I think we have a full house, and we are ready to start. Thank you very much for attending this session. The last time we had an R&D day was in May of 2015. As you'll see today, there's a lot that has happened. In 2015, we were transitioning into a fully burdened, if you will, what's called now an immuno-oncology company. What I'll start with is, of course, the disclaimers, which I need not elaborate on what this means. It's the hypocrisy of the system that can say, "We can lie all we want, and you can't sue us." That's what this statement says. Unfortunately. Hopefully we won't lie. That's right. I'm Garo Armen. I founded the company 25 years ago, and we have been in the business of immunology of cancer for the last 25 years.
We have a very exciting program today, some very distinguished guests that are on the dais, heads of different cancer centers and different disciplines. Manuel Hidalgo is the Head of cancer and hematology at Cornell. Dr. Steven O'Day is one of the very early adopters to immunology. He was the first doctor, if I remember correctly, to inject a patient with CTLA-4. That was 20 some odd years ago. Almost. Almost. 19 years ago. 19 years ago. Dr. Bradley Monk is one of the top people in gynecological cancers and Head of GOG Cervical Division. Of course, we have our own team of superstars here, and they will present to you the breadth of our capabilities and our portfolio, but with a particular focus today. You'll see for those of you who have listened to our. Of course, Dr. Flamenbaum.
Aren't you supposed to be here at the table? I think that's your seat here. Dr. Flamenbaum is the new CEO of our AgenTus subsidiary. To some of you, especially the old-timers, he needs no introduction. For those of you who listened to our earnings call, we made a statement that next year, 2020, we will have clinical readouts from six different compounds that have come out of our own research effort. For today's purpose I think we have a full house, and we are ready to start. Thank you very much for attending this session. The last time we had an R&D day was in May of 2015. As you'll see today, there's a lot that has happened. In 2015, we were transitioning into a fully burdened, if you will, what's called now an immuno-oncology company.
What I'll start with is, of course, the disclaimers, which I need not elaborate on what this means. It's the hypocrisy of the system that can say, "We can lie all we want, and you can't sue us." That's what this statement says. Unfortunately. Hopefully we won't lie. That's right. I'm Garo Armen. I founded the company 25 years ago, and we have been in the business of immunology of cancer for the last 25 years. We have a very exciting program today, some very distinguished guests that are on the dais, heads of different cancer centers and different disciplines. Manuel Hidalgo is the head of cancer and hematology at Cornell. Dr. Steven O'Day is one of the very, very early adopters to immunology. In fact, he was the first doctor, if I remember correctly, to inject a patient with CTLA-4. That was 20 some odd years ago. Almost.
Almost 19 years ago. Dr. Bradley Monk is one of the top people in gynecologic cancers and head of GOG Cervical Division. Of course, we have our own team of superstars here, and they will present to you the breadth of our capabilities and our portfolio, but with a particular focus today. Of course, Dr. Flamenbaum. Aren't you supposed to be here at the table? I think that's your seat here. Dr. Flamenbaum is the new CEO of our AgenTus subsidiary, and to some of you, especially the old-timers, he needs no introduction. For those of you who listened to our earnings call, we made a statement that next year, 2020, we will have clinical readouts from six different compounds that have come out of our own research effort.
For today's purposes, you will hear about the compounds that are slated for registration, starting filing next year. Also a very important compound that could be a game changer for us, not just as a single agent, but as a combination agent for a number of other things in our portfolio. It has the potential to be a game changer to change the sort of the deadened lack of progress we've seen with innovation in immuno-oncology in the last few years after the introduction of CTLA-4 and the PD-1s. As you know, cancer and the immune system are in a tug of war. I know that you get exposed to fashionable terminologies and fashionable ideas in the context of immuno-oncology. The fact is that as a company today, we have a substantial number of reagents that we can work with.
Of course, we're also engaged in target discovery, but we have a substantial number of agents, as you'll hear from Dr. Buell, that we can work with. The trick is to zero in on the timing, the combinations, and the sequence of how these agents need to be used. It's very simple-minded to think that you test an agent in the clinic as a standalone agent and it doesn't work, and hence that agent is declared useless. I think that's a very, very simple-minded way of looking at it. In reality, we will be discovering over the next few years, the optimal ways of using some of the agents.
Of course, we're blessed by the fact that a significant number of these agents are entirely in our control, so we don't have to beg and borrow from anybody to do combinations and other things that we have in mind. Our portfolio here includes, up until about five years ago, we were a company with a limited number of arsenals in our portfolio. In the last five years, we have transformed the company through internal development, acquisitions. Not only have we transformed the company in terms of being a discovery engine in all of these areas, checkpoint antibodies, neoantigen cancer vaccines. There are some very exciting things happening in neoantigen vaccines. For example, yesterday, we spent three hours at the company talking about some of the Star Wars kinds of ideas in neoantigen vaccines.
I don't want to scare you that we spend a lot of money on things that are not going to have results in the next year or two. Nonetheless, we are a company that's going to be driven by innovation. Just like technology companies, without innovation, your products and technologies will be obsoleted. It's critical that we continue innovation. Whereas before, if you came out with a product, you had a 10-20 year monopoly. I think that reality is changing rapidly. You'll hear about cell therapies from Dr. Flamenbaum. Of course, many of you know that our immune adjuvant QS-21, is the key driver of the success of SHINGRIX, which became a billion-dollar product in its first year of launch, and it'll be $2 billion+ this year.
While we have already transacted the royalties, we do expect to get $40 million in milestone payments or milestone-related payments next year from this agent. All right. A number of you ask, "You've got a lot going on. How do you manage all of this? How do you fund it?" This slide tells the story. We have raised over $500 million in the last four years from these transactions. Over $500 million. We have not done a marketed offering of our stock in 4.5 years. The intent is to continue to fund the company largely through innovative, so-called non-dilutive transactions. Of course, nothing is non-dilutive because if you partner, you're giving something away. Nonetheless, this has been our history, and we intend to stick to it as practicably as possible. A very brief story.
One is the history of the company, the other one are the pipeline. At the right corner, you see the pipeline slide. When people look at this particular slide, say, "You've got so many partnerships." Have you really given up everything in your portfolio? The answer is categorically no. Here, the pipeline slide on the right, on the top, shows that we have kept a very substantial number of our pipeline for ourselves. In fact, the programs that you'll hear about today, including our next gen CTLA-4, include programs that are entirely ours. All the magenta colors, magenta is the Agenus color, of course, all the magenta-colored bar charts there are our own programs, 100%, whereas from the rest, we get significant royalties.
For example, the transaction that we announced on Monday this week, a smaller transaction, but it has up to 20% royalties associated with it. As far as the history of the company, we started out as a cancer vaccine company 25 years ago. As the Irish say, it's not for the faint-hearted to be in this business. We've stuck it out, and about five years ago, we went through an important transformation through an acquisition, and that started the cascade of things happening subsequently. Not only putting us in the business of discovery engines for a whole host of things, including antibodies and cell therapy, but also a vertically integrated company, and that's a term that's confusing sometimes.
We made an intentional decision that speed and innovation are absolutely key to our future success, and in order to exercise speed and innovation, you must control a number of the functions that you're engaged in. Starting from discovery, certainly, but also very importantly, cell line development, manufacturing, clinical development, and so on. We have internalized all of these functions, and the history you see here, 2004, the acquisition of 4-Antibody, where Mark Simon was the catalyst for that idea. Mark is somewhere in the back. There you are. That started a process, and then we bought XOMA's manufacturing capabilities in Berkeley, California. It's called Agenus West now. Mark was also a catalyst in that, and subsequently, we purchased other entities and then developed a lot of capabilities internally.
Here's where we are, and with that, I believe this is just a fact check, if you will. People say, "Are you happy with your stock's performance?" The answer is no, I'm not. However, we have been outperforming the industry. That includes the drug index, the biotech index, immuno-oncology index, by a very significant margin, and yet we're not happy with our absolute stock price. Of course, facts will change that as we unfold. The bright green you see is our performance over the last 12 months, and the rest of them are the four indices that we talked about. With that, I will introduce our Chief Operating Officer, Dr. Jen Buell.
Thank you very much. Thanks, everyone, for joining us today. I'm Jennifer Buell, the Chief Operating Officer of Agenus, I'm really proud to be here in front of you today because I believe I'm standing here representing a company that is achieving unprecedented things in immuno-oncology. I'm humbled to be among the giants here, the world's experts in immuno-oncology, they've been advancing treatments, curative treatments for patients in their respective fields now for decades. We're proud and we've benefited greatly from their advisement. Due to our partnership with them, we are now on track to file a BLA earlier than anticipated in 2020. About four years ago, we presented at an R&D day in 2015, we said that in about five years, we will be on track to become a commercial company and set up for unprecedented success.
I believe we are here now and representing to do that. I will talk with you a little bit about who we are.
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What we've accomplished and where we're going, some of the key catalysts over the impending 12 months. Many of the members of our management team are well known to you. They were the inventors, developers, and supported the approvals of immune agents, starting back with Humira, and then more recently, supported the breakthrough designation and accelerated approval for some of the recent PD-1 molecules. Today, you're going to be hearing from Dr. Anna Wijatyk. She's our head of clinical development and operations, and she's going to give you an overview of where we are in the clinic. Through Agenus, we have created a company that is as innovative as it is efficient. In an era where the pace of drug discovery must keep pace with the exponential growth of scientific knowledge to truly deliver high-impact therapies for patients with cancer.
We have set up a company to do that and we've obtained and achieved some unprecedented outcomes in the past three and a half to four years. This includes making strategic acquisitions, developing formal collaborations, executing on those collaborations, and delivering from first in man now to trials that are designed for BLA path, which we believe are on track to file next year. The reason we were able to set up a company of this magnitude, and while it's small in size, we have about 300 people, it's mighty, with three sites producing from antibody discovery to full GMP manufacturing, as Garo mentioned. We were able to set up this company because we knew what was necessary to deliver high-impact therapies. We've been in this field for 20 years in the autologous space, delivering patient-specific vaccines and seeing curative benefits in some patients with highly refractory cancer.
Here you see a patient with metastatic melanoma. These data were published in 2002. What we have learned since that time was in addition to an immune education approach, the need, the necessity to actually expose the enemy, expose the tumor so that the immune system could do its job. Once you had that capacity with the vaccine, the tumor starts shutting down the immune's ability to effectively fight the tumor. We now later became to know the checkpoint blockade. We now have a full suite of tools to address this as well.
In addition to data that we had seen in patients with metastatic melanoma, we also observed in a study that we were running with our vaccine on top of standard of care radiation and temozolomide, that patients who had less elevated PD-L1 expression, so perhaps the tumor was less effective at shutting down the immune blockade. We saw some profound responses in patients with glioblastoma. These data led to a collaboration that's funded by the NIH, run through the Brain Tumor Trials Collaborative in collaboration with Merck, with PD-1 in combination with our PD-1 and vaccine in a randomized trial. The trial is ongoing and we're anticipating data over the next 18 months. Garo mentioned through the acquisition of 4-Antibody, we saw a transformation of what we could actually do for patients, taking a multitude of combination approaches and being able to efficiently deliver those to patients.
We went into the clinic with our first molecule after the acquisition of 4-Antibody, which is a first-generation CTLA-4. It's an IgG1 isotype. It's designed to function like commercially available CTLA-4. As a reminder, there is only one approved CTLA-4 molecule. That's Bristol Myers Squibb's Yervoy. Our molecule is the most clinically advanced molecule. It's designed in a BLA path trial in combination with our PD-1 molecule. These data represent the first patient who was treated with our first-generation CTLA-4. This is a patient with highly refractory angiosarcoma of the head and neck. This patient on the right visual, that was a tumor. It's presented on her face. The patient had failed multiple prior therapies. She entered into our trial, later was profiled on CBS News. When she was, she said she was in the process of planning her funeral, 62-year-old female.
She entered our trial, she's now been disease-free for about over 2.5 years, almost three years. Her physician believes that this could be a curative response. Anna Wijatyk's going to go into more detail about this case as well as a number of other cases, patients who have been treated with our CTLA-4 and our PD-1 molecules. Now, we learned early on that the necessary items for success in IO are speed. In order to have speed, we needed to have fully integrated capabilities. That is the ability to go from an idea in the lab, you're going to hear from our head of drug discovery, Dhan Chand, to a product through our GMP manufacturing capabilities at Agenus West.
