quantitative PCR from nasopharyngeal swabs that we were taking. This is a small summary of many different autopsies. As you can see, viral sequences have been obtained from many of these patients. In specific cases, as the diagram on the right side, you can see that it's in multiple organs. It's in the lung. It's in the lymph nodes. It's in the intestines. It's in the several spinal fluid. It can be also in the brain. These put us at a different momentum.
Since then, we have done many more autopsies and produced similar data. What we are observing is that in some of the post-acute syndrome, some of the long-haulers, some of the TACS patients, the autopsies that we see these days are extremely complex. These patients, many of them relatively young, come with a great deal of organ failures affecting many of the tissues that in the past we did not see as affected. May I have the next slide? One of the things that we have been able to also discover as identified in this slide is the fact that when the virus gets into cells, it promotes the downregulation of critical tumor suppressor genes. As you can see in the slide, after just 24 hours of infection, the main antigen presenting system, the HLA-plus1 antigens, disappear.
As you can not see a band in this upper site on the screen. That makes the cell escape immune surveillance, making the cell almost like a phantom. It's not recognized by the immune system. Almost at the same time, after 24 hours later, both P53 and later on RB are also downregulated. P53 allows the cell to escape mechanisms of cell death. Now you don't have just a phantom. You have a cell that can become almost like immortal. By the way, individuals that are born with a deficient P53, 100% of them develop cancer, and many of them during their youth. When we also realized that RB was also deleted, which is a critical molecule that controls cell division and cell proliferation, it allows the cell to keep growing and to produce this kind of overt inflammation and disease.
Based on these concepts, may I have the next slide? We also observed that critical pathways of chronic inflammation were very much upregulated on the contrary in some of these organs: the blood vessel development, the cell activation, the cytokines. Next slide. When you put all of that together, it has allowed us to postulate that SARS-CoV-2 infection may promote in the long term cell transformation and tumorigenesis by two possible and not necessarily mutually exclusive mechanisms.
First, the persistence of this viral infection, or at least the expression of some viral proteins in specific tissues, may allow some of these oncoproteins or part of these proteins to sequester some of the tumor suppressor genes, such as the human papillomavirus or some other virus proteins that will produce that inhibition of HLA, P53, and RB, allowing the cell again to be a phantom, to escape mechanisms of cell death and to keep growing. At the same time, since these proteins and this damage is persistent in many tissues, it produces a chronic inflammation that also promotes cell proliferation, which has been shown to lead to cell transformation.
This mechanism, it's also well known, for example, in human hepatitis, where after major repetition of the infection or the persistence of these foreign proteins and these viral attacks, we produce a response that is also the very beginning of a transformation of cells and the development of a tumorigenic mammalian phenotype. Based on all of these things, we postulate that the possible role of SARS-CoV-2 in facilitating tumorigenesis and definitely producing a very persistent and difficult chronic disease in the so-called COVID long-haulers, implications that would be important for our community at large. As we were saying, we don't want to produce an alarm. There is a difference between alarming and alerting. Alerting is sharing some data based on real findings and knowledge that allows us to take the next steps. Thank you.
Thank you, Carlos.
Maybe I would like to sort of just explain a little bit. If you go back to that slide, sorry, just because I think I saw this work about two years ago, Carlos. I think we looked at this together. And it truly scared the pants off me. I really mean that. What he's saying is completely right. We don't want to alarm, but we do need to alert. The opportunity for us to get prepared now, you talk about national preparedness. When you talk about a pandemic, this is the potential of a pandemic to happen. I don't know how many people have gotten COVID in the country or in the world, but billions, maybe. If you look on the left, on the right-hand side, when you see on the corner, you see P53. You see that blank. You see RB.
You see that blank. You see MHC1. You see that blank. That blank occurred on the left when you took a cell and you infected it with the COVID. This is real fundamental biological data. We are now testing these in people. That is why I say there is correlation of this biological work where we absolutely know of the immunosuppressive activity of a COVID virus combined with persistence. If you look at that thing called HPV above there, that is the alert. Is this an HPV cause like an HPV virus? Is it oncogenic? Just like you have Gardasil that actually prevents you from getting HPV, it does not prevent you from actually curing cancer when you have HPV. We have a trial now with adenovirus targeting HPV T cells so you can get a T cell to kill the HPV-infected cell and clear that.
