Good afternoon. Can you hear me okay ? Yeah. Good afternoon, everyone, and thank you for sharing your afternoon with us for MiNK's inaugural R&D Day. This will be the first of many opportunities where you can hear of our advancing science and an opportunity to share with you some of the findings that our team has presented just this morning at the most prestigious Society for Immunotherapy of Cancer Conference that's being held in Boston in the conference center that you can actually see. Today, you're going to hear about a new generation of therapies, actually. In fact, we can probably call this a new class in some respects, as we at MiNK are leading the charge in advancing living medicines to patients. We're also elucidating the science and the power of these cells as we're doing so.
At the conference this morning, we actually presented data that is first of its kind about the properties of B cells, their function, their features, and why B cells are considered the most powerful cell in immunity. We're gonna talk a lot more about this today. I want to take a moment just to thank those who have made this possible. Our board of directors, our scientific advisors. Dr. Mark Exley is here as well. Our courageous doctors here who are on the front line and spending their lives and saving others. You're gonna see the courage that has come about in delivering our therapies to the most severely sick patients and the most vulnerable on the front lines in the heart of the pandemic. Dr. Terese Hammond is with us today to tell you about her experience.
I'd also like to thank our friends and colleagues at Wolf Greenfield, our host this afternoon, and our partners and trusted advisors every day. I'm really grateful for your sage advice in helping us to get here. Of course, our best-in-class scientists who are joining us today. You are as persistent as you are brilliant, and you've worked tirelessly to help not only discover and advance our novel off-the-shelf allogeneic invariant natural killer T cell therapy, but also to deliver them to patients who need them most. I want to take a moment also to thank our patients and their families. They join us in this effort of advancing science, and they do so at defining moments in their lives, the most vulnerable for most of them, and we're very grateful for their contributions.
Now, today, the immune system is at the forefront, and it hasn't always been the case. Not only do we speak about antibody effectiveness, immune vulnerability in the sick and elderly, but one of the most sophisticated cancer conferences that I just spoke about, the SITC Conference, is being held here in Boston, is boasting threefold increase in attendance because we're seeing that immune therapies tuning the immune system is going to be necessary to combat some of the most widely tractable diseases that we're facing. That includes cancer, autoimmunity, infections, sepsis, lung diseases, and we're really excited to be a major part of this.
This conference and participation underscores that while the pandemic has brought immunity to our daily conversation, significant progress in developing therapies to actually address diseases is to immunity and eliminating diseases has ensured a future of designing immune tuning therapies to combat these problems. At MiNK, we believe that the cell therapy, specifically iNKT cell therapies, will lead the field in immune tuning treatments and here's how. Today, you're all sitting here, and you're carrying around living medicines within you. Dr. Hammond calls these cells sort of the 911. These are one of the most potent and quick-to-act cells in immunity. They're also the rarest cell in your periphery, so they're very difficult to get access to. Mark Exley is an expert in this field, and he's gonna tell you more about this. These cells have a very important function, several very important functions.
When you think about immunity, you have two arms of immunity: natural, innate immunity, that which you are born with, that which is very quick to respond to impending threats, and then adaptive immunity, that which you effectively develop responses to combat diseases like COVID-19, is how we think about this most. These cells are one of the most potent cells, and we believe the most powerful in actually modulating both arms of immunity. They not only choreograph how the immune system, both arms, innate and adaptive, should be working. They have the ability, with a natural engineering, we call them nature's CAR T in some ways. They have an engineered TCR, and that's common in all of us.
That allows not only these cells to function. They actually go to the site of disease when that ligand is upregulated naturally, without engineering, without any complexity, just the cells in and of themselves. Once they get there, they have the ability to directly function. They can kill, they can lyse tumor cells independently. They can clear infections, they can prevent secondary infections. This is particularly important in patients who are in the ICU. They also can do something very important. They can recruit other cells, T cells, and NK cells to the site of action. What you're gonna hear from our scientists today, we're the first to report that these cells also can take exhausted T cells, CD8 T cells, which are commonly known as one of the most prominent cells in immunity and critical for eliminating diseases like cancer.
Those cells get exhausted after treatment, common treatment, after a lot of exposure to antigens or the disease. When you administer iNKT, and our scientists will tell you this, you actually change that exhaustion. You can reinvigorate CD8 T cells. You can make them fight again. Importantly, and we're gonna show you this visually, that these cells not only can reinvigorate exhausted T cells, but they also can help those T cells get into the site of action. They actually bring them and chauffeur them into the tumor, where they can then fight and deliver very specific antitumor activity. These features have long been spoken about, but they have never been demonstrated, and our team of scientists have shown this now, and we will be presenting data to you with the esteemed panel that I'm humbled and honored to have here with us.
These are oncologists treating solid tumor cancers. These are experts in pulmonary diseases, particularly those patients who are critically ill, the critical care needs. Individuals who have been studying these cells for their life's work. Dr. Lydia Lynch is with us today, and she's gonna talk to you about how these cells stand out against others. Our scientists are going to talk to you about what we have been able to show, not only by taking these cells in their natural form. At MiNK, we were the first to isolate these cells. We could manufacture them at scale, creating about 5,000 doses from a single donor. That allows us immense development flexibility. It allows us to address major challenges in delivering effective medicines at the kind of logistically feasible and cost-effective approach of biologics.
Our team, and you'll hear from our head of manufacturing, is able to actually, from a single patient, generate 5,000 doses that we can cryo-preserve, we can demonstrate that the cells remain functional, and we can distribute them all over the world. What we have done now on our international clinical trials, the cells are at the sites when the patient needs them. That's a major breakthrough. You're gonna hear how we're doing that. I'm gonna first start this meeting with a kickoff, and I'm gonna introduce Dr. Manuel Hidalgo. Dr. Hidalgo is the Chief Hematology and Oncology at Weill Cornell Medical Center.
He's been an advisor, a strategic advisor to MiNK since its inception, and he's been in a position now to help us take these cells in the manufacturing form, in their native form, as well as to identify ways in which we might want to leverage our engineering capabilities for super targeting and employ them in some of the most prevalent diseases. Dr. Hidalgo? Oh, sorry. Let me just put it in the lanyard here. Yeah.
Well, good afternoon, and thank you very much for the invitation to be here today. It's a very important day where many new data were presented this morning, and thank you for attending the meeting. I'm going to briefly sort of provide a brief summary of where we are at the moment in cancer treatment and what opportunities we have out there, and what are the problems that sort of the most modern treatments are encountering. These are my disclosures. Cancer is here to stay, unfortunately, for a while. These are data of cancer incidence and mortality projected to 2040. As you can see, many tumor types would continue to have increase in the incidence. What is probably more dramatic is that the mortality remains basically flat.
Some tumors were making progress, non-small cell lung cancer, for example, mainly because of smoking cessation, because of early diagnosis, and because of the treatments that are more effective. But other tumor types, the ones that I treat in the clinic, like colorectal cancer, liver cancer, pancreatic cancer, actually are increasing and will be the most important or most significant killers in 10, 15 years from now. So very, very important problem, as you all know. What are we doing? We have done surgery, chemotherapy and radiation therapy, and more recently, the two newest therapeutic modalities, precision oncology and immune oncology. We will talk today mainly about immune oncology.
Before I do that, I just wanna mention that there is a very significant field of cancer genomics and targeting genomic aberrations, which is very important and likely at some point to be combinable with immunotherapy strategies. This is one field that has a lot of merit on its own. The field of immunotherapy, which essentially, Jen said before, we're talking now about two main modalities. One is the checkpoint inhibitors, and we know that CTLA-4 inhibitors, PD-1 inhibitors, they are approved in the clinic. They are used to treat many tumor types, and they work by basically, reactivating T cells that have been sort of, quiet and are blocked from killing the tumor cell because of different ligands that the cancer produces. These antibodies, anti-CTLA-4 and the PD-1, work by this mechanism.
This was a significant revolution, Nobel Prize worthy. A couple of examples in the area that I work, pembrolizumab in MSI colorectal carcinoma, perhaps one of the most sensitive scenarios in which these drugs work. You can see that it is much better than chemotherapy. There are problems. Not every patient responds, as you see, and some of the patients who respond initially, eventually progress. There is significant need to understand the mechanism of resistance to these drugs and to complement with other strategies like the one we were here today about iNKT cells, how we can make or synergize better with those immune checkpoint inhibitors. In other scenarios, these drugs, they just don't work. This is the disease that I treat in the clinic for most of the time, which is pancreatic cancer.
This is a recent, very recent trial combining chemotherapy with chemotherapy plus dual checkpoint inhibitors, both that I mentioned before, CTLA-4 and PD-1. As you can see, there are no differences. Perhaps the reason is that these tumors have a very rich tumor microenvironment that produces ligands that is excluding T cells from the tumor microenvironment. Basically, T cells don't get to the tumor, and for that reason, they just don't work. How can we do better? Well, understanding the mechanism of resistance to these drugs and complementing them, as I said before, is an important strategy.
We will hear today how iNKT cells can sort of reprogram T cells that have been exhausted to become then again effective against the cancer, and how these cells can be engineered to target very significant components in the tumor microenvironment that are linked to the resistance to existing immunotherapy. Combination is a big thing. Now, the other major strategy in the immuno-oncology field is the cell therapy. Cell therapy is not new. We have been using them for some time in the clinic. The new aspect is sort of the engineered T cells, CAR T cells, TCR engineer that have been developed and continue to be very aggressively developed with a very significant engineering sort of activity to make these cells more effective. In some scenarios, they are quite effective.
This is in multiple myeloma, relapsed refractory myeloma. As you can see, these cells targeting BCMA have a very important response rate and result in overall survival, and they are approved. The same concerns that I mentioned before about the checkpoint inhibitors apply. They don't work in some patients. Some patients eventually become resistant, and there are many tumor types that are just intrinsically resistant. Cell therapy, as we know it today, is not an easy therapeutic area. It's not easy to manufacture the cells. They are autologous. It takes time. They're expensive.
There are all kind of reasons why they just don't get into the tumor, they don't recognize the tumor, they don't permeate into the tumor microenvironment, and for that reason, are not effective, and they are associated with significant toxicities. Has been a tremendous revolution, but one that still we can improve upon. What was presented this morning, and we will discuss today is a new version of cell therapy, the iNKT cells, iNKT cells, invariant NKT cells, that actually can address many of the problems that I just mentioned before. We will see how these cells are able to kill tumors by different mechanisms. One is by blocking immunosuppressive signals in the tumor microenvironment, very important in some patients like pancreatic cancer, by directly engaging and killing tumor cells.