We have been able to break all of the industry records as it comes from time to an idea to full GMP manufacturing to dosing that first patient. We have also gone and the industry standard for going from a product, a lead candidate, to actually having the cell line that's necessary is almost two years, 18 months to two years. We've publicly presented and shared in a recent earnings call that we've been able to do it in 2.5 months with a high-quality molecule that's a bispecific, which is more complicated than some of the monotherapy approaches. We've been able to do this reproducibly. We've delivered more molecules, more new discoveries to the clinic in the past 3.5 years than any of the giants in this space.
This is a visual that I could not be more proud of our teams for delivering. This is due to the fact that while we are small with 300 people, we're incredibly agile, and we have team members who work very closely together, all innovating in their space, whether it's from how can we more rapidly discover products, Cailin will talk with you about that today, to then generate the initial lead candidates, test them, bring them to GMP manufacturing. We start early. As we have a series of lead candidates identified, we start cell line development. We pick the molecules with the best pharmaceutical characteristics, and then we start our GMP manufacturing. We can do that seamlessly, and we can do that with incredible speed. Here's the pipeline that Garo referred to. This was our pipeline in 2015, just about four years ago.
This pipeline came just after the acquisition of 4-Antibody. About a year later, just at the acquisition, we had identified what molecules we wanted to pursue. CTLA-4 and PD-1 were no-brainers to us at the time. While we came under great scrutiny because the field had moved to present to us that CTLA-4 was going to become obsolete, and you're going to hear from some of the experts today why that's not the case and why it's become even more critical. The molecule is so important and is the only agent currently available that has demonstrated the kind of curative responses that you're seeing in IO. We advanced CTLA-4 and PD-1 for flexibility, and because we knew we were going to need those molecules for novel combinations with more of our first-in-class and best-in-class agents. You're going to hear more about that shortly.
We established a collaboration with Incyte, where we've licensed our first-generation monospecific GITR, OX40, TIM-3, and LAG-3. Those molecules are in the clinic. I'm going to highlight what we still have access to be able to do. Here's our pipeline today. What you'll see is that we've made tremendous progress in advancing these molecules, both within our own portfolio as well as within our partnered portfolios. Just to highlight Garo's reference that all of the items in magenta are proprietary to us. One more critical point that is often unappreciated or underappreciated is that all of the targets here with nearly no limitation are ours to create multispecific or bispecific approaches. You can imagine the potential of this pipeline and many of our molecules or our approaches have not yet been disclosed.
I'm going to focus for a few minutes on our lead programs before I turn it over to Dr. Manuel Hidalgo, and then later Anna Wijatyk, who will tell you about our data. PD-1 is an impressive molecule. It's generating unprecedented returns in the market. It's over $20 billion in sales and projected to be $30 billion by 2024. Currently, there are two leaders with KEYTRUDA and OPDIVO. There is a need. There is a need. This agent is not only active as a monotherapy, but it's very important as a combination approach with more novel therapies. Advancing this molecule for us enables us to leverage it independently and very efficiently with combinations with our first-in-class and best-in-class molecules. It also allows us to have the flexibility in the market to ensure that every patient who needs access to these molecules will get access to them.
Our approach is to file for an accelerated approval pathway with our mono-specific PD-1 in patients with relapsed/ refractory cervical cancer, followed by the combination with CTLA-4 and PD-1, as we anticipate that where PD-1 is active, CTLA-4 could expand the response rates and durability of response, as we've seen with many other cancers, more recently with RCC, MSI-H colorectal cancer. What's important here, and a few of our panelists will speak to this today, is that right now with these tumors that are a high unmet need, these are the patients with the most vulnerable needs currently, no access to nothing that is beneficial to them. There are mechanisms in which we can pursue accelerated approval pathways, and we're taking advantage of that.
That allows us to move forward in indications where we can demonstrate activity, we can demonstrate benefit to patients through accelerated approval mechanisms, and then later expand that benefit globally. We're taking that approach throughout our pipeline. In 2019, we made impressive progress. Our pivotal trials with our lead compound, zalifrelimab, which is our CTLA-4 first generation, and balstilimab, which is our PD-1 molecule. They're in BLA path trials for accelerated approval, we've announced recently this year that we've completed accrual ahead of schedule for our combination therapy, and we're on track and potentially will deliver a completion of accrual with our monotherapy approach. Those we're expected to complete this year. We've also advanced our next-generation molecule. Our next-generation CTLA-4 molecule is the subject of this conversation today, which is an incredibly exciting molecule.
We believe it will expand the benefit to patients who respond to first generation, as well as to patients who have suboptimal responses to first-generation therapies due to genetic polymorphisms. This molecule entered the clinic in April. It's advancing through several cohorts now. Our combination with our own PD-1 is slated to start imminently. 1181, with our first-generation PD-1, may have profound benefit to patients. We anticipate that it may, based on its design. Should it produce superiority in combination with our PD-1, we have an exceptional opportunity in the market to deliver benefit beyond what's currently available with the monotherapy CTLA-4, but then to be superior to what's currently available with CTLA-4 in combination with PD-1. We're setting ourselves up to deliver on that. In addition to that, we have two very novel molecules, which Manuel will speak to you a little bit about.
One is our differentiated CD137. These molecules, this is a 4-1BB agonist that's shown some very interesting clinical signals. The development of this molecule has been hampered by its liver toxicity. We've designed a molecule that is only active in the presence of the ligand, which, based on preclinical data and cyno models, it's functioning as we expected, which is we could get the agonistic potential without the hepatotoxicity, the liver toxicity. This molecule is in the clinic right now and advancing through dose escalation actively. We created a molecule that's a bispecific. This molecule, what we notice in patients, some of those with head and neck cancer refractory to standard of care cetuximab, for example, have high T-reg infiltration, these immune suppressive cells that are within the tumor microenvironment preventing the immune system from doing its job.
What we saw was that we can take monotherapy approaches and try to dose them in combination or dose them sequentially, and we could not get the optimal T-reg depletion from within the tumor microenvironment. We designed a molecule that can optimally do so. We'll talk more about that shortly. That molecule is also in the clinic. We've also delivered on our partnerships. We've closed a deal with Gilead, announced in January, and this was the largest preclinical collaboration. It was announced in 2019 in December and closed in January. We exclusively licensed a proprietary molecule, the targets of which has not yet been disclosed. This is a bifunctional molecule that addresses very important tumor escape mechanisms, and there are no other molecules like it. That molecule is also cleared IND and is advancing in the clinic.
In addition to advancing the other molecules, we actually not only delivered on the collaboration, which was $150 million up front, and we then delivered about $22.5 million in milestones in the first nine months of the collaboration. It's off to a fantastic start. Gilead's a fantastic company to work with, and we're really enjoying the collaboration. What you can expect in 2020, we'll be filing a BLA, two BLAs. We're on track to do so. We'll also be presenting data on six clinical programs. These molecules are advancing, and these include our first generation CTLA-4 and PD-1, our next generation CTLA-4, which will be not only in monotherapy approaches, but also in combination with our PD-1. Our differentiated CD137 molecule, our first-in-class bispecific molecule. Our allogeneic cell therapy program, which Walter Flamenbaum is going to speak with you about.
This molecule, what we have disclosed is the cell format that we are using for an allogeneic approach. We have demonstrated that we could take this allogeneic cell format. It's manufacturable, it's scalable, the cells are durable. We're currently activating a program in collaboration with Dana-Farber, where we're also conducting our manufacturing. That molecule will be in IND imminently, with clinical data readouts anticipated in 2020 as well. We also expect to deliver on a number of our collaborator milestones, which will generate about $60 million at minimum next year, and these may include sales milestones through our collaboration with GSK. Today, from my own personal perspective, I couldn't be more excited to welcome Dr. Brad Monk, who's with us from Arizona Oncology. He's an expert in gynecologic cancers. He's led multiple approvals, we'll go through his bio soon.
He's been an advisor to us on the lead programs that we have in patients with refractory cervical cancer, and he's been just an incredible source of support and advisement for us. Similarly, Dr. Steven O'Day is joining us. As Garo mentioned, he was the first to dose a patient with first-generation CTLA-4, and he was the first to dose a patient with our next generation CTLA-4. We know that with his touch, we're anticipating to see really great things. I'm delighted to have him here, and he's going to give you an overview that'll help everyone better understand the criticality of this mechanism. Dr. Manuel Hidalgo is joining us.
He's the Chief of Medical Oncology now at Weill Cornell, an expert in delivering immune therapies for patients, and he has brought some tremendous benefits, specifically in the areas of pancreatic cancers to patients and some of these untouchable tumors. We've been looking at our more novel approaches with him and how we can essentially bring benefit to patients who are not responding to first-generation therapies. On our team, we're going to have them say a word about themselves when they introduce. Please, Dr. Hidalgo.
Thank you very much. Good morning. It's really a pleasure to be here and to discuss some of the burning topics in immunotherapy. This is the title of my talk, which is going to be an introduction to the field, highlights areas where we have substantial clinical efficacy and how we can optimize in those areas. Areas where we have clinical efficacy but not still substantial, and cervical cancer can be one of those tumors, and how we can do better in those tumor types. Talk also about the cold tumors, the tumors like pancreatic cancer, which is what I spend most of my time doing in the clinic as well as in the laboratory. Which strategies can we use to turn those tumors into immune-responsive diseases? This is my disclosure.
Today, we're going to talk about immunotherapy, and together with precision therapy, these are sort of the two more recent revolutions and two of the new pillars of cancer treatment. We tend to think that they're a little bit disconnected at the moment, and actually, if you look at diseases like, for example, lung cancer, patients that respond to precision treatment strategies tend not to respond that well to immunotherapy. I think that at the end, this field is coming together, and we're learning that actually some of the mechanisms by which tumors become resistant to targeted agents, to tyrosine kinase inhibitors, may put them in a situation to be more vulnerable to immunotherapy. I think there's going to be a significant merging of these two strategies. Today, we will talk about immunotherapy.
Of course, we don't need to forget that surgery, radiation therapy, and chemotherapy are still very critical to management of many tumor types, and pancreas cancer being one of them. We're going to talk about different mechanisms, and I know you're familiar with many of them, and Steve will provide more information. Just to give you a couple of cartoons on PD-1 and CTLA-4 inhibitors, which are the core of the presentations today. This is an example of a cartoon on how AGEN2034, balstilimab, works, which is by blocking the PD-1 receptor, PD-1 target, by that enabling the activity of APCs and as well as the activity of T cells. As you heard, significant number of approvals, very effective in many tumor types, though not in all of them.
I think that there is room for improvement above the agents that we have at the moment by doing mainly combinations, and I will show you some data on that. You have the CTLA-4 target. This is where the zalifrelimab works, which is by priming T cells and also importantly by modulating Tregs, by modulating regulatory T cells. When we hear today about 1181, you will see that one of the fundamental mechanisms by which this new CTLA-4 inhibitor may be more effective is by modulating regulatory T cells.
I think there is room clearly for improvement in this particular target that perhaps is a little bit less exploited than PD-1 if we look at these things all put together. This is recent data presented at ESMO, published in the New England Journal of Medicine a couple of months ago, which is, I think, perhaps the peak of the effectiveness of immunotherapy in treating a very dismal cancer like malignant melanoma a few years ago. You see here the 60 months outcome of patients treated with a combination of ipilimumab and nivolumab that shows that there is about above 50% long-term survivors. This is an amazing data. This has been obviously a significant, very major improvement for these patients.
The point here is that in tumors that are PD-1 sensitive, and melanoma is one of them, actually, the combination of PD-1 + CTLA-4 in many of these tumors is actually better. Melanoma, renal cell carcinoma, and non-small cell lung cancer being, I think, the three major examples. In those highly sensitive tumors, we can call it that way, I think the most important area of research is to identify biomarkers that will help us to segregate patients from diagnosis, whether or not they're going to do well with these treatments or they are not going to do that well, and therefore, they may be better off with some other strategies. The biomarker field is still evolving. These are the most recent data in another PD-1 sensitive tumor, non-small cell lung cancer, addressing the role of expression of PD-L1.
As you can see in the left and the right, in this particular data set, expression of the PD-L1 does not appear to predict for better survival in patients with non-small cell lung cancer treated with those combinations. There's still work to do in this field. Perhaps the better validated biomarker is MSI, tumors that have a defect in microsatellite, that has microsatellite instability because they have problems to repair some of the DNA damage. Those tumors have been shown to be highly sensitive to PD-1 blockade. With two comments, that even in this tumor set, even in this biological scenario, the combination of PD-1 and CTLA-4 is also effective and probably more effective in inducing responses. Number two, that despite the initial data showing that MSI is a very good predictor of efficacy for PD-1 blockade, is not the same across all tumor types.