Tim, you want to speak a little bi t about I think we can talk about the clinical trial.
Sure.
To start, you'll have an inundated request. I'll give you your home number. It'll be all good.
Yes, yes.
I think what's important about us starting with Tim was he has this ongoing temporal follow-up of people who didn't have COVID now have persistent COVID and can be cleared of the virus. If you want to speak about that.
Sure. Yeah. To put this in perspective, a conservative estimate from the New England Journal just a few months ago or half a year or so ago was about 3% of the U.S. population has experienced long COVID symptoms sometime after SARS-CoV-2 infection.
That may not seem like a lot, but we're talking 3 out of 100 people, millions and millions of people just in the U.S. alone. What's interesting is not only are we seeing viral persistence in people that have symptoms, but we also see some viral persistence in up to about 8% of people without symptoms after COVID. That suggests that even without long COVID symptoms, people could potentially be harboring chronic virus over time. That obviously, again, I don't want to be alarmist, but this is something that we need to think about. Even is there some silent long COVID or some type of long-term health impact to quite a significant part of the population over time? Again, not to be alarmist, but I think it's something that we need to think about and to do this.
We have been running what we call the LINQ study at UCSF. We now follow about 1,400 people longitudinally every four months. We check in. We do symptomatic questionnaires. We do blood testing. We look at gene expression levels. We look at proteomics. We look at inflammation. We biopsy guts. Not all 1,400 people, but we do gut biopsies. We do bone marrow biopsies now as well because from PET imaging, we have seen dysregulated T cell activation in bone marrow. That always has caused concern. We have actually just performed our 22nd bone marrow biopsy in people with and without long COVID. We do lymph node biopsies as well. We do a whole non-invasive PET imaging center. What this does is allow us to do these pathogenesis-focused clinical trials where we can take a drug like ANKTIVA.
We can give it to people that we know have essentially life-limiting long COVID. Not only can we follow symptomology over time, but we can do a really deep pathophysiological dive. What's happening? Can we improve our inflammation profile? Can we reduce viral persistence? Hopefully, we'll see a reduction in some of these escape mechanisms that the virus has enabled the cell from escaping immune pressures as well. These are things that we're very keen on doing. We've already ran about three or four other clinical trials of antiviral, monoclonal antibody, and some other modes. This is the one that we're super excited about because this is what we see in the data so far. We see reduced cytotoxic NK cell reaction. We see dysregulated T cells.
This is what we need to fix in order to clear out virus and to prevent some of these downstream changes potentially from occurring.
I can't tell you how. First of all, thank you for that insight. You bothered me even further the first time I heard about bone marrow T cell dysfunction, which drives me up the wall now. Having said that, the sad news and I'll just say it again. In an email in March, June 2020, I announced this to the NCI and NIH that we have lymphopenia and could we try ANKTIVA in combination or separate from remdesivir because antivirals don't actually stop this problem. Antivirals may reduce the load. It doesn't clear the virus. I've been singing this tune about we need to clear the virus since 2020. For whatever reason, we won't go into that now, we were denied.
I think this is when I think where I needed, I think there's a moral obligation for us as a company, frankly, even to speak out, even though that's at risk, that we need to actually prepare for the human race, actually for the country to actually have a solution. It needn't be our solution. It needs to be anything that can clear this virus from your body for whoever has it still in their bodies. We don't know, as Tim said, how many people have it. We do know 16 million. That's about roughly the number of long COVID. With that uplifting presentation, there is hope. I really mean that. That's why we were willing to come out now, even though we've known of this data for two and a half years, three years, to speak to the fact that there is hope.
We need the country to come together, the agencies to come together, whether it be NIH, NCI, CDC, the FDA. With that, I'll open this to questions. I hope or maybe there are some questions. Tim, maybe Tim and Carlos, you maybe have a last comment before you take some questions.