As Jen, Jennifer mentioned, by recruiting, reprogramming, and reactivating T cells that were once active but now they have been exhausted. Going through the areas that we will hear today in the presentations that were presented this morning, we have basically five major topics. We'll be talking about agenT-797 phase I clinical trial data, both alone as well as in combination. The efficacy and ability of these cells to help patients with severe acute respiratory distress syndrome caused mainly by COVID, but likely also applicable to other conditions. Then the data that they're able to sort of reprogram T cells that are exhausted in the tumor microenvironment for reactivation and killing again.
These cells can be used naive, but they can also be engineered. We will see a couple of strategies to engineer iNKT cells. One to produce or to attack FAP-expressing mesenchymal cells in the tumor microenvironment. This is a very attractive approach to sort of block signals that are extruding T cells from the tumor microenvironment in diseases like pancreatic cancer. This is probably the most relevant mechanism by which these tumors are resistant to checkpoint inhibitors. We have attempted to sort of overcome this by different approaches. We did significant work, for example, targeting a cytokine, which is very important, called CXCR4, which is activated or produced by these FAP-positive cells. Those drugs, they have not sort of shown significant activity yet, but going and eliminating the source of these negative ligands is a very cool strategy.
As I showed the BCMA CAR T cell, we can improve upon that, and you will see data of our re-engineered NK cells to target this important antigen, but with different engineering, different genes that can probably, hopefully, make them more effective. This will be sort of the topics for today. I'm gonna stop here. Jennifer, you wanna take the podium. Thank you very much for your attention.
Thank you very much, Dr. Hidalgo. I think a couple of points I'll just emphasize here, the ability to address some of the current limitations of CAR T therapies, not only the manufacturing and logistic problems, but then also identifying ways in which we can super target. BCMA is a well-known target addressing multiple myeloma, but it's largely difficult to manufacture, and it hasn't shown a significant amount of durability of response. We think that we may have found a way to improve upon that durability by armoring BCMA CAR T therapies. It's a program that we're in active discussions with and contemplating strategic collaborations for. To go into a moment of the science of the iNKTs, we have a world leader, Dr. Mark Exley, who has been working with these cell types, I think since 1996.
He'll talk with you about the biology of the cells and why we believe we're seeing what we're seeing. Mark led our scientific efforts. First, he was a professor at Harvard, leading his lab and pioneering the science. Also demonstrating ways in which he could take these cells and apply them in the clinic, showing some of the first in-man data with the cells in different types of formats, including vaccines. He was leading our scientific charge for many years, and now the leader of our scientific advisory board. Mark.
Great. Well, nice to be here and surrounded by my colleagues here who've got some really great data we wanna get to as soon as we can. Give a little bit of background on iNKT cells that we've been talking about. They're quite unusual. They're rare cells, as we just heard, and that's one of the reasons why we know less about them and very few people have studied them. It's been a bit intimidating to be able to work with them because they're so rare, especially in people. They're a lot more common in animal models, which a lot of the data has come out of. As Jen also mentioned, they really link the innate and adaptive immune system, the two halves of the immune system.
They do this by, they have their own inherent activity, and this can be directly anti-tumor, it can be anti-pathogen, it can be immunoregulatory in a very profound way. They also have the ability to activate other immune cells. They're very good at activating NK cells, other T cells, B cells, and they also mature antigen-presenting cells, myeloid cells of various types. They can really help shift the balance in favor of a protective immune response, which has been really profound in a lot of early clinical studies. Yeah, sure. Is it? Is that better? Yeah. Oh, usually. Yeah, I'll get a bit closer. How's that? Is it better? Even better. Okay. Amongst other features, they respond like innate cells.
Although they are T cells, a subset with a T-cell receptor, they nonetheless behave very rapidly, and they respond very rapidly like an NK cell would or another innate cell. They have that ability to stimulate immune response. They produce a lot of cytokine per cell basis, so compared to conventional T cells, this means that they have more profound effects locally, and further afield. They're also an unusually easy platform to work with, as we've discovered, in a number of ways. First of all, they expand very rapidly. Unlike other T cells that exhaust very easily, they will expand exponentially for a long period of time. We can grow them, and we'll hear from manufacturing, Joy, and the team about progress with manufacturing as well.
Although you start off with a very few of these cells, you can get to very large numbers very quickly. That makes a huge difference. They basically overtake the T cells and other populations that start off with much larger fractions, but take a lot longer to get to the high levels. Another feature of this, because they're so rare in each of us right now, because they're so powerful, we don't need a lot normally, there's a huge therapeutic window.
There's a big opportunity when you add, increase them and stimulate them and increase their numbers, because they're so few, it's much easier to have a big therapeutic window than with NK cells or other cell populations of which we already have a large fraction. The next slide looks at some of their particular features which are involved in their antitumor activities that have been defined over the years. This comes out of a lot of work in models, animal models, but also a lot of very good studies in humans that many colleagues as well as our lab have been involved with over the years. It shows that they can reprogram immune responses into a more Th1-like response, which is critical for antitumor responses.
That means they're able to produce more Interferon-gamma, they're able to stimulate IL-12 production, they're able to stimulate antitumor cytotoxic T cells, and we'll hear about, again, how they prevent T cells from exhausting, or they can re-energize T cells that have been exhausted. That makes them potentially very attractive in their ability to maximize the immune benefits of the immune system against cancers. They can affect the tumor microenvironment as well as the immune system and systemically. This can include their ability to kill tumor-associated macrophages, for example, which we know are tumor-promoting. They have a number of different features that can allow them to really benefit the immune response in cancer. This is just some data from others.
It confirms the data we have from internally that iNKT cells can work better, for example, as CAR carriers on the left there, in terms compared to conventional CAR T cells. Again, confirming data that we have internally, others independently have shown that they also can work better as antitumor carrier cells populations than NK cells. They do this partly by activating NK cells and T cells as well as their own inherent activity. They provide that extra benefit in that way.
Not only do they have antitumor activity, but not surprisingly, given that the similarities between anti-pathogen and antitumor immune responses are very similar in the Th1 flavor and the reduction of the immunosuppressive M2 macrophages and so on, that whole Th1 thing is really important, the antiviral responses as well, anti-pathogen responses in general. iNKT cells can do this in a number of different ways. They're activated by ligands, lipid ligands, which can be produced by bacteria and fungi. But they can also respond to viral infections in a number of different ways, including upregulation of CD1d in terms of its target, the target for the NKT cell receptor. They also have other ligands and receptors on them that can pick up other stress ligands, like NK cells, that they share with NK cells.
They have the additional benefit of being NK-like as well as being, having their own T cell receptor with its own activity. All of these things benefit antiviral responses as well. We'll hear not only about antitumor activity that we're seeing clinically as well as pre-clinically, but also potential anti-pathogen effects that they're having in patients with COVID and ARDS. A really profound potential benefit there as well. Of course, they have the ability to be engineered. We're gonna also hear to make them even more active, and that's one of the next stage of our process that we're developing in the clinical progress that we'll move into soon.
Finally, a slightly provocative slide, but we compare a lot of people are working with various other populations, subsets of T cells, NK cells, gamma delta T cells. All of them have their benefits. Some have their limitations in different areas. One of the nice things about NK T cells, we've been able to use them in the absence of lymphodepletion, which is a huge potential benefit. So far, the other populations have been used almost exclusively, certainly clinically, with lymphodepletion, which is very, you know, a real contraindication. It limits the number of patients you can treat, and also reduces the potential benefit of the rest of the immune system because of it. Obviously lymphodepletes potentially good cells.
Those are examples of how they can have these multifaceted benefits which extend out into the rest of the immune system.
Thank you very much, Mark. You can give that to David.
Yeah.
The question is, why are we the first ones to be advancing these therapies if they're so good? I'm gonna see if there's an answer in the audience. Manufacturing has been a major roadblock, and that's why we really are the first company that's been able to address this problem. Part of that is because we have proprietary reagents that allow us to take a sample of blood from individuals and isolate the iNKT cells to nearly 100% pure. We have then a proprietary process that allows us to activate those cells and then administer them to patients. That's been a major impediment to progressing these cells that now we've been able to overcome.
Presenting now is Dr. David Einstein, who's been a true partner, lead investigator of our phase I stud?, looking at these cells in their native form in patients with solid tumor cancers. David?
Thanks so much. Thanks to the whole MiNK team for the opportunity to speak here tonight and for the opportunity to be involved with this really exciting project. Thanks also to Marc-O. So f or some really hard work on data analysis up to the last minute. I see patients with prostate, bladder, testicular, kidney cancers, which are among some of those where, you know, some of those immune therapies that Dr. Hidalgo spoke about are part of our standard armamentarium, but we clearly need to do a lot better. I think that there are some previous data out there in small subsets of patients looking at this concept of iNKT therapies.
Most of these have used autologous iNKT, so you're actually freezing off a patient's own cells and trying to expand them ex vivo and then reinfuse, with the idea that cancer patients generally have sort of a depletion of their iNKTs and also some dysfunction of those iNKTs. You know, limited numbers of patients, but there's some exciting data. You know, I think that the head and neck report was one of the most interesting, where they had a number of patients that had really, you know, 50% tumor reductions through this strategy. Sometimes a combination of autologous iNKTs plus some additional adjuvants. It hasn't gone too much farther, as Jen mentioned.
These are some data that have been generated internally, kind of looking pre-clinically at models, in this case with melanoma, and looking at different immune-based strategies for trying to prevent metastasis. You can see here various combinations. We talked about checkpoint inhibitors. We talked about cellular therapies. You know, can we put them together? What you see here is sort of additive effects or even synergistic effects as you add more combination therapies, in the amount of tumor control. Certainly there's the potential for you know, combination therapies that would be very synergistic with the Agenus pipeline here. This is the phase I trial that I've been fortunate to be involved with.
This is a kind of standard d ose escalation design, initially with monotherapy, and then in combination with standard of care PD-1 inhibitors in patients who have already developed progression on those. As with a typical phase I trial, we're looking primarily at kind of PK data, safety data, dosing tolerability really. I think that some key questions that we're gonna get to are sort of where do these cells go? Do they persist in the periphery? Do they traffic to tumors or other sites? And then also certainly some exploratory endpoints about the immune effects of all of this. We've completed that dose level one, no DLTs. We were able to move quickly on to dose level two, also no DLTs.
Going on to part two, at the dose level one combination with other therapies. I wanna just take a moment here and point out that this trial has been open since May. It's now about a half year later. To have 40 patients accrued across a handful of sites is the fastest I've ever seen. Really a credit to the CRO and the sites involved in all of this. This is some basic data summarizing those patients who have been treated. You know, a fairly typical phase I population with pretty treatment refractory, multiple lines of therapy, types of patients. The clinical data here is limited by our median follow-up of only 18 weeks. Again, this is a rapidly accruing trial.