The most recent data shows that tumors like, for example, pancreas cancer, which is what I spend most of my time working on, the response rate is only about 18%, and actually, the progression-free survival is very short, is about two, three months. It's true that those 20% patients, when they respond, they tend to stay. The response tend to last, which is a common observation in immunotherapy. We have nine months of disease control rate of duration of response in these only 20% of patients. Not all the MSI patients are the same. Opposite to melanoma, kidney cancer, there are tumors that are just not responsive to immunotherapy. This is the most recent data with PD-1 and PD-1 + CTLA-4 inhibition in pancreas cancer. What you see here is that there are no differences.
The two strategies are equally bad, and the results are very poor. Of course, we can argue that these agents may not be the best agents targeting these two particular checkpoint targets. Nevertheless, the median survival is about three months, which is obviously very poor. Now, I have been interested, and many of us have been interested in trying to reverse this situation. Over the years, there have been a number of different hypotheses that have been proposed. Listed in this slide, there are some of them. Important to note that many of those targets or many of those mechanisms, actually, if you look at the pipeline that was presented before, are there or can be developed, which I think is one of the strength of what we are hearing today.
CSF1R, CXCR4, IDOs, some of those have been already tested in the clinic and actually failed. Some of them are still in progress. I've been working mainly with the CXCR4 PD-1 interface by trying to modulate the signals that come from the tumor microenvironment, from fibroblasts, which are very abundant in pancreas cancer and in some other tumor types. Those fibroblasts secrete signals that cause immunosuppression by different mechanisms, but mainly in pancreatic cancer by blocking the ability of T cells to infiltrate the tumor. Just to give you an example on how you can actually start reverting this situation. This is an example of the patient's biopsies in a study that we did combining a CXCR4 with pembrolizumab, with a PD-1 inhibitor. What you can see is that before treatment, there is very little T-cell infiltrate in the tumor.
When you prime with a CXCR4 inhibitor, you start seeing that there are T cells in the tumor. There are CD8, CD4 positive, and importantly, the number of MDSCs, the number of bad players of negative regulators decreases. This is important data because it shows that. You can really reverse, by using modulators, the mechanism of resistance to, in this case, PD-1 blockade in pancreas cancer, and we have seen some responses. Actually, these are probably one of the very few responses on MSI stable patients with PD-1 inhibitors. By alone, the response when you give them alone is basically zero. Here we have seen the first few PRs by combining CXCR4 blockade plus PD-1. This is one of the mechanisms.
It's not the only one, but I'm bringing it to illustrate that the role for combinations in these particularly cold tumors is very important, and that the pipeline that Agenus has, really has the possibility to individualize and to work with those different targets to elicit responses. As expected, in those patients with pancreas cancer where the combination induces a response, the response tends to last. The issue here is to induce a deep response, because we have learned in many tumor types that once you achieve that, the duration of response tends to be long. It is really a mechanism of primary resistance, trying to make them work early on in the course of the disease.
As alluded before, I'm going to show you a couple of new agents that have the potential to be combined with PD-1, CTLA-4s and do that switch in the tumor microenvironment, in the Tregs, in the antigen-presenting cells, and make immunotherapy more effective. This is AGEN2373 and 4-1BB agonist that, as you know, those have been developed. urelumab was in clinical trial and was discontinued mainly because of liver toxicity. This agent does not induce liver toxicity and has the potential to enhance T cell activation, enhance NK cell cytotoxicity, and also improve antigen presentation. This is an example of an agent in the pipeline with potential good mechanisms. Here, without disclosing the target, talking more about the technology, the ability to create bispecific antibodies targeting two signals that are very hard or impossible to target if you were to use individual agents.
This has the potential to, as I said before, to interfere, modulate many of the mechanisms that I have presented before. In this particular example, it's a way to boost T cell effector cells and at the same time, to eliminate the negative regulators, the Tregs that are precluding an activation. To go to the final part of my presentation, which is one of the topics of discussion today, I'm going to present a few slides to set the stage for cervical cancer. As you know, it's a viral-induced disease, it's a significant health problem across the globe, and there are about 12,500 new cases in the U.S. This tumor, when it presents early, can be treated with surgery, with chemotherapy, and chemoradiation.
For patients who have recurrent disease, the prognosis is very poor, and the base data available with chemotherapy plus/minus angiogenesis inhibitors, as you can see here, is very negative and really is a very poor prognosis situation. It affects young women and is a worldwide very significant health problem. Immunotherapy works in cervical cancer, but is not as bad as pancreas cancer, but is not as good as it is in melanoma. These are sort of intermediate PD-1 responsive tumors. This is the data of the KEYNOTE-158, single agent pembrolizumab, with about 14%-15% response rate in the PD-L1 positive tumor, PD-L1 positive patients that led to registration based on phase II data. As you can see, there is a median PFS of about two months and a median survival of 11 months in this patient population. Now, PD-1, there is a signal.
It's not 30%-40%, it's not zeros, about 15%-20%. When combined with CTLA-4, when combined with ipilimumab, in this case, with nivolumab and ipilimumab in two different schedules in the CheckMate 358, response rates went up to 20%-30% in this clinical trial. You have median survivals now in the range of 13 months for patients who have not received prior treatment for systemic disease. It is a situation where you will hear today about the designs of the CTLA-4 and the PD-1 trials with the balstilimab and with the zalifrelimab. It is clearly a situation where you could improve the response rate, which are durable, with both PD-1 blockade or PD-1 + CTLA-4 combination. Cervical cancer is attractive for immunotherapy because it's a viral-induced disease, and these tumors tend to escape the immune system, mainly through the expression of PD-L1.
That's been the most important mechanism. There is, of course, expression of other checkpoint and regulatory markers in T cells. They tend to secrete immunosuppressive cytokines and that lead to a T cell exhaustion type of mechanism. It's an interesting disease from the point of view of harnessing the immune system to target cervical cancer. To conclude, and to provide some final comments on these three different scenarios, obviously for patients that have PD-1 and CTLA-4 result in clear OS, melanoma, non-small cell lung cancer, kidney cancer, I think the field is going towards developing biomarkers, developing regimens that are less toxic. Very important to develop sequence and combinations with other standard of care agents. In lung cancer, particularly chemotherapy. In renal cell cancer with tyrosine kinase inhibitors. In melanoma, nothing works, so they're given just by themselves.
Of course, as the regimens become more complicated, cost is an issue, and how to sequence the drug and how much do we need to give of each one of them at every time point becomes very important. For the tumors that are resistant in the other spectrum, the very cold tumors, on one end, we need better drugs. We need, of course, to work on other targets. I showed you a couple of example with CXCR4, 4-1BB, and there's others. Combination strategies, in my mind, will be critical to convert these desertic tumors into immune sensitive diseases. I think this is where new strategies, and we will hear about some of those today, like adoptive cell therapy, cell therapy combinations will become very, very relevant.
In the intermediate tumors like cervical cancer, gastric cancer, liver cancer, where there is a PD-1 signal but is not as bright as it is with melanoma and kidney cancer and the others, the combination with CTLA-4 is showing increased responses that, if maintained, will be, I think, a significant benefit for patients. This is my last slide. I hope I was able to provide a brief introduction of this everyday more complex field. Now I'm happy to take questions or questions can come later. How do you want to do the QA session?
We're going to move back to the QA session. We're going to turn it over to Anna.
Perfect. Thank you very much.
Good morning. My name is Anna Wijatyk, I am the who is the head of clinical development at Agenus . It will be my role today to introduce you to the clinical development plans and activities with our anti-PD-1 and anti-CTLA-4 agents, balstilimab and zalifrelimab. I would not repeat what Dr. Hidalgo already emphasized, the mechanism of actions of anti-PD-1 and anti-CTLA-4, including the combination potential. It is important, though, to highlight that pharmacologically and functionally, our agents are comparable to commercially available agents. That's been demonstrated through a number of preclinical assessments. Importantly, those two agents have been in clinical trials in multiple solid tumors, mostly phase I, dose escalation, and expansion studies, as well as in registrational studies for cervical cancer. This is a slide that recapitulates the data that we have shown previously with our anti-PD-1 agent, balstilimab.
Clinical benefit have been demonstrated in more than 60% of patients with multiple tumors. This data has been reported at ESMO 2018. As you see, we have had a few partial responders. We have also number of durable disease stabilization. In terms of partial responders, this is obviously the data that comes from ESMO 2018, we have a little bit more information at this time. The cervical cancer patient that you see here on the left side, this patient have been in our clinical study for two years and actually completed the treatment and remained partial responder at the time the treatment was discontinued as part of the study design. The number of ovarian cancer cases, we were able to analyze those cases and present it during the SITC this year.
There were 12 cases of ovarian cancer that we were able to look at and present the data on. Before I talk about this data, I think it's important to understand what population this is. This data comes from the phase I patients that received multiple lines of therapy. As for ovarian cancer, the treatment is already pretty difficult. The success rate is not that high. This disease constitutes a significant unmet need. Moreover, the patients that enter phase I clinical trials, they are patients that exhausted pretty much all available treatment options to them. I think it's important to look at this data in this context and understand that with the treatment with our anti-PD-1, those patients show durable response and disease control. I think the case that is very important to highlight, this is the first case that you see here.
This is a patient that was stable for more than 80 weeks on the study. The other case, which you see just below the first one, is a partial responder that also was a durable case that went over the 50 weeks of treatment. I would like to talk about our anti-CTLA-4 agents. As you know, we presented the data associated with the clinical study that we've done as a monotherapy. This slide recapitulates the phase I overview. Zalifrelimab was shown to be tolerable to six milligrams per kilogram every three weeks.
We have seen the monotherapy providing activity across a range of tumors, and that includes the case that Jen had shown previously, the case of angiosarcoma patient that was treated by multiple lines of therapy with no improvement and benefited from zalifrelimab treatment, and that response is durable 2.5 years after the study start. We learned from multiple indications that where PD-1 is active, CTLA-4 has a potential to expand the response rate and durability. From different indications, we've seen that CTLA-4 enhances the efficacy of anti-PD-1, doubling in some cancers. As you can see here, examples from melanoma, MSI-H colorectal cancer, small cell lung cancer, and most recently, we've seen some hints of efficacy in the combination studies with anti-PD-1 and CTLA-4 in cervical cancer.
It is also expected that CTLA-4 would expand the durability of the response, and that's been demonstrated in the first-line melanoma in a CheckMate 067 study, where the combination treatment improved the PFS as well as OS. We at Agenus are pursuing two paths for the fast approval with our agents: the monotherapy anti-PD-L1 and combination therapy, PD-1 and CTLA-4. Those accelerated paths have been fully validated by others for monotherapy as combination therapy. Our endpoints for accelerated approvals will be based on overall response rate as well as durability of the response. As we emphasized earlier, we are on target for BLA submissions in 2020. Of course, there is an additional potential for our agents.
We are looking into expansion into other indications beyond the cervical cancer, assessing the indications where those agents could demonstrate clinical activity, and potentially also could be combined with our newest agents. Those indications would be planned for BLA submissions 2022 and beyond. Let me talk about our two pivotal studies for the BLA path. The first one, the study with balstilimab monotherapy, is a study phase I/II. We initially started it in the advanced solid tumors all comers, and then we led it now through the cervical cancer expansion cohort that is planned to be our population for the BLA filing. In terms of key inclusion criteria for the cervical cancer, we are selecting patients that have histologically or cytologically confirmed locally advanced or recurrent metastatic squamous cell carcinoma or adenocarcinoma of cervix.
These patients are immuno-oncology agents naive, they need to have measurable disease by RECIST 1.1 at the inclusion. These patients have had to be treated with the first-line treatment, platinum-based, also had to have a sufficient performance study to be entered into our study. Another criterion that they needed to have is adequate organ and marrow function. In the dose escalation phase, we looked at number of doses. That included the doses as low as one, three, 10 milligrams per kilogram every two weeks, as well as we looked at higher doses, six and 10 milligrams per kilogram dosed every three weeks. Based on the data from the phase I, we selected the phase II dose, which is three milligrams per kilogram every two weeks as a monotherapy.