Yeah. I just want to mention that, again, it has taken us over two years. We kept repeating these experiments with different cell lines, looking at different tissues from different patients. We have not published because we wanted it, again, to make sure that we were not going to alarm but that we were going to alarm. This is very robust data.
Again, together with the complexity that we are seeing in some patients, the complexity in the autopsies that we are doing, and in some patient populations, an increase in the presentation of cancer mainly in the young people makes us feel that this is time to, again, be alert and make sure that we can use the tools that we have at hand for early detection as well as for the treatments that will allow us to really clear the virus rather than just waiting to see other developments. Thank you.
Yeah. I would just say that this is a big unknown. We don't know what's happening. This is the time where we need to study. We need to investigate. We need to try novel ways of purging chronic virus. Hopefully, that will restore human health over time.
What we've seen already just from our imaging studies is that we've entered a new immune set point post-COVID. If we look at scans that we did before COVID for other reasons, control groups versus those after, they're different. The T cell activation states are different. We've reached a new population set point. We don't know what that means in terms of human health. It's really urgent that we look at that and we understand how dysregulated T cell or even NK cell function is will impact us over long periods of time.
I think you sort of hit the nail on the head about a new immune set point. I mean, I don't know if people really realize what you just said is so profound.
If we as a nation have hit a new immune set point, all I can say, I hope this administration understands of all the programs that they should actually support people like Tim and Carlos. It's really doing, I think, amazing work with regard to understanding this long COVID. We really need to not only prepare but really figure out how we can actually change that set point to the immune system because NK cells and T cells do matter, as I said. With that, are there questions?
I think we see thank you, Patrick, for being this very patient to compelling presentations. A question for Tim and for Carlos. Tim, do you know if there's any correlation between your clinical descriptive phenotypes, the immunological changes you've found, and the epithelial biological and the molecular changes that Carlos has described? Is there a trifecta of all three?
I mean, I should put the triad together as it were.
They're certainly interrelated. I think it's difficult to pick out specific, for example, clinical symptoms or phenotypes that correlate with specific immunologic phenotypes that correlate with specific gene response phenotypes and cellular host viral responses. We do know there's a very close connection there. I think understanding what that is is very difficult, partly because it's such a heterogeneous disease. There are heterogeneous presentations clinically. It's difficult when we're working with patient surveys and interviews that there's a lot of variation in that setting. I think the overall finding is that regardless of the symptoms that people have and we have seen, for example, people with neurocognitive symptoms or cardiopulmonary symptoms do tend to have, for example, more EBV reactivation, different types of inflammatory markers. There's a lot of crossover.
There’s a lot of the Venn diagrams are very overlapping, I guess you could say, in that setting. We do know they’re related. I think we really need to parse out what those are. Again, the common themes are immune dysregulation and the failure of the immune system to really purge viral-infected cells that may be there.
I think the question from Carlos was, have you seen any morphological changes in epithelial cells that you looked at when you’ve seen the molecular biological changes? Is there ways they are changes in differentiation? When you look down the microscope, being famous as a very typical pathologist, do the tissues look funny?
This is what we are doing right now. I mean, we are moving from the profiling of autopsies to start also looking at biopsy tissues.
As has been discussed, I mean, there is a lot of overlapping. At the end of the day, with numbers and in-depth analysis and with the new technologies that we have at hand, I think that we can really start unveiling some of these mysteries. I think that it would be very important for the good orchestration of clinical trials addressing this patient population, which is going to grow with time for sure.
I think the question is, Carlos, do you start seeing dysplasia and aplasia and adenomatous changes in polyps?
In some of these tissues, mainly, we have seen that. It will be now important because with the autopsy, essentially, you are capturing just a moment in time. It is at the end of a life and a journey that has been also very much hampered by many other developments.
I think that what we are seeing now, and we've got the right studies, is to do it more on a time frame and start looking at biopsies. We need the resources to do that well.
Yeah. I mean, anecdotally, we have seen, for example, B-cell clonal proliferation in bone marrow in people with long COVID. Whether that's a normal finding that we can see in the population of background or not, I think we need to wait to see. I don't have any definitive statements on that. We are now going forward, actually, with PolyBio support.