We're still waiting for a lot of that really good clinical data. I think what we have to share tonight is really about the safety and tolerability. What we see here on the left is what we call swimmer's plot. This is showing individual patients who have been treated at these different dose levels or in combination. The combination is shown in purple. The two dose levels as monotherapy are blue and green. You're seeing patients, the duration that they're on treatment, arrowheads indicating ongoing follow-up, and dots indicating coming off a progression of disease. What you're seeing here is not a waterfall plot, and that would show you actually, you know, reductions in tumor size. Those data are still very immature. We're not ready to build that yet.
I think that, you know, across the limited number of patients that we are able to evaluate, we are seeing some reductions in some target lesions on scans. We wanna be able to confirm that and, you know, apply the usual RECIST criteria to come up with a overall response rate. I think the other thing that's intriguing, of course, is disease stabilization. Certainly with some IO therapies, we don't always expect tumor regression, but sometimes stabilization over the long term is a very good correlate for overall survival. There are some patients here who have had, you know, stable disease for many weeks. This is a little bit about our safety data. It's pretty boring because there's not a lot happening here. That's very good, okay.
There's really no treatment-related adverse events grade three. You know, I think, you know, one reported, but no irAEs. Importantly also, no cytokine release syndrome, which is a real problem with some cellular therapies. You know, we're talking now about the toxicity of the drug itself or the product itself. But I think that it's also worth sort of coming back on something that Dr. Exley mentioned, which is the lack of lymphodepletion, which is a major barrier to rolling out CAR Ts across solid tumors. Really favorable toxicity so far. We also see no increase in the typical cytokines related to cytokine release syndrome. Finally, are these cells active? Well, yes, it seems so.
On that second day, you can see a little spike in interferon-gamma, which is a key cytokine that drives a lot of anti-tumor cytotoxicity and antigen presentation, and recruitment of more immune effectors. That's good to see. This is a parallel trial phase I in multiple myeloma. I was not involved with this, but I will share the data. Similar design with increasing dose levels, all as monotherapy, and similar endpoints, albeit with, you know, myeloma clinical endpoints, not solid tumor ones. These are the patients who have been treated so far on that trial. A couple of stable disease patients, including one who had kind of an interesting decrease in the what we call paraprotein, which is kind of the abnormal protein that's the problem in myeloma.
It's the what the abnormal plasma cells are cranking out. That decreased while on therapy, eventually progressing, but with a nice response initially and some stabilization in those abnormal plasma cells in the bone marrow. More to come. Again, in the myeloma patients, a very similar safety profile. No immune-related adverse events, no cytokine release, no increase in the cytokine release syndrome cytokines. To put all this together, I think that we have some very promising data as far as tolerability, both as monotherapy and in combination. We've been able to dose escalate with no DLTs, no cytokine release, no neurotoxicity, no immune-related adverse events.
I think that, you know, there's some exciting science that we're gonna hear a little bit more about, you know, what could be going on. I think clearly, we wanna continue expanding this effort, and we're planning some further specific dose expansion cohorts and specific tumor types, both alone and in combination. I think that thinking broadly in terms of future trial development, in my mind there's sort of two directions. One is sort of circling back on that melanoma data and thinking about how this could be combined with other checkpoint inhibitors in the pipeline. I think that that's both justified based off of preclinical data and safe to do based off the tolerability, unlike, say, combining ipi/nivo and CAR Ts, which could be, you know, quite toxic.
I think that the other thing that allows us to do is to think about moving into earlier disease spaces where the immune microenvironment could be significantly less immunosuppressive. This is disease spaces like, you know, first-line therapies or adjuvant therapies or early recurrence, based off of circulating markers. Those are situations that you would never wanna base a patient with, you know, something like a CAR T, but this, I think, is a much more reasonable proposition. With all that, I'll thank you for your attention and turn it over to our next speakers.
Thank you very much, David . Actually, we're gonna try to elucidate some mechanisms now with some flash presentations from our scientists at MiNK, who are gonna give you a very brief overview of the data that were presented at the SITC Conference today. I think importantly, based on the data observations that we're seeing, we will continue to advance these cells and mature the data and looking forward to providing an update at upcoming conferences. The solid tumor data, as they mature, we expect we'll be able to better understand the potential of these cells as we have more mature time on study from these patients. Multiple myeloma is an indication in which, again, as I mentioned earlier, still is an unmet need.
What we will be doing is we've now demonstrated that we could administer the cells without lymphodepletion, and now we have an opportunity to look at super targeting with an armored BCMA CAR therapy, which Eleni is gonna tell you about. First, Dr. Sapana is here. She's a superstar, and she's the pioneer of the data that actually has now elucidated that these cells may reinvigorate partially exhausted T-cells that return them to tumor killing. Sapana?
Hi, everyone. My name is Sapana Pokharel, and I'm a leading scientist in MiNK Therapeutics, leading the project with our unmodified off-the-shelf allogeneic iNKT product, agenT-797, and how it interacts with other immune cells that are critical for antitumor responses. Like Dr. Hidalgo and Dr. Einstein mentioned in their talks earlier, with current immunotherapy and immunosuppression that occurs in the tumor microenvironment, there is an unmet need which needs to be addressed using novel cellular therapies such as our iNKTs. Today I'm gonna show you how we can use our unmodified iNKT product to target three key immune cell types that are present in the tumor microenvironment, and how agenT-797 can improve antitumor functions in those immune cells. First, T cells, which are the primary effector cells.
Second, dendritic cells, which are also known as DCs and are the key antigen-presenting cells that are known to help the recruitment and activation of T cells. Third, macrophages, which are often associated with immunosuppression. Today I'm gonna show you how agenT-797 firstly can reinvigorate partially exhausted T cell, enhancing their killing capacity. For this, we perform the co-culture of agenT-797 with partially exhausted T cells that will be generated using our exhaustion platform. We saw that either with co-culture of partially exhausted T cells with agenT-797 or supernatant from pre-activated agenT-797 that contains the soluble factors secreted by this iNKT, you see enhancement of killing of this partially exhausted T cell, as shown in the graph on the left.
Furthermore, we wanted to investigate if we can utilize agenT-797 to target myeloid cell in a way that you can improve the antitumor functions of these myeloid cells and then promote a immunostimulatory effect. For that, we performed co-culture of agenT-797 with dendritic cells, where you can nicely in the panel in the middle here, that agenT-797 was able to activate the DCs as shown by the enhancement of co-stimulatory molecule expression like CD80, CD86, which is associated with T cell activation. Not only the iNKTs were able to activate the DCs, but the DCs were also in turn able to activate the iNKTs. Lastly, we wanted to address one of the major challenges that remains in the immunotherapy field, which is how do we reduce the suppression that happens to the immune cells in the tumor microenvironment?
For this, we performed the co-culture of agenT-797 with pro-inflammatory M1 macrophages, which is actually beneficial to the anti-tumor function and immunosuppressive M2 macrophages, which actually is detrimental to the tumor microenvironment. When we performed the co-culture of agenT-797 with either of these macrophages, we were nicely able to show, as shown in the panel on the right, that agenT-797 were able to selectively target immunosuppressive M2 macrophages while preserving M1 macrophages with a pro-inflammatory effect. Altogether, our data nicely shows that agenT-797 can promote the anti-tumor functions of partially exhausted T cells by restoring their killing potential, activating the dendritic cells and targeting the immunosuppressive M2 macrophages, altogether creating a hostile environment for tumor cells to grow.
Next, you will hear from Xavier and Eleni on how we can further engineer these iNKTs to further enhance their anti-tumor functions. Thank you.
Thank you very much, Sapana. You've heard it first here. This is going to be really magnificent, building on these mechanisms that we're observing now. To tell you more about our capabilities is Dr. Marc van Dijk, our Chief Scientific Officer. Marc and I have been partnered together for about 13 years, where we had been working with Agenus, the parent company of MiNK. Marc is a molecular biologist, technologist who had delivered the antibody, created the antibody discovery platforms at Medarex, at Genmab, and later at Agenus, which has given rise to some remarkable molecules, including the subject of the plenary session at SITC on Saturday. Marc's going to talk to you about how we've leveraged our tools and technology to now engineer these cells for super targeting.
You'll hear about two of our engineered CAR platforms that are advancing into IND-enabling studies now for first-in-man studies to start early next year. We'll hear from two of the lead scientists behind those platforms, and then we'll turn to the clinical data that we have in ARDS.
Thanks, Jen. Okay, I'm Dutch. I'm a little taller, so let's see if it holds up here. Yeah. Okay. So pretty cool cells. Can we make them even better? Yes, of course. Why? Because solid tumors do present a formidable barrier for T cells and CAR T cells, and also for cell therapy in general. Manuel Hidalgo has laid out the field and actually shown that, yes, we have made a major difference with IO therapy. Still people progress. There are still also people that don't respond, and a lot of the reasons why they don't respond has to do with the word that we've heard, resistance, immune suppression, the environment within the tumor that actually keeps T cells out. What do you do with this? We actually think that cell therapy can actually make a huge difference in the paradigm by which we treat solid tumors.
We do this also by enhancing the cells in a way that actually makes them even better than their natural state. We have two platforms that I'm gonna introduce you today, one for chimeric antigen receptors and one for bispecific iNKT cell engagers that are both intended to increase tumor homing and also activity within the tumor and make these cells even better at overcoming resistance than they already are by nature. The big thing with the immune therapy is this resistance. What do you need to do to actually overcome that? Once you have to have a cell type that is able to already, by nature, counter some of the mechanisms that actually suppress the activity within tumors.
Sapana has very elegantly shown that we have evidence that these mechanisms by the cells themselves already are able to change some of the microenvironment in favor of actually an antitumor response. We also don't use lymphodepletion, and that's important not just because it's easier for the patients. It's also better because you have more of the immune system around to then take over and actually get actively engaged when the tumor microenvironment changes. What else can we actually do to just actually make this better is to add properties to these cells that make them even stronger. That is actually by adding CARs, so chimeric antigen receptors that really enhance the activity of these cells, specifically within tumors, and also by redirecting more of these cells to tumors with the bispecific antibodies. We have two platforms for this.