The primary endpoints on this study are objective response rate per RECIST 1.1, and this is assessed by the independent core lab, not investigator's assessment, but independent core lab. Secondary endpoints include safety, pharmacokinetics, the duration of the response, disease control rate, PFS, and OS. I wanted to share with you some cases that we have seen in our monotherapy study, cases of response. This first patient is a patient that started treatment in May 2018. She's been on the study for about 1.5 year . This is a 64-year-old female that was initially diagnosed with the FIGO IIIa stage squamous cell carcinoma. She received prior treatment, in 2016, with carboplatin and paclitaxel, and then the patient progressed and was included in our study. On the left side, you can appreciate the lesion resolution from screening to cycle 36.
This is a case of a complete responder. The patient had a target lesion in mediastinal lymph nodes, and on cycle 6 onwards, the patient resolved the lesion. A second example from the monotherapy anti-PD-1 study. This patient had been treated for 52 weeks. As you can appreciate on the left side, the patient had a supraventricular conglomerate that is compressing on neighboring structures. Progressively, the patient improved in terms of the lesion, so there was a regression of the lesion. The patient was assessed as a partial confirmed response. The patient continued to evolve, and finally, at the end of the treatment, we've seen a complete resolution of the lesion. Unfortunately, the patient developed new breast cancer and was discontinued from the study. However, at the time of discontinuation, the patient was complete responder for the lesions that were selected on the study.
Let me move on to the introduction to our combination study, an anti-PD-1, anti-CTLA-4 agents. The study design was similar to what I've described for the monotherapy. Same inclusion criteria, same plan for the dose escalation and dose expansion. The dose escalation was a little bit more reduced. We only looked at a couple of regimens. For the anti-PD-1 agent, one milligram per kilogram every two weeks, or three milligrams per kilogram every two weeks. Anti-CTLA-4 agent was dosed at one milligram per kilogram every six weeks in both regimens. Based on the data from that dose escalation phase, we selected the dose for the dose expansion, and that is three milligrams per kilogram every two weeks for anti-PD-1, and one milligram per kilogram every six weeks for anti-CTLA-4. The primary and secondary endpoints are same as for the monotherapy study.
Here, I would like to show you a couple examples of the responses on treatment. Here you can appreciate a patient that started treatment in January 2019. She has been on treatment for more than 10 months. The patient has a liver lesion, and you can appreciate here on the images that that lesion was considerably decreased between the screening and week 36. This is a 30-year-old female that initially was diagnosed with the FIGO IIIB stage and underwent chemoradiation in 2016 with adjuvant carboplatin and paclitaxel in 2018. She had a combined treatment. Another case example represents a patient that is continuing on treatments since March 2019. The patient is a 57-year-old female that was diagnosed with a FIGO IIIB stage squamous cell carcinoma of cervix. She underwent hysterectomy and chemoradiation in 2015.
She relapsed and received the first-line treatment with carboplatin and paclitaxel in 2018. She relapsed again, and she went on our study. This patient represents a local recurrence in the vaginal stump. You can appreciate here on the left side that this lesion is very close to the bone and is causing some osteophytic reaction on the bone. When you look at this image at week 27, you see that the lesion is completely resolved. This is another case of a complete response. To conclude, I would like to highlight our goals for 2019 and 2020. In 2019, we are planning to completely accrue for our BLA trials. As Jen has mentioned, we have completed our accrual in the combination therapy studies, and we are planning to do so before the end of the year on the monotherapy study.
We completed one preplanned, pre-specified interim analysis on the combination therapy study. We are in the process of completing the other analysis on the monotherapy study, and we are also getting ready with the commercial supply. In 2020, we are planning to file two BLAs, monotherapy and the combination therapy. We also anticipate to accelerate the combination treatment between our anti-PD-1 agent balstilimab and our next generation CTLA-4 agent AGEN1181, as well as we are planning to expand strategic clinical collaborations. Thank you.
Thank you very much. Good afternoon. Before we kick off our first Q&A panel, we're going to have Dr. Monk say a brief five-minute overview on Agenus and the cervical cancer landscape. Dr. Bradley J. Monk is the professor and director of Gynecologic Oncology at Creighton University and the University of Arizona, both in Phoenix. He is also the research lead for gynecologic cancer for US Oncology and the co-director of the GOG Research Consortium. Dr. Monk chaired the NRG Cervical Cancer Committee for 11 years and is currently the Chair of the Gynecologic Cancer Intergroup Cervical Cancer Committee. Of course, his paper in Journal of Clinical Oncology in 2009 established platinum plus taxane as the global standard for treating metastatic cervical cancer. Of course, his paper in New England Journal of Medicine led to the 2014 FDA approval of Avastin in cervical cancer.
This was the first FDA-approved targeted agent in gynecologic cancer. He's a passionate developer of immunologic agents in gynecologic cancers and was instrumental in the 2018 FDA approval of Pembro in cervical cancer. As I mentioned, he's also an investigator on Agenus studies, and we are honored to have him here from Arizona. Without further ado, I give you Dr. Monk.
Thank you. Is this active? Yes? Thank you for having me. I know you guys are very busy. I want to thank Garo Armen for his leadership, for trying to bring new medicines to my patients. Gynecologic cancers are a challenging situation. My specialty, though, has evolved. I used to say that I was a surgeon that gave chemotherapy. Now I'm a medical oncologist that operates. Our specialty really has evolved to a medical oncology opportunity. It's my pleasure to talk to you a little bit about cervical cancer in general. It's estimated that there'll be 4,250 deaths this year in our country from cervical cancer, and those would be the sorts of patients that would be eligible for these medicines, Anna, that you've described. Globally, 311,000 patients with cervical cancer. I get many of those are in underdeveloped countries.
Cervical cancer is the fourth leading cause of cancer in women and the fourth leading cause of death. It's a high unmet medical need. It's been a challenge to get medicines to patients. In 2006, working with GSK, we got topotecan approved, a very toxic, ineffective drug. We had eight years where we really had nothing approved in gynecologic cancer. Eight years. Also in ovarian cancer, endometrial, everything. Eight years, nothing. There were three things that changed during those eight years. One of which, this law in 2012 that allowed us to get accelerated approval. I think you're aware that most drugs are brought to market today through single arm trials, generally about 100 patients, that show a surrogate of clinical benefit and a high unmet medical need, generally overall response rate with an unprecedented duration of response, even some complete responses and acceptable toxicity.
That's 2012 law, and that really was helpful. The second was to show that in our randomized trials, that progression-free survival was an opportunity. You know from pancreatic cancer that overall survival has kind of been the threshold. Us showing to the FDA that these patients, at least in ovarian cancer, get lots of treatments, that PFS is okay. Third, the Gynecologic Oncology Group has really been able to sustain the Institute of Medicine reorganization and all of these external pressures. Many of these trials and outcomes were through the GOG, which I'm honored to serve. As a result of that, in ovarian cancer, you've seen we've got seven PARP inhibitor indications since 2014. Seven. We got three Avastin indications. You even saw what we did in endometrial cancer in September, pembrolizumab and nivolumab, right? That was 94 patients, close to 100.
As you mentioned, thank you for your kind introduction, bevacizumab was the first targeted agent. We had that eight years from 2006 to 2014. We got bevacizumab approved, and that was interesting. There was a survival advantage, and thank you for showing that. Ultimately, last June, pembrolizumab was approved. Three FDA-approved medicines in cervical cancer, topotecan 2006, bevacizumab 2014, and pembrolizumab, second line metastatic, accelerated approval. We actually got on 77 patients. I told you you needed 100. We got 77. The response rate for pembrolizumab was a whopping 14%. That's the high unmet medical need. With, again, Garo, I call him Garo, probably you guys do too.
With his leadership, we had an advisory board, we said, "Look, you have these wonderful medications, we can do what Merck did, but we can do it even better with CTLA-4." As Professor Hidalgo said, CTLA-4 makes warm tumors hot. It doesn't really make a cold tumor warm. It works the best in the cancers where there's a little bit of a signal. We went to ESMO, you showed us that the response rate in cervical cancer was three to four times more when CTLA-4 was added. The good news is we'd already been working on that for 1.5 year . Anna, you showed the progress that we've been making, those trials are close to enrolling or finishing enrollment, hopefully we'll be able to bring the combination and probably the single agent PD-1 as well.
We're really excited about the combination, and that the beauty of the Agenus pipeline is that there, I think, you guys can correct me, I think there's only three companies that have both PD-1 and CTLA-4. We talked about BMS. BMS is distracted. We're way ahead of them. They're not going to pursue it. Regeneron. Regeneron is focused on a single agent cemiplimab program, and then Agenus. Agenus really is going to be the leader in PD-1, CTLA-4. It's a proof of concept, so you can ultimately have confidence in their medicines. Importantly, it's so I can have these medicines in the clinic. That's what I'm here to thank you for. I'm here to put into context, here to really put into focus what the competitive landscape is.
Thank you for your support of our ovarian and endometrial cancer programs as well because without investment, we can't really drive those opportunities. Thank you for having me, and thank you, Garo.
Thank you so much, Dr. Monk. That was very well stated. We've very much benefited from Dr. Monk's advice to us as we've advanced these programs. I'm going to now welcome Dr. Steven O'Day, Executive Director, the John Wayne Cancer Institute. Dr. O'Day?
Thank you. Is this on? Can you hear me? Test. You got it? Okay. It's great to be here, and I'm here to really talk to you as a clinician also. I'm a melanoma specialist, and I've been at the forefront of immunotherapy. I'm a clinical researcher, and obviously, I have had extensive experience with drug development. I really want to share with you the story a little bit better on this revolution, because this really has been a tremendous frame shift. As Jen said, I was lucky enough to be in melanoma. No one says that, but now they do. Back in 2000, it was considered the graveyard of drug development.
There was a small company, Medarex, that came to us with a molecule that we took on as a new potential immune stimulant agent, and I was involved with the group that put the first human patient on that study. Well, who would have known that 10 years later, I got to present a phase III data in melanoma at ASCO in front of 50,000 people, showing the first randomized data improving survival in a drug that was a 10% response drug. Last year, the Nobel Prize was awarded for this discovery of CTLA-4. What a ride. You might ask, why would I risk that by picking a new next generation CTLA-4? Well, I don't know. I think lightning strikes twice. We'll see, but let's go forward. What I really want to talk to you about is this revolution.
I'm going to be a little bit agnostic to drugs and specific for targets, CTLA-4 and PD-1. I want to tell you about the resurgence of CTLA-4, historically, this was a drug, as PD-1s were developed, everyone thought, well, PD-1s are just a better version of CTLA-4 with less toxicity. I hope you come out of this with the understanding that they're completely different drugs. Yes, CTLA-4 has more toxicity than PD-1, but it has more memory and durability and we've now figured out how to manage the toxicities better and the dosing of combinations, where I think it's an essential part of the platform going forward. I'm going to talk a little bit about the complex immune tumor interactions that's now really the state of the art of the field and where we're going to go.
First of all, the reason why drug development I'm optimistic about in immuno-oncology is unlike chemotherapy, where responses were difficult to predict eventual clinical benefit because heterogeneity of tumors allows for rapid responses, but then aggressive clones become resistant and can actually shorten survival. There was always this disconnect between responses, progression-free survival, and overall survival. The FDA got a little worried about how do you do this, and that's why they required big phase III studies, randomized, long follow-up with this survival. I think the world's different now because responses are so durable with these immune drugs, and stable disease, which historically was not very relevant in chemotherapy drug, is relevant in proportions of patients.
Disease control after about a year to 18 months is highly predictive of survival, and it will allow for benefit to be shown earlier with single-arm studies when there's significant added benefit. The reason for this is the immune system. Unlike chemotherapy that's directed towards the cancer cell, the whole approach here is giving the cancer cell its due. It's very heterogeneous. It has the ability to really resist so much. The immune system is really, that's its game, right? Viruses, any foreign, it's very good at managing resistance, finding memory in its T cells, and then relaunching attacks when there's subclinical relapse of viruses. To the extent that we capture that ability in cancer, it's hugely impactful. Now we have to have real advances, but when we see these deep responses in early studies, they're much more predictive is my point.