We're finding all kind of new incident cancer cases, especially in younger folk, and enrolling them in our LINQ study to try to do a really deep pathophysiologic dive to understand if there is a viral persistence and if there are immune response similarities between long COVID and what we're seeing in some of these tumor folks as well.
I know what I'm going to put in my paper. The cells look funny. So
I want to thank the eloquent presentation. More of a comment than a question. I think for me, as a cancer physician, what is truly striking is hope. The hope that answering these key questions, especially with COVID as a model system, will finally unlock some of the key questions we have about HPV, about its treatment for head and neck cancer, for cervical cancer, being able to use this potentially to target nasopharyngeal cancer and EBV. These are the things that have bothered you. Patrick talks about the things that keep me up at night, right? These are the things that we know that people get cancers because of oncolytic virus, and maybe for the first time we can bite back. Thank you again for your work.
Thank you. Thank you very much for your work.
Thank you.
Thank you, Heath. That sets up us. Thank you for that question because that sets up perfectly for the next session because it is virus against man. You know whether you get infected or whether it causes cancer. If we are going to bring up Dr. Sender, I think we have—let me see if he is available. Oh, good. Dr. Tewari, Krish, you are going to talk today about ovarian cancer, and we will also talk a little bit about the HPV, virally induced cancer. As you know, ovarian cancer, sadly, is a very devastating disease because it is really picked up late from a symptom perspective. Again, we will share with you some data that is very exciting if we can pick it up early. Maybe, Krish, if you could introduce yourself and thank you for attending.
I know you had patients today, so you couldn't be here, but thank you for coming on the Zoom.
Yeah, I'm really happy to be here and to see everyone virtually. My name is Krishnansu Tewari. I'm a professor at UC Irvine Medical Center, and I'm a gynecologic oncologist. I take care of patients with advanced ovarian cancer, newly diagnosed and recurrent metastatic cervical cancer, and endometrial cancer. Those are the three main types of patients or main types of cancers I take care of, and I've run clinical trials in all three of these diseases. I'm really honored to be part of this discussion today.
Let me put up the first slide on really where we're going, and this to tell you about the opportunity. If we think of this as a bioshield where, for example, you could use the adenovirus to teach a cell that can go after HPV. You can use ANKTIVA to activate your body's NK and T cells, and you could even use PD-L1 CAR NK to actually kill the suppressors and maybe an MSANC. That's this not crazy combination, but it is really just basically an in vivo and ex vivo lymphocyte rescue that you could see at the bottom. If I may, we had the privilege of looking after a patient that we were made aware of that was about to get surgery for ovarian cancer in the Finkel CA1225. If you can put up that slide.
The patient came to us in October 2024, and you could see her levels as 477 or 502. She is a Kaiser patient. I picked up the phone and we called the Kaiser doctor and said, "Look, we know what your standard of care is. It's going to be carboplatin and Taxol. That's the standard of care. You go do surgery. Now, Taxol will require steroids. It will wipe out the lymphocytes. Carboplatin will create ANCs or neutrophils. That's fine. I think you're going to need to do that. Would you then allow us to bring the patient into our clinic?" Dr. Sender is here. We wrote to the FDA what we call a single-purpose IND. She came in on the 5th of November, got ANKTIVA, and then you see that.
By the 26th of November and by the 10th of December and just by Christmas, completely undetectable. You see by the 23rd of December. Interestingly enough, she not only had CT scans but physical exams, and they could not palpate this tumor, which they could easily palpate before. By the time she had the surgery on February the 7th, there is a 98% drop in her CA2 levels down to undetectable levels. She had the surgery. She had circulating free DNA tumor cells present in the blood, and now they are not detectable. I want to share with you this possibility just as I shared with you in the prostate cancer patient. We get them early in the neoadjuvant setting. There is a real opportunity to change a paradigm of cancer care. This is all done as an outpatient. All as an outpatient.
With that, next slide. We want to start a protocol, and this is the protocol I'd like Krish and Lenny to discuss where we'll be addressing this in ovarian cancer. Krish, maybe you can take it away and your thoughts on ovarian cancer. He's a little modest. He's the foremost thought leader in the country on ovarian cancer. I think you're hearing truly the foremost thought leader in ovarian cancer. Go ahead, Krish.