I'm gonna focus today on our CAR platform, and I'll update everybody next year when we progress to mature the platform for iNKT cell engagers. Today I'm focusing on our CAR platform. We call this CARDIS. It stands for CAR display for reasons that I'll actually show you in a few minutes. You know, what are chimeric antigen receptors? Just as a brief recap. They're custom-built receptors that actually have two parts. One part actually is what sticks out of the cell, is the part that recognizes the tumor target. It's an antibody part, and we actually engineer that to very specifically recognize tumor targets with a very specific binding strength. That's important. The solid tumors actually have targets that are very specific and over-regulated on solid tumors, but they're also expressed on normal cells that you don't wanna kill.
You have to really create that therapeutic window very, very specifically. That's why we build our platform the way we build it. There is an obvious synergy between the top part that recognizes the tumor and the bottom part that actually conveys the signal to the iNKT cells when the tumor target has been recognized, and that you need to tune very carefully. There is a synergy between the top and bottom part of a CAR. There's also a synergy between the CAR and the iNKT cells in which we want these CARs to act. That's because the cells don't just react to the CAR you put in there. The tumor target it recognizes. It actually also reacts to all the other ligands that these iNKT cells naturally recognize. The TCR recognizes CD1d on myeloid cells that actually are potent suppressors.
The NK receptors react to distress ligands expressed on tumor cells, and together, this integrated response actually starts the whole cascade that ends up not only killing the tumor cells but also changing the environment and bringing in other cell types. That's a reason why we think iNKT cells are such a good host. They're not just only able to directly kill tumor cells, they also change the environment, and we can beef up their activity by actually adding CARs to these cells and armor, which I'm gonna talk about later. How do we do this? How do we make these CARs work very well together, the top and bottom part, and also work very well in iNKT cells? We have our own platform. We have two platforms, and for CARs, we use this longstanding experience we have with antibody-based drugs that Jen alluded to.
We use the antibody parts to actually build the top part of our CARs, and then we very cleverly have a technology that actually allows us to integrate this antibody part with the signaling part and really find the best Goldilocks activity combination between the top and bottom part. This is a typical screening funnel that everybody who does drug screening knows. You start with a huge amount of molecules at the top. It could be small molecules, it can be antibodies, and then you work your way down through several steps to the ones that actually brings you the final candidate that you're going to put into your product.
Traditionally, for CARs, most people stick with the antibody part for most of the journey, and only at the very bottom you convert it into CARs, and then you sort of look one by one what's going on. We think that's not good enough. You actually compromise on the numbers. You're really not able to pick the best CAR if you do this so late. We do this a lot earlier. We have built a specifically value-added step in this process, which we call CAR display. The reason for that is that we are able to, very early on in the process already, put a lot of antibody pieces on CARs in specific reporter cells that we can then interrogate for the exact function that we're looking for. How do we do this?
We actually have a special custom-built reporter T-cell that we can grow to large quantities, put a lot of different CARs in there, and at this stage, we're talking about up to 1 million different CAR molecules. Each cell has one CAR molecule with a specific antibody portion, and they're all together in one big library. What do we do with this library? We actually add tumor cells to this mix, incubate them for a while, and then those CAR cells, those library cells that actually have a CAR that responds to the tumor in the right way, they light up. With this light signature, we can isolate them from the library, and we immediately have, also based on the strength of the light signal, the CARs that have the function we're looking for, that recognize the target we want to recognize and do not have background activity.
That's important. Why is it? Why that's important? Well, this is a bit of an example from our BCMA screening campaign, which Eleni will go over to later. It actually shows you in the red circle that only 1%, less than 1% of the antibody binding portions that already recognize the tumor targets are able to support a functional CAR. An even smaller proportion of this 1% is the CAR that you're looking for with the exact level of signal activity you're looking for. That's crucial for solid tumors. As I mentioned, you need to know your therapeutic window. You need to pick the spot where you want the activity because you want to just kill the tumor cells and nothing else. This is why we built our platform the way we built our platform.
We not only built these cells with CARs, we also armor them. By the way, we actually put so much NGS and bioinformatics works in this process. They're not just armored trucks, they're actually cyber trucks by this time. Anyway, I could go on. This is what we do. We build a platform that allows us to build CARs for solid tumors very effectively, very precisely, and we armor them. In this case, we armor them with interleukin- 15, which is a cytokine that's crucial not only for iNKT cells 'cause it drives persistence, but it also recruits and activates NK and T cells that are already in the tumor that they can bring into the tumor. This package is even better than a cyber truck, I would say. Now we're gonna talk about two of our programs.
First, we're gonna talk about MiNK-215. This is a solid tumor targeting CAR-iNKT product that secretes IL-15, which targets fibroblast activating protein, which is really key to tumor stroma and resistance. Then we're gonna talk about our BCMA next generation iNKT CAR program. Xavier, floor is yours.
Good afternoon, everyone. My name is Xavier Michelet, as indicated there. One of my responsibilities at MiNK Therapeutics is to actually elucidate the mechanism of action of the cell therapy products that we develop. Today I will show you the data on the most recent innovation, which is a CAR iNKT that targets the tumor environment and is a really great opportunity actually to provide curative potential for solid tumors. Despite the tremendous excitement generated by CAR T therapies for leukemias and multiple myelomas, they reveal themselves poorly effective towards solid tumors. Even if those CAR Ts are very efficient to target the tumor cells, they reveal themselves actually poorly fitted to infiltrate and survive the core of the tumors.
This core is extremely immunosuppressive. What does it mean? It means that it excludes any T cells who could directly target, supposed to target and kill those tumor cells. MiNK FAP-CAR is changing this paradigm in directly targeting the tumor environment to allow those T cells to reinfiltrate and kill those tumor cells. To evaluate the curative potential of the MiNK FAP-CAR, we did generate it, non-small cell lung cancer mouse model. This model is not only a model that represent one of the most prevalent and deadly cancers, but also is a perfect example where we can show where the actually the human system and some of the PD-1 therapies are currently failing, and where we do believe that the MiNK FAP-CAR can turn the tide.
In this model, as you can see, so the tumor cells express the markers that allow us to track the development of the tumor within the lung of this mouse, as you can see on these pictures. These mice are completely immunodeficient, so they do not have any immune system. For that, we do infuse them with the FAP-CAR iNKT cells, but also with some T cells that are specifically designed to target the tumor cells. What about the data? When we look at the data, when the mice were infused with the FAP-CAR iNKTs only, which is a red dashed line, we didn't see an increase in the survival of these mice. Which indicates the first mechanism of action here. Which is what?
It's like by targeting the tumor environment, the tumors, it impairs the capability of the tumor to actually engraft and develop itself as a tumor. Interestingly, when infused with the T cells only, and these T cells are targeting directly the tumors, we do observe an increase of the survival, but it's not good enough. Most of those mice end up dying, despite the fact, once again, that they are supposed to kill the tumor. They're not. However, when actually these mice that do have a bit of these T cells are infused with FAP-CAR iNKT cells, we did observe over 90% of survival of these mice 100 days for the tumor challenge, which is really impressive. The most interesting part is that six days post-treatment, sorry.
As you can see on the under the images on bottom right, those mice didn't show any more tumor burden. It's like they were almost completely cured of this cancer, as you see by the absence of the signals. While actually mice treated with the T cells, the tumor burden remain unchanged, as you can see. That suggests the second mechanism. That the FAP-CAR iNKT cells were able to enhance the activity of these T cells to promote the curative response. If you are wondering where are those missing mice, they are actually in the next slide. The question remains: How does the FAP-CAR iNKT cells can enhance activity of those T cells? To answer that question, we're actually looking bit more in details in those lung tumor tissues.
In those images you can see, in blue are represented all the cells present in there. Normal cells, stromal cells, cancer cells. In orange, you have the tumor cells itself. In yellow are all those tumor-specific T cells that are supposed to kill the tumors. On the left side, in those images of a lung treated with only the T cells, as you can see, in absence of the FAP-CAR iNKT, those T cells, even if they are present in the lung tumor tissue, this seems to be unable to infiltrate the core of the tumor tissue present at the bottom here. However, when treated with the FAP-CAR iNKTs, the image on the right, not only we found like tenfold more T cells in the entire lung of these mice, we also found that those tumor-specific cells are extremely close to each tumor cells.
Like, as you can see on these images, it seems like those T cells are embedded within the core of the tumors, so they get in. When we look at the numbers, we observe that there is threefold more CD8+ T cells, tumor-specific T cells, that are inside the core of the tumors, that compared to the control. I showed you today that the FAP-CAR iNKT cell can promote a curative response in this model by two different mechanisms. First, it will impair the engraftment and the development of the tumor itself. Secondly, it will actually enhance the activity of the system in promoting their infiltration and their survival inside the core of the tumors, an area that is usually unreachable for them.
One very important point to remember is that the FAP-CAR iNKT is a first-of-its-kind product that showed tremendous benefit in this lung tumor cancer model, which is difficult to treat, but also toward the target that is widely expressed in cancers. Thank you very much.
Excellent, Xavier. Thank you very much. The engineering capabilities that Marc spoke about earlier were, of course, applied to this technology, targeting for the first time the type of biology showing the elimination of cancer this powerfully to a FAP target, which as Xavier mentioned, is really widely expressed on a number of different solid tumor cancers. It's hugely opportunistic, and we're quite excited about it. Further, will that technology now allow us to break barriers and improve upon what is currently available for patients with multiple myeloma? Eleni is gonna tell you how we can.
Thank you, Jen. Hi. I'm Eleni Chantzoura. I'm the Director of Discovery in MiNK Therapeutics. In the next few minutes, I'm gonna introduce you MiNK-413. I know what you are thinking, but this is not another BCMA CAR T-cell therapy. I will go through why. We designed this product having in mind the limitations of the current approaches. Xavier mentioned tremendous excitement with CAR T-cell therapy in multiple myeloma. The truth is that only two weeks ago, FDA gave accelerated approval to a BCMA bispecific that has an overall response rate of around 60% and less than 30% complete response rate. To me, this shows that there is a lot of room for improvement. These are some of the limitations of the current treatment that we try to address with MiNK-413.
One of the parts of improvement is obviously the CAR. Marc very nicely introduced you to our CAR-T platform and also to what a CAR is. Just a reminder, a CAR consists of two domains. The binding domain, usually an antibody, but it can be also a nanobody or anything else that recognize the target of interest, and the activating domain that activates the iNK T cells in order to kill the tumor. This acts synergistically. This is what we have taken into consideration in our CAR-T platform. We start with a selection process. Imagine that we have around 10 billion different sequences. We select for BCMA binding, and we end up with a couple of million. But then we transform into a CAR format and express it in mammalian cells.