On the left is the tumor. Let's talk about tumors that are more visible to the immune system and less visible. I hate to say, I hate the term like melanoma's immune sensitive and other tumors are not. Every tumor has immune sensitivity. Melanoma, more of it is sensitive, so and renal cell and smokers with lung cancer. Every tumor, to some extent, is seen by the immune system on the left. It releases its antigens, its proteins, that are then picked up by these antigen-presenting cells that then go talk to the T cells in blue on the right. The T cells get activated, and then they go back into battle. All of what I'm going to talk about is really related to the T cells engaging and expanding, building the army. That's CTLA-4.
Think of CTLA-4 building that priming army, and then PD-1 is really helping those T cells when they're in the midst of the battle. Very different endpoints of this cycle. It's only become apparent more recently that CTLA-4 not only builds the army, but there are regulatory or suppressive T cells in the tumor, and it may also suppress that so that the ratio of the good T cells in the tumor and the bad. CTLA-4 may actually be working in a couple different ways. These are the two endpoints. On the left is CTLA-4 activating T cells early, PD-1 activating them at a later phase of the cycle. This really explains the durability, the kinetics of the response, and the toxicity.
When you're building a battle of troops, it takes time, and the CTLA-4 data showed us it took three to six months to really know whether somebody was really benefiting. With PD-1, it's only two to three months. That's because the T cells are already where they need to be, and they're resurrected. The problem is, when you're resurrecting exhausted T cells, I'm going to show you shortly, they may not be as durable in terms of response and the memory features of those T cells. They do produce responses, but different than CTLA-4. When you have fresh troops in the battle, they're more durable, and they have memory. These are important distinctions. Side effects are a little worse with CTLA-4 because they're adolescent T cells that are out there circulating in what we call the peripheral immune system. More chances for toxicity to organs.
PD-1, these are middle-aged exhausted T cells. They're in their careers, in their tumor fighting. We bring them back to life, and they're not out there causing as much side effects. Same side effect profile, but the incidence of toxicity is greater with CTLA-4 than with PD-1 because of how these T cell works in terms of the life cycle and the targets. Please understand, CTLA-4 blockade and PD-1 are absolutely distinct drugs and distinct. What they have in common is a T cell target, but T cells have a really beautiful life cycle. It's important to distinguish this for the development of these drugs. This just shows you on the left a naive T cell, then it starts to get activated. CTLA-4 is a break.
Normally, what CTLA-4 does is you clear your viral infections within about 48 to 72 hours, and then you need a way to turn your T cells off and put them back in memory. That's very efficient, and that's what CTLA-4. By blocking it, you keep these T cells alive in a very early stage of their existence. Whereas PD-1, as you can see, gets expressed in the middle, and then there's these other markers called LAG-3 and other T cell markers. TIM-3, you've heard about all these. A lot of T cell targets now by pharma are going after these late markers. It'll be not clear yet whether resurrecting these very exhausted T cells, what we call terminally differentiated, actively dying T cells, will that really bring the same benefit as activating early T cells? We'll see. This will be an interesting experiment.
This is the study that I was fortunate enough to be part of. The curves on the top, the blue and the yellow represent CTLA-4, either with a vaccine or not a vaccine in metastatic melanoma. Here was a drug that only shrank about 10% or 15% tumors, but another 10% or 15% stopped the disease in its track for years. About 25%-30% of patients were benefiting, and that created a plateau of 20%-25%. This may not seem great in today's term, but historically, this disease had an average survival of six months and a five-year survival of zero. Metastatic disease, people in their 40s and 50s, young kids, this is who I saw day in and day out.
The fact that we were curing with 4 doses of a single drug 1 in 4 patients with widespread melanoma was a phenomenal beginning to this revolution. It was a proof in concept in a randomized trial. That's in yellow. That's the example of CTLA-4. Of course, PD-1s came on the market, and you saw single agents in melanoma, highly sensitive disease, 30%-35% long-term survival. We combine them, 52%. Now, it's important to understand that on these curves, PD-1 blockade or CTLA-4 blockade as monotherapy is really not mono versus combination because those patients then were sequenced. That's why these curves are a little higher than you might see. You really want to focus on the top curve. If you really look at the monotherapy curves before we were alternating, they're essentially additive, right?
CTLA-4 has about a 20% long-term survival, PD-1 in melanoma, about 30%. The combination is 50%. That suggests that there isn't a lot of synergy, that these are really different targets approaching different life cycles of the T cell. I think that's pretty important information. We got to get better, and we will in melanoma and all diseases. Here's the five-year data from ESMO that has shocked the world, and Manuel will show you. 52% of these patients are cured with combination therapy. The majority of them only get three to four cycles of combination, and they're done. This is like the days of childhood leukemia. All the kids died. A single agent, methotrexate, 10% of the kids survived. Combination chemotherapy, 30%- 40%. Bone marrow transplant, 70%, 80%, and now above. We are in the days in melanoma of childhood leukemia progress.
What's really cool on the left is that out of these five-year survivals, 74% of them did not need any additional therapy after they got their ipi/nivo. In fact, some of them are still on nivo maintenance for unclear reasons. If you really take it all, it's about 85% of them never had to get another treatment, and all their treatment, the median duration of their treatment was nine to 12 weeks. It's extraordinary. Not only are these patients cured, but they're not on treatment. They're back in their lives. Yes, there's more toxicity for sure. It needs to be managed, and now we have algorithms to manage the toxicity better, primarily with steroids. The fascinating thing is steroids don't seem to interfere with the anti-tumor effect, which was a huge issue in the early studies. This is the data that was presented in brain metastasis.
The reason we made such great progress with this combination of ipi/nivo or CTLA-4 and PD-1 is that these T cells, unlike chemotherapy and other drugs that don't penetrate the brain well, the immune drugs, T cells, go in and out of the brain very well. melanoma is a disease where brain metastasis were a huge issue early in the course of metastatic disease. The bars below are the people whose tumors are shrinking, and the bars above are growing. These are patients with brain metastasis, untreated, who then got ipi/nivo because they had disease throughout their body in addition to their brain. You can see the response rates were equally high, 60%. Essentially, this is the same response rates we see in melanoma with disease outside of the brain. Basically, the brain now becomes just another organ.
That may sound like just a throwaway line. That's a huge, huge line. It's basically changing how we treat kids. My neurosurgeons basically tell me, "You're killing us." You were treating the disease below the neck, but at least we had the business of the brain to deal with. Now they see very few that they have to really treat. It's really a transformative treatment. These are the survival curves, and on top, you can see the ipi/nivo. Again, these are small patient numbers, but it looks like 50%-60% of these patients are going to be long-term survivors, just like the big study I showed you before. We're not satisfied there. There's no question that CTLA-4, when you combine it with PD-1, you generate more immune-related toxicity.
I think the next generation you're going to hear about, what I'm banking on, is can we do better at priming? In other words, building that army. Can we reduce some of these regulatory T cells in the microenvironment? Can we reduce toxicity? You're going to hear plenty about this, but this would be a huge advance. In the meantime, it's pretty well established now, the melanoma data then we went into kidney cancer, now lung cancer, that you don't need full doses of CTLA-4 to have this magical activation of these early priming cells. In fact, the dose is now reduced by a third. Normally, we used to give three milligrams per kilo of ipilimumab. Now we're giving just one milligram. Instead of every three weeks with the PD-1, it's being spaced out every six or even 12 weeks.
The data in melanoma, renal cell, and now lung suggests low dose. This is ipilimumab, the standard right now, CTLA-4. Low dose and more intermittent dosing seems to preserve that additive component and certainly reduces toxicity. There's still toxicity, but it's reduced. Let's go to drug development now. In melanoma, you might say we've got a pretty high bar, right? To get from a high bar to a higher bar will require larger studies unless you have dramatic new drugs. As you can see, because of the resurgence of CTLA-4, it used to be everyone was just picking PD-1 and adding the next best drug to PD-1, their new drug. The next best drug to PD-1 is CTLA-4. It's established now. Now that we have dosing schedules that are better in terms of toxicity, it's the new platform.
You're going to see a lot more in first-line melanoma with new drugs plus the combination. There's still work being done with PD-1+ new drugs in melanoma in first line. In the second line setting, the same thing. Patients may get the combination and a new drug second line, or there's an opportunity to look for better CTLA-4+ another drug in the second line. It depends on whether the patients are getting sequential monotherapy or combinations front line. Let's go to how we're going to develop better drugs in melanoma and other diseases. Like Brad talked about Manuel, now pancreatic cancer, we'll talk about it, but in diseases like cervical or other diseases where there is a signal but it's low with PD-1, tremendous opportunity for single agent combinations because there's a lot of room. If you do 100 patients.
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Study, you see durable responses from 15% with PD-1 alone to 30 or 40%, that's going to drive those survival curves. That's a very low-hanging fruit to making an improvement. In melanoma, probably second line reversing resistance is going to be a very key development problem. The bar is high when you have already an immune resistant tumor and you're trying to reverse it. We're already seeing drugs data showing that drugs that can reverse PD-1 resistance in the second line will be a much easier pathway to approval. You got to have good drugs, and lots of drugs are failing in that resistant phenotype. I think what we do know in metastatic disease now, these deep responses, whether they're partial responses, complete responses, or stable disease that's durable, meaning beyond six months, they're driving this progression-free survival plateau.
At 12-18 months, those curves get very flat. No matter whether you're doing adoptive T-cell therapy, high-dose IL-2, PD-1, because the immune system has that ability to adapt and to have memory. That's really important from a strategic investment point of view, from my point of view, because that does hold up. That's going to be our landmark across any disease is what does the disease look like about 12 months after exposure to an immunotherapy? If there's stability, if these responses are plateauing and people are not progressing, that's going to be highly predictive. The other space that's hugely advantageous is this, what we call neoadjuvant space, where patients have more limited disease in their lymph nodes, but they're palpable lymph nodes, and now they get exposed to the drug, and then they get their surgery.
It turns out, at surgery, if you have a pathologic complete response, meaning they don't see any cancer after just six to eight weeks of exposure. In melanoma, essentially none of those patients have relapsed. The FDA is going to really probably consider approval in this area based on these very durable pathologic CRs. There's not a huge number of patients necessarily that present in that way where you can study that, but in melanoma, you can definitely, and it's being looked at in lung cancer and many other cancers. A company that's got a lot of pipeline, it's hugely valuable that they have CTLA-4, PD-1, a new generation CTLA-4, and then as Jen talked about, all these bispecifics and having it under your disposal is hugely advantageous for obvious reasons.
You still have to be smart in the biology and the translational science, and you have to be adaptive, and you have to understand clinically meaningful endpoints. I hope I've shared with you some of that real from the trenches of the clinic, what matters to us is does the patient's tumor stop growing for prolonged periods of time or regress completely? Those are both really meaningful endpoints because the toxicities of these treatments generally are quite low overall, and when they do get severe, we can reverse them with steroids. If we can maintain that status quo or eradicate the tumor for prolonged periods of time, it's hugely impactful. I'm just going to finish a few minutes talking about, I've talked a lot about T cell optimization.
I think CTLA-4 early, PD-L1 is sort of a mid marker. You're going to see a lot of work with these exhausted late aged markers. We'll see. I'm not sure how much more you can activate the T cells. We're certainly getting them well activated with CTLA-4 and PD-1. There's a whole field of adoptive T cell therapy, very exciting, taking T cells out of the body, growing them up, and then reinfusing them after they've been genetically modified. Lots of work in the T cell. To get pancreatic cancer, optimizing the T cell's not going to work. Pancreatic cancer creates a fibrous, basically a structural inhibitance to T cells. These fibroblasts actually upregulate PD-L1 and nuke the T cells as they try to attach. There's a physical barrier. The cancer takes over the PD-1, PD-L1 axis and expresses PD-L1.
We got a lot of work to do in that. It's not T cell itself. We're going to have to disrupt that cancer with radiation or ways of getting cells into the tumor better with vascular agents and other things. There's more work to be done in the priming process and the tumor microenvironment. On the terms of T cell checkpoints, the two red markers are the two drugs I've talked about. There's obviously all these other markers, both agonists and antagonists. I think what's now becoming clear, I'm just going to build this slide a little bit, is that there's really three phenotypes that are developing in cancer. People love to say hot, cold cancer. There's cold cancers called immune desert, where you actually don't see any T cells anywhere near the tumor. That's a completely different challenge.