Thank you for that. I wish my mom was alive to hear that. That patient that was discussed, Dr. Sender and Lenny had contacted me in the fall last year about this patient, and I was thrilled to hear that she was able to get this novel treatment and did so well. The reality is most patients are going to respond to neoadjuvant chemotherapy prior to surgery for ovarian cancer, but the response is not as dramatic as what you saw on the CA125 biochemical profile in the previous slide. That was remarkable. Further, to have the circulating cell-free tumor DNA go to zero, it's just not, it's unheard of.
Again, it's an N of one, and that's why this study right here, which seeks to enroll up to 40 patients, is going to be important because it needs to be, it can't be emphasized enough that the majority of women with advanced ovarian cancer die of this disease. The percentage of patients with advanced ovarian cancer amongst all ovarian cancer patients is about 90% because, as you've heard, there are no early symptoms for this disease, and there are no validated screening tools. The vast majority of patients have advanced disease. They respond initially to chemo. They undergo surgery, but invariably the disease returns. Studies like this, this treatment schema here, it's like a phase II design in a sense, up to 40 patients.
They get a neoadjuvant treatment period where they're getting standard of care with nanoparticle albumin-bound paclitaxel and carboplatin along with study drug, and then undergo cytoreductive surgery. Now, these patients at the time of interval cytoreduction undergo intraperitoneal therapy, which is not really standard these days because we've just not studied the right drugs to give intraperitoneally. All our studies have come out negative. Again, here we're doing something unique and novel. Intraperitoneal therapy, whether it's heated intraperitoneal chemotherapy or just straight IP therapy that's not heated to 41 degrees, scientifically and mechanistically should work, but we just haven't had the right drugs. I think this study has an opportunity to study the right medicines to be able to deliver on the promise of IP therapy. There's a lot of stuff going on. Following that, the adjuvant period cycles four through six.
You can see the schedule, the sequencing of the medicines. After that, there would be a maintenance phase, maintenance therapy. It's not on the schema, but the maintenance phase is dictated or predicated on the genetic profile of the tumor. Patients with BRCA1, BRCA2 germline and somatic mutations, they can be placed on maintenance PARP. If you have non-BRCA germline somatic mutated tumors, but they do show evidence of homologous recombination deficiency by virtue of loss of heterozygosity, large-scale state transitions, or telomeric allelic imbalances, they can go on to receive maintenance therapy with PARP inhibitor plus bevacizumab, which is our anti-angiogenesis drug. This is a unique opportunity. It's not being done anywhere else. This is a novel drug. It's using standard of care treatment and also doing it reflects what's being done in the community.
Most patients do get neoadjuvant chemotherapy, but the idea with the IP therapy portion at the developing surgery is also really takes us to the next level, and it's a very promising trial.
Thank you very much. Let me, if I may, show you why this is not only novel but not crazy. If you remember, I said one of the things we needed to do was to expose the tumor. And the BRCA1, which we develop in carboplatin, given at a low dose, stresses the tumor so it exposes its surface. Once it exposes its surface, the ANKTIVA with the NK cell and T cell can recognize the tumor and kill it. But the tumor then does something against that. It sends out the suppressor cells to suppress these NK and T cells, and this PD-L1 CAR NK kills the suppressor cells. And this Cytokine, which is now in phase II, suppresses the endpoint of TGF beta of the suppressor cells. There is a real biological rationale on this protocol. It's not, let's throw something at the wall and see what happens.
This is the same protocol that we use for pancreatic cancer, glioblastoma, other drugs, other tumors, because whatever you use, whether you use SBRT, ultrasound, whatever you use for low-dose chemo to expose the tumor, activate your killer cells, suppress the suppressors. It's really what you need to do. I want to call that a sort of a full circle of why this is not some combination that is not rational, which is another challenge. Which of these cells don't you want? An NK cell, a T cell? Which of the cells don't you want to suppress? The myeloid-derived suppressor cell? And which tumor don't you want to expose? That's what I need to now bring to the FDA. I'm so grateful because the RMAT that we got approval for actually allows the concept of these combinations.