From this actually 2 million, the only around 20-25% form a CAR or bind as a CAR. We can get rid of all this noise very fast, as you can see here in the middle of the schema. Even more interestingly, from this 20%, most of the CARs are actually not functional. This is around 70%. What I find very dangerous is that around 10% of them are functional, but they are not specific. They can be activated by other cells as well that do not express BCMA. As Marc said, less than 1% of the initial binders are antibodies, actually functional CAR Ts. For me, the most important thing here is that functionality doesn't really correlate with binding.
When you have CAR T cells there that are the strongest binders, obviously they are not the strongest soldiers. We want to take our strongest soldiers in our battle with cancer. The next thing that actually has to do with our CAR-T platform as well is the clinical challenges. The clinical challenges can be lymphodepletion related toxicities, can be lack of persistence or can be the phenotype of the T-cells. I have to say at this point that our libraries are fully human. The CAR T-cell products that are now in the market are humanized, which means that they can induce immunogenicity which decreases their persistence, whereas our, ours are fully human. Also, obviously, you have seen this figure before. We are using iNKT cells. iNKT cells have different mechanisms to kill the tumor.
Obviously, they express a CAR that recognizes BCMA. Through the invariant TCR that Jen mentioned at the beginning, they recognize CD1d, which is actually expressed very highly in multiple myeloma cells. They have the natural killer cell activating receptors that recognize stress ligands on the cancer cell, but also they do not express the inhibitory receptors that NK cells express. What I personally, however, find fascinating is that iNKT cells are great team players. They activate, they recruit and activate the T cells and the NK cells of the conventional immune system, which means that they keep working even after they disappear because they have activated the immune system. It's like my favorite saying.
It says, "Give a man a fish and he can eat for one day, but if you teach them to fish, they can have food for the rest of their lives. This is what actually iNKT cells do, teach the rest of the cells how to react to the tumor. Another thing that both Sapana and Xav mentioned was the tumor microenvironment. iNKT cells counteracted the hostile tumor microenvironment, which actually very recently has been shown to affect the persistence of the T cells and to lead to relapse as a BCMA CAR T cell treatment in the liquid tumors.
Furthermore, as it was shown very nicely from the clinical trials, we do believe that BCMA-CAR iNK T cell therapy won't need lymphodepletion, which means that we can avoid this kind of lymphodepletion-related toxicities, and iNK T cells naturally home to the bone marrow. Even after discussing the clinical challenges of the current therapies, I think the most formidable challenges have to do with the manufacturing. We have autologous cell therapies that they use cells from heavily pre-treated patients through a very long manufacturing process. Which means that there is a high failure rate, but also the end product is very unpredictable and very diverse. This process lasts four weeks, and unfortunately, many of these patients do not have this time.
The process, even so there is like a huge evolution in the manufacturing, processes and protocols, still this is not accessible to many people and also very expensive. Joy is gonna go into more details in a bit, but what we have done by leveraging our experience with agenT-797, is that we have developed an in-house manufacturing process that consists of three steps, iNKT isolation, transduction, and enrichment. I show this here because we can start with a very low transduction efficiency and enrich the cells over 80%, which means that we keep the genetic modification very limited, a very low copy number. This process can give up to 5,000 doses from a single healthy donor. It is scalable, reproducible, robust, and it's gonna be, as Joy is gonna say, cheap. Right.
To conclude, we don't believe MiNK-413 is another BCMA CAR T cell therapy. We have built the best CAR to express it in the best iNKT cells, which are also armored since they express IL-15, and we have a manufacturing procedure that's gonna make it accessible to many patients while maintaining the characteristics of the cells and their functionality. Thank you.
Thank you. Dr. Joy Zhou has been an expert in cell therapy. A leader in the field, actually, with leading the cell therapy charge at Takeda, J&J, and joining us just earlier this year. She fully internalized the manufacturing process at MiNK, and we are now able to manufacture cells in our own house without the capital-intensive requirements commonly associated with CAR T manufacturing or cell therapy manufacturing overall. Joy?
Thank you very much for the introduction. My name is Joy Zhou, VP at MiNK Therapeutics. I have been leading cell and biologic product development as well as GMP production for over 20 years. As you already heard from today's speakers and also our outstanding internal researchers, how amazing the science about our iNKT cells can potentially offer curative treatment to the patients with cancer and/or immune-mediated diseases. Now, I want to switch gears to talk about how MiNK CMC overcome the CMC cell therapy large scale manufacturing challenges to allow us to transform this amazing science into actual accessible and affordable off-the-shelf product to benefit our patients.
As we all know, for the cell therapy, the biggest challenge is to produce multiple batches from one donor to reach many patients, as well as donor dependency. For all the autologous drug products available on the market, linking the patient to their own cells. That allow the only to lead to high cost of production. In most cases, it will cost more than $500,000 per treatment, but also limits the product to the patients. Now, at MiNK, we develop our iNKT cells into allogeneic off-the-shelf products, which should be easily accessible and available to the patient via our large scale manufacturing. You might ask, how would you be able to achieve large scale manufacturing from one dose per patient to more than 5,000 doses per batch?
Our unique and proprietary manufacturing process combines our unique reagents, large-scale, cutting-edge technology for cell expansion, cell purification and the fill finish with minimal dependence on the donor. This is automatic large-scale manufacturing process with limited donor dependency, allow us to manufacture more than five doses per batch, and also multiple batches per donor. That would drive down our cost of goods significantly less than 5% of our current available cell therapy product. Besides, our fully internalized manufacturing capacity well-positions MiNK in a strong position to ensure stable, timely and a robust product supply. Now, with our accumulated knowledge and extensive manufacturing experience, we are confident that we are able to deliver more than 600 doses per year to meet our potential clinical commercial demand.
To conclude, our MiNK right now is ready to transform our novel iNKT cells into a ready, accessible and affordable product to benefit millions of patients in the very near future. Thank you very much for your attention.
Joy, thank you very much. I'm just going to add a couple of zeros to your doses per year, 600,000 doses per year from our internal manufacturing. Very well done. As a result of the effort that Joy has launched at MiNK, we've been able to supply cells to be at the sites when the patients need them, and that's no more important than patients who are really in the ICU suffering at the edge of life. I have to honor Dr. Terese Hammond, who's with us tonight, who at the beginning of the pandemic, before we even understood what this virus that we were facing was, she was on the front lines and treating patients with her own hands.
In a setting where even autopsies were being eliminated, Dr. Hammond was actually going in and invasively getting samples and sending them to the NIH so that we could better study and understand the virus threat that we were facing. We had the great fortune of working with Terese as a leader on our phase I clinical trial, where she courageously took these cells and administered them to patients, and she's going to share the outcome of our trial results now. Dr. Hammond.
Thank you, Jen, for your kind words. I hope I can live up to this during the presentation. I'm very honored to be here, and it's through the, I think, the vision of Jen, the amazing scientists from MiNK, and my dear friend Steven O'Day from Agenus, that I'm able to tell you a very unique story today. Hopefully, this will just be the first chapter of a book that evolves and becomes a very, very long story for these unique cells. You know, maybe it's because we're both first responders that I feel so devoted to these cells. Or maybe I'm just anthropomorphizing them a little bit too much. But anyway, let me see if I can make this work. I wanna talk to you a little bit. I'm a practicing physician.
I'm a pulmonary critical care physician in a community hospital in Santa Monica. I had the honor of being able to treat five critically ill patients with COVID-19 respiratory failure with these unique iNKT cell iNKT cells. To be honest, I just wanna sort of set the stage for you to frame this in a different way, because I know that really you've been hearing about solid organ and about cancer today and through SITC. I aim to sort of convince you that critical illness, respiratory failure, invasive infections that cause sepsis, COVID-19, kill many, many more people with much more lethality than most cancers now. Because frankly, oncologists have been leading the way. It's hard for me to admit that as a pulmonary critical care doctor.
Oncologists have really forged the path for cell therapy and for making advancements in how they treated their patients, that now I think it's time for us and other fields of medicine to sort of embrace. The ability to use cell therapies in critical illness I think is just sort of coming to the forefront. Again, these cells are so special. They are able to go to areas of damaged tissue, whether it's the lung, the kidney, the liver. They're able to really have the situational awareness in those tissues to activate the right components of the immune system. At least in our patients, they were able to, in these very early trials, show really astonishing survival benefits. This includes in the very sickest patients.
I personally gave these cells to five of my patients, and four of them were actually so sick that they would have died without the most advanced therapy we have, which is a lung bypass machine, something called extracorporeal membrane oxygenation or ECMO. Essentially, when the lungs are so sick that they can't even extract oxygen or give oxygen or extract CO2, you have to use an outside oxygenator or an outside way of getting oxygen into the blood and then returning it back to the patient. We were able, for the first time in history, to give these cells to four patients who were actually on this lung bypass machine. Altogether, in this phase I trial, we treated 20 patients. My five patients were actually in the third cohort, so they received 1 billion of these special cells.
I think as you've heard from several people already, the most amazing thing was that we were able to give 1 billion cells in a community setting. We got these cells in a Mr. Frosty in our pharmacy. We were able to use a Plasmatherm to thaw them, and we were able to infuse them in patients that were in my ICU on tremendous mechanical support successfully. We were able to do it with essentially no side effects. We had one significant event that we reported, but it was probably related more to COVID-19 than anything else. Without any cytokine release syndrome, we were able to give these cells to these patients, and we were able to improve survival.
Now, at the beginning of the pandemic, I think I speak for a lot of clinical people, a lot of physicians that were at bedside, we had very little that we could offer patients with severe COVID respiratory failure. In the first two cohorts of the study that I'm talking about and talked about this morning, elderly patients who were placed on mechanical ventilators for COVID, at least in my institution, 90% of them died. I think that sort of bore out across the board. As COVID advanced, as COVID continued, as the pandemic evolved, we started to use steroids and other therapies, monoclonals. With Dr. O'Day, we were able to actually be part of trials for monoclonal antibodies.
That improved survival, but it also presented another problem, because these patients were all on steroids now, and they were very immunosuppressed. Frankly, when my patients survived the first two weeks or three weeks of their COVID, they often succumb to systemic fungal infections, terrible reactivation viral infections, or healthcare-associated or acquired pneumonias. Not only were we able to give these cells in a community setting safely without activating cytokine release syndrome, but we were also able to do it in a way that these cells significantly reduced the occurrence of other types of opportunistic or other forms of infection in these patients that were treated. We were able to demonstrate, at least in these 20 patients, that we increased the anti-inflammatory response.
We also decreased the amount of pro-inflammatory cytokines that were seen pre and post-treatment in these patients. Overall, a cohort of people that had an average of 60% mortality rate, a 40% survival, we were able to demonstrate a 70% survival rate, a 70% or better survival rate. In my ECMO cohort at 90 days, our survival rate was 75%. Finally, in this study, we were also able to show that there was just a transient autoantibody production when the cells were given to these patients. By day 14, those autoantibodies were, even the ones that were circulating there, going away. There's the potential to redose these cells in people that remain critically ill.