CTLA-4 may help if you bring in new troops to that area, but it's certainly not going to help exhausted T cells through PD-1. You have this interesting immune-excluded phenotype where the tumors, there are T cells, but they're at the periphery of the tumor. Very different. That maybe they need a little help with PD-1. Maybe they need the regulatory T cells suppressed so these can enter. Maybe they need bispecifics to pull the T cells literally into the tumor. Lots of different strategies around that phenotype. The last one that gets overplayed, but the inflamed or hot tumor where the tumor has lots of T cells. I can tell you, we have plenty of tumors that are killing patients that are nice and hot. That's because it's the ratio of these T cells. Suppressor, it's very delicate.
You just have to have a little bit more CD8s than CD4s, the regulatory and the effector T cells. Hot tumors are not always good hot. There's good hot and there's bad hot. We have to be much more sophisticated. The advantage of CTLA-4 is it may help make hot tumors that are unfavorable more favorable by regulating that ratio. We'll see. Lots of work to be done in hot tumors, too. We got work to be done in the desert tumors, we got work to be done in the peripherally defended tumors, and we have a lot of work to be done in the hot tumors. I believe in time, we're going to know who needs a PD-1, who needs a CTLA-4, who needs both very early in the course of treatment.
If we're successful in that with these new drugs, then we can give short exposures to these drugs, step back and watch this amazing immune system work because it truly is phenomenal to watch these fast or slow, durable immune responses. It's really extraordinary. I've only talked about the immune-immune combinations, the upper right. In other diseases, we obviously have targeted therapies like BRAF in melanoma, EGFR in lung cancer, and there's lots of work being done on how to target the cancer and the immune system at the same time. There's ways to use radiation to make the tumor, to injure the tumor, to make it bleed so that it reveals itself to the immune system, and same thing with chemotherapy.
You're going to see a resurgence of short courses of chemo and chemo-sensitive tumors just to break the tumor up, make it more vulnerable, and then having that immune platform ready to attack. That's going to be the future. It's not all I-O I-O combinations, although once you get your best I-O I-O, it's magical. There are tumors where we're going to need short courses of other disrupting agents to make it reveal itself. My final thoughts is, if I haven't already said it, the immune cascade is beautiful, it's complex, it has memory, adaptability, and durable power. We've shown that with CTLA-4 blockade, we've shown that with PD-1. The combinations now in melanoma, renal cell lung with more tolerable combination regimens are just extraordinary.
Cancer cell-directed therapies, even though we've taken a step away from the cancer cell with this, I think can be effective, but it's fraught with the peril of genetic heterogeneity and resistance. You can't expose a tumor to too much before it will resist. Going forward, I think if we have IO/IO combinations or even single agent IOs that work and low-hanging fruit, it'll be a home run. Obviously, short bursts of cell-directed therapy in combination with whatever the best immune platform, I think will really change the landscape of cancer in the coming years. I think this next decade is really going to be an extraordinary time. Thank you.
Thank you, Dr. O'Day, for that insightful overview and highlighting the importance of CTLA-4 therapy. My name is Dhan Chand, I am the head of drug discovery at Agenus. Today, I'll be giving you an overview of our next-generation anti-CTLA-4 therapy, AGEN1181. As you heard from our experts, CTLA-4 is a critical regulator of immune function, and antibodies that target CTLA-4 have shown remarkable responses in the clinic, the hallmark of which is durability of response. The reality today is that response is limited to a small subset of patients. About 20%-25% of patients see this durability of response. What is missing? How do we raise the bar? How do we go beyond that 25%? Is it that patients are not seeing the best possible CTLA-4 therapy? Will combinations be the only way to raise the bar?
Or perhaps both. We believe that AGEN1181, an Fc-enhanced anti-CTLA-4 antibody, is best designed to give better monotherapy potential and better combination activity than the current generation of CTLA-4 agents. Why is Fc-enhanced important? Well, two things. An antibody by nature binds to two targets. One side binds the target, in this case CTLA-4, and the other side binds the Fc receptors if you allow it. CTLA-4 therapy depends on Fc gamma R co-engagement. This has been shown extensively. We published on this in "Cancer Cell" last year. AGEN1181, being an Fc-enhanced CTLA-4 antibody, is able to capture and improve known mechanisms of actions that the current generation CTLA-4 therapies address, but more importantly, harness novel mechanisms of action that are important for CTLA-4 therapy. The first of which is T cell activation, as you heard from Dr. O'Day.
All CTLA-4 molecules that bind to CTLA-4 and block ligand interactions promote T cell activation. Because AGEN1181 is an Fc-enhanced molecule, promoting better co-engagement to Fc receptors and better immune synapse formation between that T cell and antigen-presenting cell, we see better T cell activation. Secondly is Treg depletion. One of the physical barriers that Dr. O'Day and Manuel described that limits the anti-tumor response. Treg depletion, in fact, is thought to be one of the main mechanisms of Yervoy, but it hasn't been shown clinically. It's been quite elusive. AGEN1181 was designed to improve binding to the relevant activating Fc receptors that are important for driving Treg depletion, and I will show you data to support that later on. Third is enhanced T cell priming and memory.
You heard about the importance of CTLA-4 in regulating T cell priming and the importance of anti-CTLA-4 antibodies to create memory formation and memory activity. AGEN1181, we discovered when you enhance the binding to Fc receptors, you enhance T cell priming, you enhance better memory activity, something that the first-generation agents do not adequately capture. Apart from enhancing the efficacy with AGEN1181, we've also addressed safety. This has been the Achilles heel of anti-CTLA-4 agents and why some people try to move away from CTLA-4 and said, "Well, PD-1 may be a better option." As you heard from Dr. O'Day, they are two distinct mechanisms with two distinct activities. We address safety by engineering our CTLA-4 antibody, AGEN1181, to avoid certain toxicities, which I will cover later on. Now, I also wanted to briefly highlight how AGEN1181 compares to CTLA-4 bispecifics.
I know bispecifics is quite fashionable because people think that if I add the other target there, I'll get added activity. When it comes to CTLA-4, the current CTLA-4 bispecifics are really designed to address safety. They miss the mark on efficacy. They're not capturing the mechanisms that we have demonstrated, and others have demonstrated, as being important for anti-CTLA-4 therapy. These particularly include the Fc gamma R co-engagement and promoting better T cell priming and better Treg depletion. Bispecific molecules targeting CTLA-4 today do not address these mechanisms. Lastly, therapeutic reach. This is something that we're very excited about. How do you take CTLA-4 therapy into areas where CTLA-4 has not worked or where it's not working well?
I'll show you how AGEN1181, through our ability to Fc enhance this molecule, is able to broaden the therapeutic potential of anti-CTLA-4 therapy. We were the first to discover and report on in Cancer Cell the importance of Fc gamma R co-engagement for enhancing T cell activation and T cell priming. We identified the particular Fc receptor that was important. It was Fc gamma RIIIa. We engineered AGEN1181 by introducing point mutations into the Fc region to better co-engage Fc gamma RIIIa. In turn, what we observed was a molecule that better enhanced T cell activation, T cell priming, and Treg depletion as monotherapy, in addition to enhancing the activity when used in combination. Shown here is an example of AGEN1181 head-to-head comparison with IgG1-like molecules such as Yervoy and most other CTLA-4 agents to date.
What you see is that AGEN1181, in an assay that measures T cell responsiveness, outperforms the IgG1 molecules and the afucosylated, which includes the BMS next-gen approach. What you see is AGEN1181 showing enhanced potency with respect to enhancing T cell activation and T cell priming, and also the maximal response compared to the first-gen molecules. As you can see, compared to the BMS approach, we also see slight improvements compared to their afucosylated antibody. In addition to enhancing T cell activation priming, which is critical for the activity of CTLA-4, we've also enhanced the ability of this molecule to promote Treg depletion. As you heard earlier, this is a very potent physical barrier that prevents T cell immunity. While many have postulated that Ipi works by depleting Tregs, this mechanism has been quite elusive in the clinic.
In fact, Padmanee Sharma recently published that ipilimumab does not deplete regulatory T cells. Shown here is a comparison of AGEN1181 to that of an IgG1 or Yervoy-like molecule. What you can see is that AGEN1181 significantly enhances Treg depletion compared to that of a parental IgG1 CTLA-4. In fact, as you can see here, it's a very poor depleter of Tregs, perhaps the reason why we haven't been able to see this in the clinic. We've hit three different mechanisms. We've enhanced T cell activation, we've enhanced T cell priming, and we've enhanced Treg depletion, all important for the activity of CTLA-4 as monotherapy. When we look at the activity of AGEN1181 in combination settings, in this case shown with anti-PD-1, what immediately stands out is that AGEN1181 by itself is more active than the combination of first-gen CTLA-4 and PD-1.
More importantly, when you add PD-1 on top of AGEN1181, you see a more potent response and you see a better maximal response. This is because of that novel Fc mechanism we're able to leverage that promotes better single agent activity and better combination activity. In addition to enhancing the efficacy, the big question is, well, how are you going to address safety? To address safety, we use, again, engineering capabilities within our antibody AGEN1181 to limit certain toxicities associated with CTLA-4, in this case, complement-dependent immune-related adverse events. In our non-human primate studies, dosing cynomolgus monkeys up to 100 mgs per kg well beyond what patients would see, we saw no added toxicity compared to that of CTLA-4 agents. What we did see was enhanced activity, enhanced pharmacodynamic responses that are consistent with the activity of the molecule.
Compared to that of your first-generation CTLA-4, such as IgG1, including the afucosylated or non-afucosylated approach by BMS, what you see is that AGEN1181 fails to target complement binding. As I mentioned earlier, this has been attributed to certain toxicities associated with the first-generation anti-CTLA-4 agents, such as chronic inflammation of the pituitary. This is important because chronic inflammation of the pituitary, which subsequently leads to hormone dysregulation in these patients, is a chronic condition, this leads to intolerable headaches, diabetes insipidus, visual loss. With AGEN1181, we've eliminated or mitigated that possibility that the current generation does not address and neither does the afucosylated or non-afucosylated generation of antibodies address.
AGEN1181 is the only CTLA-4 agent that has enhanced efficacy and anticipated better safety profile that's available today. One of the key features of AGEN1181, the one that I'm really excited about both as a scientist and an Agenus drug developer, is the ability to bring CTLA-4 to patients that don't currently benefit from CTLA-4, expanding the therapeutic potential of anti-CTLA-4 therapy. What we have discovered is that there are settings where patients don't respond to CTLA-4 because of a genetic predisposition, which 1181 addresses, as well as the enhanced priming which, when used in combination, gives you profound responses. I'll show you an example of that.
Last year in "Cancer Cell," using a retrospective analysis of patients treated ipilimumab in metastatic melanoma, it was revealed that patients who expressed the high-affinity Fc gamma RIIIa receptor, the same receptor we previously discovered as being critical to the activity of CTLA-4, was important for the response to Ipi. Those patients that had a high-affinity receptor and high mutational burden had a better clinical outcome compared to patients that only expressed a low-affinity receptor, even though they had high mutational burden. This is really important to note because up to 40% of patients only express the low-affinity variant, that critical Fc gamma R receptor. These are 40% of patients who are not getting the best possible outcome from CTLA-4 therapy. AGEN1181 addresses this. When we Fc enhanced our molecule, we demonstrated improved binding to both the low-affinity and the high-affinity receptor.
If you look on the right, you will see that AGEN1181, when you look at the F allele, the low-affinity allele that I mentioned, AGEN1181 is a much better binder to this Fc receptor than IgG1. In fact, it's a very poor binder correlating with the poor clinical outcome you see in patients treated with ipilimumab. When you look at the binding to the high-affinity variant, the V variant, you see more potent binding with AGEN1181. When it comes to raising the bar, when it comes to bringing treatment to patients that are genetically predisposed to not even respond to the first generation CTLA-4, AGEN1181 is designed to bridge that gap. What does that mean for activity?
Well, when we compare head-to-head AGEN1181 with that of an IgG1 molecule in assays that are measuring T-cell responsiveness, and when you look at donors that only express the low-affinity variant, what immediately stands out is that AGEN1181 enhances T-cell responsiveness far superior than that of an IgG1 antibody, as you can see on the left. Again, correlating with the poor binding for IgG1 and correlating with the clinical evidence we've seen for Ipi in metastatic melanoma. Here's an example of where AGEN1181 has bridged that gap. By enhancing the binding to the low-affinity variant, we're able to enhance the activity in donors that only express that low-affinity Fc gamma RIIIa receptor, that receptor that we have shown is critically important for the activity of CTLA-4 therapy.