With that, at least, Krish, I want to thank you for taking your time to come and see us. Dr. Sender has been working on this PD-L1T HANC that we spoke about at the last session. I think, are there any questions to Dr. Sender and Dr. Krish before we sort of wrap this session of FISI chats up?
I don't know if you want to mention Krish about the HPV because it's in the cervical cancer.
Oh, okay. Krish, maybe we're going to talk about that then on the cervical cancer that you're starting that trial now. Have you started a trial?
Number one is we have this trial just about ready to go, Krish, so you'll be getting the final drafts of this protocol. Also, the HPV, we've done the phase I of our adenovirus HPV, and the data looks really good. The safety data looks excellent. Clearly, and since you're one of the leading experts on cervical cancer, there's about 500,000-600,000 women who get cervical cancer from HPV. We also know the head and neck cancers with HPV and the anal cancers from HPV. You and I have been talking about the next study and follow-up on the Lynch syndrome where the addition of N-803 ANKTIVA plus our adenoviral vaccines is so powerful in the BioShield. We thought that this would be perfect for the cervical cancer.
I don't know if you want to just comment on cervical cancer and sort of the paucity of opportunities for women these days once it's recurred.
You're on mute. Sorry.
You're on mute.
Yes. Cervical cancer is a very important disease. HPV still creates a disease of epidemic proportions. 600,000 new cases globally, over 360,000 of these women die. This is a disease that really affects young women when they have small children at home, women that may be in the beginning of their professional careers. It is a very, very tough disease. We have made some progress. Anti-angiogenesis therapy and checkpoint inhibitors have improved median survival in patients with recurrent and metastatic disease to about 24-25 months. Still, two years is really not enough time for these relatively young women. The advances we have made in first-line recurrent metastatic therapy have created a new population of patients that comprise a high unmet clinical need, and those are patients in need of second-line therapy. Right now, we have an antibody drug conjugate to sotomethidone that is FDA approved.
This is a medicine that the objective response rate is about 17% in the second-line setting. Not great, but it's been approved because we really don't have much else. Most patients will have been PD-1 checkpoint exposed, at least in this country. Re-challenging them with checkpoint is not going to be feasible unless we add something to the mix. The protocol we've proposed is to use a therapeutic HPV-16 vaccine, combining it with checkpoint inhibitor. It could be nivolumab. It could be another anti-PD-1 antibody. Testing them in patients that have progressed on chemotherapy plus pembrose, i.e., those patients that are in need of second-line therapy.
This adenovirus HPV vector is really a therapeutic vaccine, which is likely to not just cause tumor shrinkage, like for example, the antibody drug conjugate Tisotumab does, but maybe even move the needle forward and maybe even improve survival because at the second-line setting, there are very few options. The other options that may be available, if they're HER2- positive by immunohistochemistry 3+, they could get Enhertu. Response rates are good with that antibody drug conjugate. Again, the responses are short-lived. Patients who respond to first-line therapy but relapse and need second-line therapy, invariably they're going to die. I think this is an opportunity to study the therapeutic vaccine together with checkpoint inhibitor in these patients in need of second-line treatment. These are young women. It's a high unmet clinical need and an opportunity to do some good.
Thank you. Thank you very much. I think really you keep on hearing this word of short-lived. When you think of antibody drug conjugates, which has become another sort of hot potato or hot toy, whatever you want to talk about, it's just another chemotherapy. It's really a chemotherapy that's attached to an antibody. If a chemotherapy gives you the short-lived, which then takes us all the way back to the beginning of the talk, we've got these assumptions that are embedded with us for 50 years that we have to go chemotherapy, radiation, checkpoints. When you do that, you actually almost with certainty push yourself into short-lived responses. You think about that, which is exciting now through this activation of all this. Thank you, Krish, for calling it a therapeutic vaccine. We now have to call it a bioshield.
I saw that on the slide.