In the few minutes that we've had together, I hope that you've sensed my passion for using these very unique cells in other modalities, in other ways, beyond cancer in critical illness. I think there are multiple aspirational visions of how these cells could be used in critical illness beyond just acute lung failure, beyond COVID-19. COVID-19 has certainly given us all an opportunity to collaborate, and I think that, again, because of Jen's vision, we've all been able to come together and do something very unique here at the bedside that I hope becomes a much greater, much bigger and much greater story as it plays out. I guess I just sort of want to end with the concept that we have a much bigger opportunity with cell therapy in critical illness.
I'm optimistic, I'm excited, and I'm enthusiastic to continue to offer these kind of novel therapies to patients that I care for in the intensive care unit who have very little chance of surviving with the traditional therapies that we use now. This is really, while early, has certainly given us great enthusiasm and promise that we'll be able to better treat these patients at some time in the future.
Thank you very much.
Thank you. Thank you very much, Dr. Hammond. We share your passion for this. The data that we've generated through these trials have actually generated the interest of DARPA to start to advance this science even further. It's so novel. DARPA, as we believe that these cells may actually be more beneficial beyond what we're seeing with respect to anti-inflammatory, pro-inflammatory, cytokine release, stimulation, also immune dysregulation as a whole. We're in discussions with DARPA now and going through the contracting process to support the advancement of these cells in treating the types of illnesses that Dr. Hammond just shared with you. I'm gonna ask Dr. Marco Purbhoo to just share a couple of words about some of the translational findings. Marco Purbhoo has been working with some of the world's experts in identifying ways in which we can understand the persistence bioavailability of these cells.
Where are they going when we dose them? We've shown some data pre-clinically, but now we're gonna continue to expand that clinically. We're showing some preliminary data at this time, and more data will be coming out towards the end of this year that will help us to understand where the cells are trafficking to, and what are they doing when they get there. That will further explain some of the key features and benefits that we're observing in the clinic. Marco.
Okay, thanks. Thank you, Jen. My name is Marco Purbhoo. I'm Director of Translational Research at MiNK Therapeutics. My background is in immunology, in particular T cell biology. For the best part of the last 10 years, I've been working towards bringing iNKT cells into therapeutic applications. I'm very excited to work with MiNK, who are the leading company in bringing unmodified iNKT cells into therapy. Of course, as Mark and the R&D team have explained, they also do quite a few pretty cool things in their plans to modify iNKT cells.
As some of the team previously, and Sapana in particular, have mentioned, agenT-797 is MiNK Therapeutics' unmodified iNKT cell product for use in allogeneic applications. As you've heard today, iNKT cells, their reactivity span the pro and anti-inflammatory spectrum. We believe that iNKT cells have applications in multiple fields given their variety of reactivities. We have been using, as you've heard, iNKT cells in clinical trials in diverse settings, including ARDS and COVID, as well as settings of cancer, including multiple myeloma and solid tumors.
I think our idea that iNKT cells are, you know, able to act in these different settings is kind of validated by the results you've seen today, the encouraging initial results from our cancer trials showing induction of stable disease, and also the robust data from our COVID trial. How do we think that iNKT cells are working in these different settings? Obviously in solid tumors, for example, in the solid tumor settings, in progressive tumors, particular tumors that are refractory to current treatments, they tend to be highly immunosuppressive, and the tumor microenvironment is immunosuppressive.
Now, as you've heard, iNKT cells are able to counteract the immunosuppressive effects within tumors by targeting suppressive myeloid cells and also recruiting downstream immune effector cells, in particular NK cells and cytotoxic T cells. We would hope to see in the solid tumor setting that there are signatures of biosignatures of actually pro-inflammatory activity induced by the iNKT cells. In the ARDS setting, in the COVID associated ARDS setting, it's an entirely different environment. In this case, we have a hyperactivated immune system, which basically leads to hyperactivated immune cells, which induce injury of the lung.
In the ARDS, in the COVID ARDS setting, we would hope that the iNKT cells are acting by reducing the inflammatory environment and inducing an anti-inflammatory immune response. It seems that our biomarker signals are actually indicating that these differential effects are occurring in each respective trial. Here you can see data from interferon gamma levels in serum from our solid tumor trial. As you can see, and as has been mentioned by David Einstein, that there is a spike in interferon gamma on the second day of treatment in our patients. This does seem to be dose level related. It most frequently occurs on the patients treated with a higher dose.
As mentioned, Interferon-gamma is the key pro-inflammatory cytokine secreted by iNKT cells, indicating that agenT-797 in this case is activating a pro-inflammatory mechanism in solid tumor. Now we see this only in our solid tumor study. We haven't seen this in our ARDS study, this spike in interferon-gamma, and we haven't seen it in our multiple myeloma studies. This does seem to be an effect of agenT-797 in the context of solid tumors. You should remember that in solid tumors, the actionable activity is going to be highly localized where the tumor is. The fact that we can detect it in distal areas in serum is encouraging and would tell us that actually there's a lot more to see in the tumor.
We do have tumor material, localized tumor material, and currently, the analysis of that is ongoing. Hopefully we will have our initial readouts on the actual tumor material and biomarkers, then by the end of the year. In the COVID ARDS setting is entirely different. In this case, as mentioned, we see no indication that there is an enhancement of Th1 interferon-gamma-induced Th1 pro-inflammatory activity. As Terese mentioned, there's actually indication that interferon-gamma is reduced in the COVID ARDS setting. Instead what we observe is a durable and quite impressive increase in the key anti-inflammatory cytokine, interleukin-1 receptor antagonist, so IL-1RA.
The mechanism of how this works, it's not a cytokine secreted by iNKT cells. Don't know how this exactly works. It's not fully elucidated, but there are many candidates which secrete IL-1RA, which iNKTs interact with potentially. The fact that we see this increase in the setting of COVID and ARDS again would indicate that iNKT cells are driving an anti-inflammatory response in this setting. A response which would downregulate the hyperactivated immune system and therefore mitigate lung injury. Another thing you should remember in ARDS, on COVID, is that all of these patients are being treated with steroids. You know, steroids which are immunosuppressive.
It is known that iNKT cells are refractory or more refractory to the effects of steroid-induced immunosuppression than T cells and NK cells, for example. What we would see from here that actually the iNKT cells can modify it when, you know, when infused into patients treated with immunosuppressive steroids, that the iNKTs could nevertheless modify the cytokine profile in these patients. They are active in these patients, where other cell therapies may not be active.
If you basically compare, you know, these different, very different settings and the activity of the iNKT cells in these different settings, you'll see that the iNKT cells are able to respond differentially and that they are responding in a context-specific manner, which again is quite a unique capability of iNKT cells. They don't seem to behave like a traditional monotherapy. They seem to be a lot more adaptable in their responses.
Marco, thank you very much. I think what really resonated with me on the translational data that we're observing is that the iNKTs themselves are actually addressing biology that we're trying to address with other therapeutic modalities, and they're doing it on their own. Our final speaker before we go to your questions is Dr. Lydia Lynch. I'm so thrilled that she's our closer for tonight because I think of her in some ways as my therapist, my cell therapist. I often go to her and I say, "Oh, my God, you're the world's expert in MAIT cells and gamma delta T cells and iNKT cells and T cells. What is the best cell type to use? I'm completely consumed by iNKT cells.
Do you agree?" I've asked her, I'm hoping she's gonna answer it in a way that I'd like her to answer it, but I've asked her to give you a picture of what she sees, what she knows about these cells, and where she thinks the possibilities are for the application of these cells beyond some of the observations that you've seen tonight. Lydia?
Thanks. Thank you so much, Jen, and to MiNK. You know, I'm really delighted to be here. It's a setting that I'm not used to speaking in because I'm coming to you with the view of the basic biology of innate T cells. As Jen mentioned, I don't just study iNKT cells. There's a group of innate T cells. There's gamma delta T cells and MAIT cells as well. They're grouped together because they're set apart from all the other T cells which recognize MHC and peptides. These do not. But they are, you know, I'm really quite unbiased because I like them all.
I'm gonna talk to you today about, you know, why I feel these are particularly exciting in cancer, but also in other future directions because we're not with these innate T cells, we're not limited to cancer. We've heard today, this is just a summary of, you know, some of the reasons why the current adoptive cell therapy have been less successful for solid tumors. Potentially there's tumor heterogeneity. If the therapy is directed only at one antigen, the tumor could potentially escape. CAR T cells, for example, have difficulty trafficking and infiltrating into solid tumors. Once they're in there, it's quite a hostile environment. It can be hypoxic, it can be nutrient deprived. Also the starting product is really very important.
If you require autologous T cells, a patient with cancer is often older and also has cancer, so generating a cell therapy from this starting material is not ideal. Actually all innate T cells can overcome these limitations. Because I am a humble PhD with actually no skin in this game, we play this unbiased competition in the lab. Well, I'm convinced innate T cells are the best job for adoptive cell therapy in cancer, but which innate T cell would win? iNKT cells, as we've heard, they can kill. They can kill in vitro, they can kill in vivo. They do a very good job. They also help other cells to kill. They're transactivators. This is why I think they're so potent.
We know the antigen, and we can expand them. This is a really key feature because, you know, it's actually unprecedented, the expansion that you can get with iNKT cells. MAIT cells, on the other hand, can also kill tumors in vitro. If you look at a lot of different solid tumors and look at single-cell sequencing, MAIT cells have the potential to turn bad in the tumor. They can produce IL-17, which is associated with metastasis, so maybe you don't want them there, whereas iNKT cells don't. They may require antigen, but one feature of MAIT cells is that they're very limited in their expansion. Gamma delta T cells can also kill. They don't produce IL-17 in humans. They do in mice, but not really much in human tumors.
However, they can also turn into wound healers in the tumor, which you might not want. They don't require antigen, which initially you might think is a good thing, but it means that we can't expand them. We're very limited in the expansion. For this reason, independent of MiNK, we have come to the conclusion that iNKT cells are the winners. Again, this is like unbiased because I don't mind which one wins. We believe iNKT cells can naturally address problems with current adoptive cell therapy. They can recognize CD1d and antigen via lipid and also CAR, but they can also recognize stressed tumor cells specifically. They naturally home to tissues.