When you look at patients that express the high-affinity variant, the patients that respond better to Ipi, AGEN1181 shows a more potent response in these settings, consistent with the improved binding of AGEN1181 to the all-important Fc gamma R receptors. Not only have we enhanced T-cell priming and Treg depletion combination potential, but now we have a molecule that can broaden the application of CTLA-4 therapy, particularly in indications that may not be responding to CTLA-4. Shown here is an example of that. You heard from Dr. O'Day that there are some cases where the immune system are not seeing the right tumor antigens, or they're blocked from attacking the tumor. Here is an example of AGEN1181 in combination with focal radiation, and this is a model where checkpoint therapy does not work.
Even the combination of PD-1 and CTLA-4 does not work in this model. It's CPM refractory. When we put this next gen CTLA-4 with anti-PD-1 in combination with focal radiation, when you expose that tumor to the immune system, and you give that model next gen CTLA-4 and PD-1, you see much better outcomes. We see this as being critical because AGEN1181 is designed to promote better T-cell priming, better Treg depletion. In fact, patients today that receive focal radiation, when you look at these biopsies, they're infiltrated with Tregs. We have developed a molecule that promotes better depletion of intratumoral Tregs than the first-generation molecules. When you expose the immune system, and you need to prime that immune system to recognize the tumor, AGEN1181 is designed to enhance T-cell priming.
This makes it the ideal combination partner when you start to go into these, what people call immune cold or immune deserts. This gives us two distinct paths to a rapid BLA. As I've shown you, we expect AGEN1181 to drive deeper monotherapy responses, particularly in patients that are genetically predisposed to have poorer clinical outcomes to ipilimumab due to that Fc gamma R receptor polymorphism. AGEN1181 binds to both the low and high affinity FcγRIII receptor, and we see better responses in our preclinical assays. We expect better monotherapy with AGEN1181 in this setting. Secondly, as you heard from Dr. O'Day, when we start to think about expanding checkpoint therapy, IO therapy, combinations are going to be critical. Raising the bar with monotherapy is going to be good, and raising the bar even further with combination therapy is even better.
AGEN1181, as you have seen, is an optimal combination partner, particularly at anti-PD-1 and other agents. We expect this to play out in the clinic. In fact, an opportunistic path includes melanoma and lung cancer, where these agents are already active. We expect AGEN1181 to provide much deeper responses here. This brings us to two upcoming catalysts that we're very excited and look forward to sharing with you. As you heard, AGEN1181 is already in the clinic in phase I trials. Dr. O'Day was the first doctor to dose patients with AGEN1181, and we're excited to start our first combination study with anti-PD-1 imminently, in fact, later this month. We look forward to providing an early clinical data readout from our monotherapy and combination therapy with AGEN1181 as early as the first half of 2020.
With that, thank you very much. I'm happy to take questions.
Hi, everyone. We're going to take a quick five-minute break. Lunch is served outside. We're going to reconvene in five minutes to do a Q&A session with the presenters as well as the KOLs. Thank you.
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All right. Good afternoon, everyone. We're going to be starting the Q&A panel right now. A couple of us are going to go around with mics. I request that before you ask a question, please state your name and affiliation for the webcast. That would be appreciated. Thank you.
Hi, Julian Harrison, BTIG. Dr. O'Day, thank you for giving a very nice and comprehensive overview on the hierarchy of checkpoint inhibitors and comparison of survival benefits beyond PD-1, CTLA-4, and PD-1/CTLA-4 combos. Just wondering if you could talk a little more about the continued need for new combinations and improved patient screening. Of all the IO combo strategies going forward, you briefly touched on, which ones are you the most excited about?
Great question. The question is, I guess, apart from obviously the CTLA-4/PD-1, what do I see as the next? Much of the field's been dominated by PD-1 plus the new drug, and not this backbone. It's going to be interesting because I think third drugs brought into the combo might work differently. For now, most of our data is with PD-1 combos that don't include CTLA-4. I will say, I have a very high bar, and small incremental changes are really not going to be easily seen. I'm waiting for big things. The front lines setting is obviously very different than the resistance setting. I will say, the TKIs, particularly lenvatinib and others that are now coming on board, look impressive. We have seen in preliminary melanoma studies in the resistance setting and obviously in endometrial and liver now.
I would say as a class outside of the T cell, these TKI. In renal cell, of course, we have combo data with different TKI. I think the TKIs are not functioning obviously as targets necessarily. They may have some very interesting tumor microenvironment changes. I would say these look the biggest I've seen outside of true immuno combinations. I'd say that's the most exciting thing, particularly because I've seen resistance be transformed in the PD-1. I can only imagine using those drugs first line like they did at a low PD-1 responsive tumor like endometrial.
Got it. Thanks.
Yeah.
Appreciate the color. Just a quick question for management. How do you see next-generation CTLA-4s like AGEN1181 affecting the market for first-generation agents? I guess I'm trying to get a sense of whether this is really a mutually exclusive situation, or are there opportunities for both to coexist?
If I'll speak here. Okay. If I understand the question properly, you want to know how would AGEN1181 change the landscape for us, our combinations, and maybe even the first generation immuno-oncology drugs.
As both Dr. O'Day, Manuel Hidalgo, and Dhan Chand mentioned, AGEN1181 was specifically designed to address the deficits of the first generation CTLA-4, IgG1, and enhance the activity of a molecule way beyond that. For example, not just the T cell activation, T cell priming, but also very importantly, the regulatory function, and the inhibition of Tregs, and also addressing the safety component of it. The readouts from the clinical trials, both as monotherapy and in combination with our own PD-1, will be out in reasonably short term, meaning over the next six to nine months. That will inform us in terms of our strategy of how do we position. When we talked about, for example, our PD-1 2034, the name is still a challenge for me to pronounce, as is most of the generic names with MAB behind it.
These compounds, the first generation compounds, a lot of the questions that we've been asked is, does the world need another PD-1? Does the world need another CTLA-4? You heard from Dr. O'Day, the world definitely needs CTLA-4. The question is, can it use a better CTLA-4? The answer is yes. Most importantly, the point that all of the clinicians made today is, we're just perfecting the art of how do we use immunotherapy combinations. We're understanding the biology of cancer better, biology of the immune system better, and having many reagents available in order to be able to test them rapidly becomes critical. This also is true with our cell therapy, which I hope you will hear about later on.
The world may not need another PD-1, but what the world needs is a company that can quickly bring combinations and smart combinations and with the proper sequence of these combinations into the clinic and demonstrate the activity of not just one reagent, but many reagents behind it. We believe AGEN1181 will play a very, very substantial role in our ability to do that. In our ability so we look at AGEN1181 as a compound that will significantly enhance the capacity of PD-1s and potentially the capacity of other drugs in our pipeline. That's why it is an important and an exciting program. Does that address your question?
Yes.
Thank you.
Good afternoon. Jeet Mukherjee from Jefferies. Thank you for hosting, and thank you for taking our questions. A couple from me. Just first on cervical, you've talked about some of the responses seen with agents currently available, but wanted to get your perspective on what you believe is the bar set by the FDA on ORR and DOR in your final analysis for cervical. Second, are you looking to commercialize on your own or eventually partner for that indication? Thank you.
I'll answer the second question first, then perhaps I can ask Brad and Anna to address the first question. The answer to the second question is yes, we are positioning ourselves to commercialize directly, certainly in the U.S. ourselves. In ex-U.S., we will probably look for partners. A very important component of commercialization, as Anna mentioned earlier, we are ready to commercialize from a commercial product perspective. We have built an inventory of both our agents, PD-1 and CTLA-4. In fact, depending on how you price the product, that inventory right now that we have on the shelf, the commercial inventory, is in the range of $500 m illion- $1 billion worth of product, depending on the pricing. We're ready to go. We're not looking for any real help for launching it in the U.S.
Brad, Anna, would you like to address the rest of the question?
First of all, accelerated approval is generally only a U.S. opportunity. That's not true, right? There are some clear examples. In the pembrolizumab/lenvatinib endometrial cancer approval in September, we leveraged this Project Orbis opportunity and simultaneously actually got Australian and Canadian approval at the same time. I get it that that's not a large market, I think it creates the paradigm and the opportunity for synchronous multi-country approvals. The other example is cemiplimab, because cemiplimab in squamous cell skin cancer was so transformational. Actually, a single-arm trial led to EMA approval and even reimbursement in the European marketplace. To the point, though, what's the bar? We've tried to teach the agency and the rest of the world that existing medicines in second-line metastatic cervical cancer is about 10% with a very short-lived duration of response, generally 2-4 months.
Although you show up with a 14.3% response rate of pembrolizumab, because more than half of those patients had a duration of response that was greater than six months and the median was not reached, that's okay. We really don't know exactly what the threshold is, but we can kind of know what the historical experience is. 10% response rate with a very short duration and a 14.3% with a longer duration that achieved that. That's kind of what we would say is basically the existing pembrolizumab KEYTRUDA Merck label would sort of be an acceptable opportunity. That's a low bar. Obviously, the accelerated approval doesn't eliminate the opportunity for other agents to be approved. It's only a full approval that would meet the unmet need.
There's no plan or competitor that would meet the unmet need in 2020 and eliminate the opportunity for this accelerated approval.
Thank you, Brad. Anna, would you add anything?
Well, I completely agree.
Okay. Yeah. We've answered that.
I would just add that in melanoma, obviously, you had a drug that also the comparator at that time, chemotherapy, was a 10% short-lived drug and a response rate of 10%-15% led to median and long-term survival. We have an MSI indication for pembro that's agnostic to tumors that was a single-arm study. Now there, they showed 30%-40%-plus percent durable responses. I guess it all depends on the magnitude of the effect. Once you get into 30%, 40% durable responses as a single-arm trial in an unmet need, second, third line, very powerful. First line was going to be more challenging, depending on the disease, though.
As Steven said earlier also, I think the next paradigm for immunotherapy, and that doesn't mean for every single clinical trial strategy this applies, but the next paradigm is to have agents in our arsenal that can achieve really breakthrough responses in cancer, just like the example in melanoma with the addition of PD-1 to CTLA-4, taking it up to the 50% range. Not just the historical responses have been very short-lived. If we can make those responses durable or curative, that's going to be the game changer for us, and I think our portfolio is designed for that purpose.
Thank you for that. Just two more from me. In terms of the combo approach that you're going with, are you considering lung as another indication going forward? If you could just remind us of how the safety profile of your combo therapy compares to Yervoy. Thank you.
Jen, would you address the lung challenge? How we are at least positioning with our first set of drugs to gain traction there.
Thanks, Garo. Thanks for the question, Jeet. Yes, lung, melanoma, RCC are all indications in which we can continue to deliver our therapies. We're going to do so very quickly with a publication strategy for NCCN guideline inclusion for reimbursement purposes, of course, then be able to pursue expanded opportunities, potentially with our first generation, but we are also looking at superiority with our next generation CTLA-4 in combination with our PD-1. I'll ask Anna to speak to your question on safety and tolerability of our products.
Well, in terms of the safety, I think you've seen previously the data from our phase I, where we had used the combination. The safety profile was considered positive with no new safety signals found. Obviously, the currently run studies, the analysis are yet to be completed, I can say that we haven't found any safety signals that will change our assessment of this combination.
I'm just going to add one thing to remind you that we're dosing our CTLA-4 as 1 mg per kg Q6. What we've learned both from within our own data set as well as that presented by Bristol, that you can do so tolerably. We're seeing that as well. Patients are not coming off of either of the therapies due to toxicity when they're dosing combination.
Rob Andrew, William Blair. Dr. O'Day, you mentioned that you're not sure whether the combination study is truly having a synergistic effect or whether in fact it's patients responding to one or other drug of the two that they're being given. You think that's just an IO combination thing, or whether that's the case in many of these other combination studies, angiogenesis inhibitors, TKIs? Just a second quick question for management. I think you showed a near-term opportunity of about $165 million in cervical cancer. Could you just give us an idea of the kind of assumptions that gets you to that point?
Would you like to address the first question, Steve?
The question was So yeah. I think synergistically, certainly there's not clinical evidence for synergy, and based on the mechanism I talked about. I think this is going to get really interesting with other non-IO combinations. We will see. I do think what's fascinating is, and this is emerging again, needs to be rigorously studied, is that patients who fail IOs, whether it's CTLA-4, PD-1, or a combination, it was a very important seminal observation in melanoma. The Germans actually first reported this. At that time, it was CTLA-4 and not PD-1. They gave DTIC, a drug that was ineffective, essentially a placebo in melanoma. It was our standard before IO. They gave it to CTLA-4 failures, and they reported response rates of almost 40%. Some of them were durable in a small study.