We have this opportunity to really go from long-lived to long complete responses, whatever you may call that. That may even be the cure if we get the younger people early on. Thank you so much for attending, Krish. I appreciate that very much, which I think closes this FISI session. Thank you, Lenny. Which answers it takes us to the closing now. If I can then summarize and ask first of all, Rich to give his little report, and then if you can come up here, Rich, and we can talk full about the bioshield if you can put that up, the first slide. Go ahead, Rich.
Yeah. First thing I want to do is just thank everybody for being here. I know it's been a long day, but I think you probably saw there's a lot going on. Anytime you stop and think about this, the first thing I always want to do is I always want to thank the patients and families, whether it's on the commercial side or whether it's on our trial side. It's never just the patients, the patients and their families. I heard the word hope at least a half a dozen times used today. It's not just hope. It's the realization. I also want to take time to thank all of our investors and analysts for being here. I know that there's a lot of you that came in in person. We had over 1,000 that were online throughout the day.
That takes a lot of real effort, and I appreciate you to actually show up and do those. I want to talk specifically to the employees now. Working at ImmunityBio is not a job. It's not a career. It is a true calling because I know there are a lot easier places to work because we literally work seven days a week, and we are working for one reason. It is this man's mission and vision right here. I really want to thank Patrick. Patrick, you are.
Thank you.
You're the reason everybody's here, but you're the reason for that hope. Patrick and I have now worked together for a number of years, and I've told him this many times. I said, "I don't know anybody who works as hard as you, and no one's ever called me an easy, lazy guy through these." Literally, he could be sitting on a beach somewhere doing nothing, but yet he's devoted his life to saying, "I want to bring a cure to cancer and let people throw stones at me for saying that in my lifetime." We're literally on the brink of this right now. As we close on this piece right now, I always tell everybody, think about ImmunityBio in two sides of this house. One, what are we doing in urology? We're not a urology-only company. We're not an ANKTIVA-only company.
It is really important, and we love that space, but also think about what we are doing in all of oncology, infectious diseases, and everywhere. On the urology side of the house, Matt, who I am looking at right now, wakes up every morning with an email from me or a text message saying, "Okay, we need to do more than we did yesterday." Literally every day, he gets that same message from me, and every day he replies back, "I understand. I get it. And I assure you we are." When you saw the chart on there, it is coming true. What is really important this year was that submission that we just announced of the papillary BLA. We will be the, well, others have tried to hold us back. We are the only company that we are aware of that has submitted for that.
Having a true regulatory approval is very different than just guidelines. It also allows you to then submit that globally. We've already submitted, and again, to our knowledge, we're the first and only who have submitted for EMA and MHRA approval in this space. While the trials in Naive are very important to us, the things that make me just absolutely blown away is the lymphopenia, the pancreatic cancer, the non-small cell lung cancer, what you saw with prostate, ovarian. All of that is going to change the face of what it is that we're going to do. For all of the employees that are here dedicated, and I know sacrificing, and I appreciate it, we are making a difference. With that, I'll turn it over to Patrick.
Thank you. Phil, if you could put that Cancer BioShield slide up. Oops. I do not think it is up. Is it up? I think I am going to close now, and it will be a two-minute close so that you all can be relieved of this long day. I thank you all for being here, just as Rich has said. As we started this discussion, when I say lymphocytes matter, it is not just two words. As you heard throughout the day, NK and T cells matter. Duration matters. Survival matters. The most important, quality of life matters. There is no point of us actually treating a cancer patient and giving them the last few days of their life pain and suffering for both them and their families. The opportunity for us to actually do that. Next slide.
The idea that we have had this missing link for all these years, and it's not a fault of doctors that don't look at ALC because there was nothing else there. Next slide. The opportunity now to change that course is really a simple yet profound change, which I believe will be a paradigm change in cancer. Phil, is that the slide? Is that the? This is how, as I said, this was a flexion point for us in April 2024, which really allowed me to come out now and express this missing link. That triangle offense, and I thank Luka Dončić, and we're all in good shape with the Lakers. That triangle offense is really what's going to change, I think, the paradigm of cancer care for hopefully for the next 50 years. Thank you for all of that.
If there are any questions, I'm happy to take them. We can take them after the fact. I know it's been a long day. Again, thank you for your attention today.