In work that I've done in Mark's lab and also in other labs show, you know, we did parabiosis and show that they live in tissues, and when you take them out, they go back. They also have limited side effects, and we can do mass production, which is what we've seen today. You know, this is what is. We've been studying these for a long time, and we've been waiting for this to finally be realized that they are probably the best living medicine that we have. I think today we've seen that. Actually, MiNK have demonstrated how iNKT cells agree with our unbiased competition. They are an excellent choice for immunotherapy.
They've actually proven that the inherent features that I've just mentioned, but that we've been talking about for 10 years, and we long suspected would be beneficial for adoptive cell therapy, actually are. The question is, for thinking to the future of iNKT cells, how might we make them better? Here we've heard like three or four different ways that they've already that MiNK has already tried to make them better. Xavier's presentation on FAP-CAR IL-15 iNKT cell is the most exciting work that I've probably seen in about 5 years. I was telling Jen, if it was done in my lab, I would have submitted it to Nature for publication already. I think it's amazing. Then also the other CAR and all the other modifications.
One thing that we're interested in, because you know, my lab studies immunometabolism, other things that could be done to enhance them even further is metabolic reprogramming to help them deal with the harsh tumor environment. Here's just some reasons why. You know, we know, actually, you probably all know this, in the tumor it's hypoxic. The tumor is very metabolically active, pumping out lactate. All of these things can impair the T cells once they finally get into the tumor. We kind of know these iNKT cells inside out by now, and here's just an example. You know, we've done a multi-omic approach to see what pathways they use, what transcriptional programs, what metabolic programs they use.
Here's just a little example of iNKT cells at steady state, iNKT cells four hours after alpha-galactosylceramide activation, which is when they're producing a lot of cytokines, and after 72 hours, which is when they're proliferating. We're able to see what metabolic pathways and what cytokines they need for each of the features that they do. Then, just as a proof of principle, what we're calling George's Marvellous Medicine, we have tweaked, you know, the food that we feed them to help them to overcome the harsh environment of the tumor. This here, this picture just shows that we've been able to improve the metabolic fitness of an iNKT cell.
We have been able to make them have more mitochondria, which is important for their longevity in the tumor, and these are just plots of seahorse, which measures their energetic activation. Here, Gen 1 is, you know, the starting material that was known, and Gen 2 is with these metabolic enhancements. You know, the gold standard to actually test this mitochondrial fitness is in vivo in humanized mouse models. Here, when we can metabolically enhance them, we can see clear infiltration, increased infiltration and survival in the tumor, and they keep their metabolic fitness, and as a result, the tumor is decreased. These are in already established tumors.
Okay, finally, this is, you know, beyond cancer. iNKT cells have been called the Swiss- Army knife of the immune system. We've heard today a lot about cancer and also infection, but it's not the only side of of iNKT cells. They have also been implicated in graft versus host disease, in weight, body weight, energy expenditure, metabolism, helping to restore metabolic disorder and obesity. That's probably because they are like smart cells. This is just an example of how we may, you know, because we have a lot of information of the different cells that are the different things that they produce and what they need to produce them, we could take, for example, the ones that make interferon-gamma for antitumor action and anti or against infection.
There's a small population that make IL-10, and these may be beneficial for anti-inflammatory situations, graft versus host metabolic disorder. Then just final, an example of this. This is iNKT cells in green here. iNKT cells in tissue. This is in vivo in a mouse. They're not just sitting around waiting for something to happen. They're actively patrolling. Here their patrolling is very important for metabolic health. When you don't, we actually came to find this with Mark. When you don't have iNKT cells, we noticed that mice were more obese. When you activated them or when you adaptively transferred them back in, the metabolic disorder was restored. The mouse lost weight, not through any sickness behavior, but through increase of energy expenditure.
Finally, I hope this kind of is a little snapshot of showing that iNKT cells are versatile. They're, they transactivate other cells. They've been known to be the conductors of the immune cell orchestra. MiNK have shown that they can be expanded beyond anything we had hoped, and they can also be manipulated for distinct functions in different diseases. Thank you.
Thank you. Thank you very much to our speakers, our panelists, our presenters. I want to open up the floor for questions. We have those online can log in through the chat. We'll be monitoring that, as well as those now in the room.
Hey, good evening. Kalpit Patel from B. Riley. Thanks, Jen and team, for hosting this wonderful R&D event. Maybe a couple of questions, starting with Dr. David Einstein. I understand that these data in solid tumors are still a little early, but are you seeing any evidence of deepening of responses, you know, over time in those select patients with stable disease?
I think the short answer is it's too early to tell. I don't know if this works. In any case. We haven't seen, I think, enough time points to make that assessment yet.
Okay. There was a chart in the presentation showing modulation of interferon-gamma. There were certain spikes in certain patients. Did that correlate with stable disease or do we not have that data?
That is a good question. Marco might be able to talk about that. I remember that we have the information about different dose levels, but I don't know if
Increased dose level, that is within that spike of certain dose levels.
It's a fairly small end.
Okay, fair enough. Then Dr. Exley mentioned that there's a wide therapeutic window for dosing iNKT cells. I guess how should we think about, you know, dose escalating going forward in these patients?
That's a great question. We're already up to 1 billion cells, which is certainly a lot more than you'd have normally. Typically in patients, they're about 0.01% of your T cells, so pretty rare cells compared to 5% or more NK cells, MAIT cells, and gamma delta cells that Lydia was talking about. There's hundreds-fold difference in them compared to these other very active cells that we can increase the amount of substantially. Because we can get large quantities of them, we can have that huge therapeutic window. It really is quite unusual. You can think of it as like antigen-specific T cells, which are pretty rare as well. It's sort of like that's the sort of therapeutic window you want to get.
Okay. One maybe just preclinical question for the FAP CAR iNKT. Are there certain biomarkers that you would recommend evaluating as this program maybe enters the clinic next year for that asset?
Yeah, I guess that's something that we are trying to evaluate for the IND for the next clinical trial. Definitely T cells will be one of the biomarker we will have to follow very, very specifically. That would be a major point. Their activation, their level of infiltration, all of that will be very important to read.
Okay, thanks very much for taking the questions.
Thanks, Kalpit. I'll just add to that I think particularly in the context of FAP expressing tumors such as non-small cell lung cancer, we would look to go for a biomarker agnostic approach and then interrogate response both clinically as well as immunologically based on the phenotypic changes that we're observing.
Okay, thank you.
Hi, this is Yuan Zhi from B. Riley. One follow-up here. Just curious, before and after the infusion of the agenT-797, what cell population have changed in the tumor microenvironment?
Before the administration, the characterization of the product, the formulation?
No. Within the tumor microenvironment after the infusion of this cell therapy.
Okay. Those data are forthcoming. We've developed some very specific assays to interrogate that. Pre-clinically, we have made some observations, and perhaps we could have Sapana speak to some of the modifications that we see intra-tumorally, in the solid tumor preclinical models of the work that we published last year at SITC. Phenotypically, administration of the cells, we can see cells can home to the tumor, persist. Any additional data that you can share now that's publicly available on what's happening within the tumor microenvironment?
What we do know is there was a pro-inflammatory response that we could have observed, so it's an increase of interferon-gamma within the tumor microenvironment. It has been a bit difficult to look at all the cell types, as most of the studies have been done in immune-deprived mice. You want to follow up?
Yeah. Like, I think a lot of our preclinical studies are done in a xenograft model, which, like, doesn't have, like, the other human components, and that's why we developed these in vitro assays to investigate that, and we have, like, future direction going forward to look them in a, like, a model where we can have other myeloid cells, which we know might get activated by those agenT-797.
Yeah. Got it. Thank you.
Yeah. Just a small thing to add is that, I mean, what Marco showed was you see this interferon-gamma spike in the solid tumor trial. If we do this in our xenograft model, you see that agenT-797 is a product that is balanced in terms of Th1/Th2 cytokines it produces. The cells we retrieve from the xenograft tumors are all Th1. They're all Th1. The cells do seem to do what we think happens in the solid tumor patients, which causes this interferon-gamma spike, is that they are really getting pro-inflammatory when they're in the tumor. This is actually borne out by the models that we run internally and also by Sapana's in vitro work.
Thank you. Great. It's Jack Allen here from Baird. Thank you so much for the thoughtful presentations. A lot of ground was covered today. I guess maybe to start on the preclinical side, I'd love to hear any thoughts about the selection of IL-15. Did you evaluate other interleukins as well while looking at IL-15?
I mean, IL-15 is a pretty logical point for us to start with because it's one of the cytokines that drives sort of persistence of iNKT cells, and it's a very good cytokine, you know, for tweaking IL-15 performance, specifically in cancer also. We also know it's a critical cytokine for NK cell activity and also for T-cell activity. As a first choice for armoring, it was obvious. Also, we're not the only ones using this particular bit of armor in their cell therapy. Given what we know about iNKT cells and also what it does for NK cells and T cells that we know we need to attract more of in the tumor, this was a very logical first choice.
We do have, of course, other cytokines and other ways of armoring cells that we're currently exploring, that which I think would add even more oomph to the whole product. You know, for some of these cytokines, you have to be a little careful because they're pretty toxic if you overshoot this.
Great. On the clinical side, I had a question for Dr. Hammond. I was wondering, of the three patients that responded on ECMO, you mentioned that they were, I guess, surviving out to 90 days. Did any of those patients come off of ECMO? I'd love to hear how that, I guess, aspect of their experience compared to what you'd expect without the cells.
Yeah. Absolutely. There are actually four patients. I treated five patients altogether. Four of them were on ECMO. One patient, one of our first patients to be treated actually had came off ECMO, had a double lung transplant and kidney transplant about five weeks ago. The average length of time for the four patients that we had on ECMO was 133 days, which was pretty astonishing. Certainly much longer than our other cohort. I've treated a total of 78 patients with VV- ECMO and COVID. When we look at our other cohorts, our average survival time on ECMO was about 42 or 43 days. We certainly saw that these patients were living longer. They were having less nosocomial infections.
Two patients actually succumbed, one at, I think, 91 or 92 days, and one at about 160-some days. The reason that they died was because we withdrew care. They weren't lung transplant candidates, and they were unable to come off ECMO.
Great. You know, with the long duration response in mind, how do you think about multiple doses of cells as well, both in oncology and in the ARDS setting?
Yeah, definitely. I think that that's a great question, and that sort of goes to the idea, you know, we're giving 1 billion of these cells. Do we need more cells, or do we need another dose? We certainly saw that around 30 days, because we were able to follow these patients out for a very long time. Around 30 days, we started to see an increase in nosocomial-type infections in patients that these patients had been CMV negative, for example, in the first few weeks of the time that they were dosed with iNKT cells. five, six, seven weeks out, we did a lot of bronchoscopies, and we started to see that suddenly these patients had CMV positive results from their bronchoscopies.
My gestalt, my gut says that we should be redosing these patients, and the science says that it doesn't look like they're generating autoantibodies to the iNKT cells, so I think it's feasible that we could redose. Of course, I would give that back to the scientists to really speak in detail about it.
Great. Love to hear from the oncology side as well.
Yeah, I think we'd certainly like to redose. We have the potential to redose because the donors we have can be matched, partially matched to the recipient, but different from each other. That might prevent, you know, because we have a bank of them, thanks to Joy and colleagues, we're able to potentially give them different ones. We should have less likely to have the risk of accelerated rejection. I think it's very feasible, very practical, and very desirable.
Yeah, from a clinical perspective, I think that certainly one very valuable piece of information from this trial will be the on-treatment biopsies, both for persistence of the product as well as kind of the immune microenvironmental changes, that kind of addresses a prior question as well. I think from a tolerability perspective, there's every reason to think that they could be redosed. I think the real question is, do you need to? Obviously from the patient's perspective, the fewer doses, the better. I think that remains to be seen. You know, what's needed for maximum effect.
Hey, Matt Phipps, William Blair. Thanks everyone for this. Dr. Hammond, you just said that you didn't think that the patients had autoantibodies to the iNKT cells, but they did report some donor-specific antibodies. Just maybe could you clarify that?
There were some, so when they were matched, MHC class I was matched. We certainly saw that the more matches that the donor matches to the donor, there were fewer autoantibodies generated, and these were small amounts of autoantibodies. There didn't seem to be any effect when you matched the MHC class II and the generation of those autoantibodies, and correct me if I'm wrong from a scientific perspective, but by day 14, we actually saw that those autoantibodies were starting to decay and go away. You know, I think the conclusion is that there certainly we saw no cytokine release syndrome.
We saw no overt side effects from dosing these cells and at least the small autoantibody bump that we saw decayed over a very short period of time. Would that be fair to say, Mark?
Yeah.
He's my call a friend.
I guess just wondering if you have seen any autoantibodies or haven't been able to look yet in the oncology or multiple myeloma trials, or if you think it's a difference given the inflammatory state of the ARDS patients?
No, no. Data's pending. We have collected serum, but we also in COVID, we were collecting serum day three and day 14, and then some patients
Mm-hmm.
At least we have a much longer time period in the cancer trials to follow. We are basically batching the entire sample, so we can analyze them in one go. That data is pending.
Mark, this I know might be a question for you, but do you think that there's a need for alpha-GalCer pulsing or, you know, addition there?
Yeah.
I know you've done some work on that in your lab.
Another great question. It's something that allows us to control and tune and enhance the activity of the iNKT cells uniquely. Again, there's an on switch in addition to having a depleting antibody as an off switch, for example, built in without any engineering. It's another level that we wanna explore. I haven't explored it hugely because we haven't yet had the need or and we're building up from, you know, a very logical fashion, I think. But absolutely right. That's certainly another thing. There's one of the nice things about some of these lipid ligands. There are lipid ligands which can produce a more Th1 bias from a Th2 bias. You can choose the flavor of the response you actually want. They have this unique ability, and you really can't do that with other even innate cells.
Last question for the company, I mean, for Jen, you guys talked previously a little bit about bispecific approaches or, you know, some kind of a redirecting antibodies. I wonder if that's still something under the hood or if you're leaning more towards a CAR approach at this point.
The CAR approaches have some obvious benefit, and the preclinical data, I think, speak for themselves. The iNKT engagers and the ability to develop are absolutely something that we'll be advancing, and we'll be talking more about it. I wanna give Marc the mic for a moment to just share what we're thinking.
Yeah. We're still building that platform because it's an obvious question. In the conceptual side of things. They both redirect iNKT cells to the tumor, one with an antibody, one with a CAR. The CAR, of course, does more because it adds signaling and it adds armor. We think if you think about the native product of agenT-797, there's a huge potential to optimize the sort of numbers in the diseases where you wanna go, and that's probably easier with an antibody. That's a reason, one of the reasons why we're still developing the platform. It gives us flexibility to work with the native cells in indications that are probably easier to address with an antibody than with a gene-modified cell.
Of course, down the line, we think you can even further enhance the activity of a modified cell by adding more ways that it can see the tumor. That's of course, down the line because the clinical path to get there is quite lengthy. We think that both of these options and the way we're using them and our experience with antibody-based drugs allows us a huge portfolio opportunity to either combine or separately develop these products. Also, from a manufacturing perspective, they have quite different costs associated with them as well. We're pursuing them both. The CARs obviously are now first and foremost, but we are definitely working on the bispecific platform.
I just wanted to add one observation. ARDS is a spectrum. Adult respiratory distress syndrome is starts as an inflammatory process, but 10% or 15% of people who develop ARDS will eventually go on to fibrosis and end-stage lung disease. The question is: Can these cells also modify that disease process as well? I think that that's really intriguing from a pulmonary perspective.
Yeah. I think some of the features of these cells that we're continuing to elucidate is, but they may be protective with the lung epithelial tissue, which opens up a number of development opportunities that we'll be exploring. Do we have a question online?
Yes. There's a question from Justin Zelin from BTIG. He was wondering if the panelists could talk about the potential synergies for MiNK's iNKT cells to be combined with additional agents and any plans to do so in the future.
Maybe I'll just make one introduction, which is very important. I mentioned it earlier. MiNK was born out of Agenus, the parent company, which has been an immuno-oncology company for 28 years, launching first one of the industrialized vaccines, individualized industrialized vaccine products, and now building a pipeline of over 27 antibodies that are advancing in the clinic. A number of them have been advancing in the hands of our esteemed partners. The most recently announced was, of course, our TIGIT bispecific with Bristol Myers Squibb. Agenus has a molecule named botensilimab, which is an Fc- engineered anti-CTLA-4 molecule, which is delivering remarkable benefit across a host of tumors that have never responded to immune therapies previously. We have the plenary presentation on Saturday at SITC and an R&D Day to follow.
Agenus and MiNK share something very important, certainly a vision to advance programs very efficiently and to leverage a really rapid and innovative engine in order to finance our business and expand our innovations to patients as quickly as practical, and that includes through partnerships. Agenus and MiNK also share an alignment and non-exclusive access to our pipelines, which allows us to not only identify optimal combinations, but also to deliver those combinations, which is, I think, first of its kind in the industry, actually, to be able to do this. We have the opportunity to identify what would be the best biology and the products to address the biologic targets. What are the problems we're trying to solve, and how do we solve those problems using our platforms, our agents, and our combinations?
We have very sophisticated in vitro tools that you'll hear more about to help us understand those mechanisms and how to approach biology with different therapeutic approaches. We also have a host of clinical stage assets that are now bearing out quite remarkable data that we believe will be complementary. David Einstein presented a slide that we had shared at AACR a couple of years ago, and it shows that using this Fc- engineered botensilimab, murine model version, combining it with PD-1, we saw an elimination of metastatic lesions to the lung in a melanoma model of about 30%-40%. When you add the cells to that combination, you see complete tumor eradication. That's a combination that we're gonna be evaluating in the clinic.
Now that we've demonstrated these cells can be administered tolerably, they could be administered in combination with commercially available anti-PD-1 Keytruda and Opdivo. We have the opportunity to now accelerate our development plans in tumor types that are otherwise unresponsive to what's available. Yes, combinations are at the forefront of what we plan to do. I'll turn it over to David Einstein to share his thinking on where he believes we may wanna take this.
Yeah. I think there's a lot of exciting places this could go. You could imagine certainly, you know, a traditional kind of post-checkpoint inhibitor setting, for trials. You could imagine up front, right? Certainly in the kidney cancer world, we're very used to using dual checkpoint inhibitors, as first-line therapy for metastatic clear cell kidney cancer, but with, you know, much room for improvement, in both toxicity and response rate, with a goal of kind of, treatment-free survival, actually coming off of treatment entirely in the long term. I also think that there is room in kind of early recurrent settings, for some of these approaches, provided the toxicity is low. I think we would start in some of those advanced settings.
Thank you.
Hi, Hunter Rogers from William Blair. Was wondering if, with the engineered CAR-iNKT products, if you see any changes to the tissue homing properties, compared to the natural iNKTs.
Yes. The short term says yes. Interestingly, as Lydia mentioned, the iNKTs are to go to tissues, and the agenT-797 is going to the tumors. It's attracted by it, but it's also going, for example, in the bone marrow. Interestingly, when we have an engineered iNKTs, the proportions of cells going into the tumors compared to the bone marrow, for example, is huge. So much more of them are going directly into the tumors. Engineering them or redirecting them with an engager, for example, would actually increase their homing toward where we would like them to go and exert their activity.
Hi, Emily Bodnar from H.C. Wainwright & Co. Thanks again for hosting the event. I think this is a question for Dr. Einstein. Could you just talk a bit about your interpretation of the initial combination data in solid tumors? I know it's only three patients, but how does that kind of compare to what you saw in the monotherapy arm? Could you just discuss how many months of disease stabilization you think would be considered positive for patients that have pretreated? Thanks.
Yeah, great questions. I think that certainly, we're all eagerly awaiting more long-term data. I think that, you know, you certainly saw some, maybe enrichment for some degree of tumor response in the combination arms, albeit with three patients. You know, two of three of those had some degree of tumor shrinkage. That may be promising, but I think it's still very early. As to what would constitute a clinically meaningful stabilization of disease, you know, we know from some other disease spaces that six-month PFS is a pretty good surrogate for IO therapies, in terms of overall survival. I certainly think that, you know, that kind of long-term data would be very suggestive. I think we also have to recognize that stable disease is not just one entity, right?
There's, you know, anything between +30% to -20%. You know, that's a big range, right? I think we'd want to look a little bit more granularly at those stable disease. You know, does the stable disease deepen over time, or is it, you know, +10% that isn't really stable? I think we'll have to get down into the weeds a little bit on that. Of course, you know, any of the responding lesions, we want to see whether that's confirmed with follow-up imaging.
Thanks, Emily.
Oh, we have one more question.
This is a serious comment, but, I've been fantasizing for quite some time about having infusions of iNKT cells, native, not modified, by the way, for prophylaxis and rejuvenation purposes. Now, Lydia, your presentation convinced me more than ever that my fantasy should be born to be a reality. Any reason not to do that?
Not that I can think of.
Bingo. Thank you very much.
Joy will be taking orders for your infusions. Just go over it, she'll mark them down. I'm going to go ahead and close the meeting now. I want to truly thank our distinguished panelists for your time, participation, your work on our trials, your work with patients and in science, our scientists, and for all of you for your support. Thanks for joining us today.