It's an important observation because failure of IO doesn't necessarily mean a failure of T cell activation. Right? The T cells can get activated, for all the reasons, other reasons, barriers, transit. When you hit cytotoxically the tumor, even if it's just a minimal bleed, you might really regenerate. The reason why that was interesting is because the durability of the chemo responses was striking and certainly not reported previously with DTIC. Having said all that, there's been other data in chemotherapy being given post-IO failures, where there seems to be a lot more durability in platinum resistance and other things. I don't want to overstate that case, but my point, getting back to yours, is that what we add, either concurrently or subsequently, combinations or drugs that are being developed may have impacted whether they got IOs in terms of synergy, possibly.
This is future-oriented statements. I want to be sure everybody's very clear. These are real palpable things that we're sort of feeling in the clinic, and I think it's relevant to convey them in that regard. They're going to be rigorously studied.
Manuel, would you like to add?
Yes, just a couple of comments. I think that the combinations with chemotherapy, across many diseases, they appear to be synergistic or at least additive. Lung cancer, I think, is an example.
Yeah.
The most effective treatment remains chemotherapy plus pembrolizumab in the selected patients. In GI cancers, pancreas cancer, gastric cancer, we're seeing the same very good data in combination with chemotherapy. As alluded before, with the TKIs regorafenib plus nivolumab, very interesting emerging data. I think that's a very mechanism to be determined, a very interesting field. An area that I think has not been studied as much as of yet, but it's also a very important subset, are in the lung cancer, the oncogene-addicted tumors, the tumors that we treat with the EGFR inhibitors, with ALK inhibitors. They tend not to respond to immunotherapy as well when they were studied sort of in frontline.
Those who become resistant, by emergence of new mutations, emergence of resistant mutations in the same genes or new mutated genes, at least preclinically, they appear to be a subset that could respond to immunotherapy. I think that's going to be, it's about 15%-20% of lung cancer. That, I think, is going to be an important group to develop these agents.
Thank you. Jen, would you address the commercial question?
I can address that, too, if you want me to.
That'd be fine. Go ahead, Brad.
I said there's more than 4,000 patients, right? Certainly not every patient that dies will get immune therapy, but most. Let's just say 2,500. That's just a little over half. 2,500 and about average is six doses. I don't know what this drug is going to cost. Nobody does. Let's say $10,000 a dose because that's what everything costs. That's $150 million.
Very well said.
Back of the napkin.
I think we need to hire you as the head of our commercial operation.
Back of the napkin, based on how many patients get it and what the pricing is. That's a sort of back of the napkin, Brad Monk sort of estimate. That's $150 million. They say $165. I think that's a very reasonable estimation.
Yeah. Thank you.
I think we have time.
I think, Jen, you're off the hook.
I can see her squirming.
Okay, I think we have time for one last question.
Hi, guys. Sahil Kazmi, B. Riley FBR. Thank you for having us, and appreciate you answering the questions. Briefly for Dr. Monk, as you consider your population of relapsed/refractory cervical patients, on the basis of clinical data that you've seen, for products such as Iovance's LN-145 and other sort of late-stage clinical development assets, what considerations would you have in choosing between these assets?
Thank you for that question. Just for the rest of you in the room, we got breakthrough designation in May for a tumor-infiltrating lymphocyte, a cellular-based therapy. Again, Iovance is the company, tumor-infiltrating lymphocytes. As you know, that was only 27 patients that we presented at ASCO. Dramatic response, that's why we got breakthrough designation. The hassle factor is off the chart, right? The toxicity that they measure is from the infusion of the TIL onwards, which means they kind of forget about the marrow-depleting chemotherapy. I get it that it's a wonderful proof of concept because it could be active in checkpoint inhibitor failures in melanoma, where it's being studied. It could be active in head and neck cancer. I don't think really from a competitive landscape it's relevant.
I think really the relevance of that wonderful observation at ASCO and that breakthrough designation shows that the technology is feasible, and that the concept is basically validated. Doesn't mean it'll gain approval or what the commercial opportunity is. Genmab in Seattle, that's one thought. The second is this Genmab and Seattle Genetics have an antibody drug conjugate against tissue factor. Tissue factor is part of the coagulation cascade. You're all familiar with the really exciting data in liquid tumors, certainly leukemia, soon to be myeloma with GSK's asset, and even in breast cancer and so on with T-DM1. That's an opportunity in cervical cancer. Again, antibody drug conjugate versus tissue factor, Genmab, Seattle Genetics. I don't know if that will ever see the light of day.
It's difficult for me to give a commercial assessment because I'm not sure that they'll ever cross the finish line. I hope they do. As you know, it's in the public domain that they realize their vulnerability, and so they're adding it to bevacizumab, and they're concerned about a coagulation blood clot dose limiting toxicity because they both are associated with thrombosis, and they're adding it to checkpoint. I don't really know what that's going to mean. I think that's why we're here today, is we're hypnotized by IO. Most of us would probably preferentially pivot to IO because of the tolerability and probably the enhanced activity. It's very difficult to do cross-product comparisons when the Iovance tumor-infiltrating lymphocyte is so toxic and inconvenient, and when I really don't know what the Genmab Seattle Genetics antibody drug conjugate activity is.
I'm sorry that I couldn't answer it more a long-winded answer.
Thank you, Brad. I mean, another point that I think is important to mention, we've had encounters and meetings with advisory boards comprised of payers and payer providers, and there is a threshold number for tolerability, especially as you expand into many, many more cancers, that if you go much beyond $200,000-$250,000 for any-therapy or combination therapies, that's a break point for them, and they're getting increasingly more anxious about it. When you talk about cell therapies, it's not just the cost of cell therapy, which is in the neighborhood of $400,000 or $500,000, but additionally, it's the cost of care that adds up to another $500 million . Just for cell therapies by themselves, including the cost of care, without the addition of any IO treatments, the costs are topping $1 million per patient, and that is a problematic number long term.
Yeah, we're doing better with CAR T cells, as you know, but that's a 70%-80% response rate, there are cures. There's no indication that the durability of the Iovance technology is going to be to that threshold. The other thing about what I call the hassle factor, some of these antibody drug conjugates, again, this is in the public domain, published in "The Lancet Oncology," that antibody drug conjugate against tissue factor has eye toxicity, patients don't like to put drops in their eyes every day, they don't like to sit there in the infusion chair and put this cold thing over their face and nose because it causes nosebleeds. Their face and nose, they can't breathe, they can't see while they get the infusion. That sounds fun, right? The hassle factor for these is great. I get it.
There's an immune-related adverse event potential for immunologic agents as well. All of this has to be weighed, cost, activity, and toxicity. That's sort of the three-legged stool, and it only takes one leg of the stool to fall.
Right. Should we continue? All right. Let's continue with our program. Next is Cailin.
Hi, everyone.
Hi.
My name's Cailin Joyce. I'm an associate director of business development at Agenus. I've been with the company for about 1.5 year . Prior to that, I spent several years at Dana-Farber. Immuno-oncology is an area that's near and dear to my heart. Today I want to elaborate on something that Garo touched on in his introduction, which is companies that don't continue to innovate will become obsolete. Agenus's commitment to sustained innovation is a key pillar to our future success. 3.4% is the approval rate for oncology clinical trials in a recent 15-year period. 3.4% means that the majority of cancer patients aren't having the opportunity to see benefit from experimental therapeutics. It means that an enormous amount of money is going into failed drug development paths and leading to higher price tags on the approvals.
At Agenus, we're very deeply committed to increasing the probability of success in our clinical trials, even at the very earliest stages of drug discovery and development. Today, I'm going to tell you about a research platform that delivers deep early reads on the mechanisms of actions of our agents explicitly for de-risking our clinical trials. As you may know, Agenus already has a long history of translating mechanistic insights into novel therapeutics. You've heard today about AGEN1181, our next generation CTLA-4, designed based on our observation ahead of the field that Fc gamma receptor interactions were critical for CTLA-4 therapies. You've heard also a little bit about AGEN2373. This is our conditional CD137 agonist antibody.
This antibody is expected to have reduced toxicity relative to the first-generation of agonists that are constitutively active, it's differentiated from most of the other second-generation approaches, which are targeted to the tumor microenvironment. Our agonist is conditionally active both in the tumor microenvironment and also in lymph nodes, which is expected to deliver better efficacy. These insights and many others have been validated through big pharma partnerships, not just one, but many. Most recently, you've likely heard about our Gilead partnership, which as Jen mentioned, is off to a really exciting and productive start. Today our focus is really how we industrialize our discovery research processes in order to enable the type of sustained innovation that's critical for our success. Our VISION preclinical research platform is a critical capability for this goal, the platform is comprised of three elements.
First, we have in vitro ecosystems. Simply stated, these are primary human culture systems that isolate the processes that are required for anti-tumor immunity outside the body. For example, we model how T cells become activated against cancer cells. We model how they enter the tumor microenvironment and how they kill cancer cells when they get there. We can also model the interactions, both positive and negative regulatory interactions between different types of immune cells that affect the ability of the immune system to fight tumors. Additionally, these systems are designed to be modular and scalable, such that within our platform, we can systematically test how our agents, both alone and in combination, alter the tumor immune interface. Through these types of experiments, we generate large multidimensional data sets that give us a deep, granular read or prediction on the mechanism of action for our molecules.
We analyze these data sets using tailored bioinformatic approaches, in order to enable some very specific applications. First, we're looking to discover novel targets and approaches that are directed against unmet clinical needs. For example, as Dr. O'Day pointed out, the lack of durability for anti-PD-1 therapies. Secondly, we test our agents systematically to optimize their molecular properties and how we may introduce them in combination, for example, through best sequencing. Together, these types of information help us to ultimately design smarter trials focused on areas where we can offer the most clinical benefit. In the next few slides, I'm going to give you an example of one of our VISION culture systems and tell you how we've applied it at this point. This is a system that models how T cells respond and behave in the tumor microenvironment when they're chronically exposed to cancer antigen.
In other words, how T cells become exhausted. By co-culturing T cells with cancer cells, our system drives T cells to a terminally exhausted state where they're no longer responsive to PD-1 over a period of about two weeks. Throughout this process, we deeply monitor the function of T cells and their molecular properties all the way down to single cell resolution. What this allows us to do is, in a very clean system, to associate the molecular features of a successful T cell response to cancer, with the actual phenotypes of T cells. Through this deep longitudinal profiling, we have been able to discover novel approaches for generating a more durable PD-1 response. Additionally, we've identified a transcriptional signature associated with a poor response to PD-1 that can be used, for example, to shape exclusion criteria within a clinical trial.
As I mentioned, there's a lot of power in dissecting these systems down to single cell resolution. Our T cell exhaustion system, in fact, drives a heterogeneous population of T cells that is reflective of T cell populations that are present in human tumors. Here's an example of a potential target that we've identified within this system and its expression in the presence or absence of anti-PD-1 antibody. What you see is that there's a fairly rare subpopulation of T cells that express this target, and that subpopulation is expanded in the presence of anti-PD-1 antibody. This suggests that we may be able to target this particular protein in combination with PD-1 to enhance PD-1 responses. Our platform is not just focused on T cell exhaustion. As I mentioned, we also profile T cell activation and other features of antitumor immunity.
Here's an example of our systems coming together. Here we've looked at T cell activation in the presence or absence of AGEN1181. We found that the same target that's responding to PD-1 therapy is also expressed more frequently in the presence of our AGEN1181 agent. This is telling us something new about the mechanism of action for AGEN1181 and posing another potential combination path. We apply some of our similar informatic approaches to publicly available data sets. Just as an example, is this particular target. These data are showing that this particular target is expressed specifically in intratumoral immune cells as opposed to within the periphery. As another example of how we would apply this system, as I mentioned, we did deep longitudinal profiling throughout the entire time course.
In particular, the transcriptional signature that was present in terminally dysfunctional T cells when they're no longer responsive to anti PD-1, was predictive of anti PD-1 response in a completely independent study of melanoma patients. In contrast similar signatures that are associated with exhaustion and have been discovered in the context of primary tumor-infiltrating lymphocytes have not had this type of predictive power. This illustrates the ability of the VISION platform through isolating processes that are critical for anti-tumor immunity to gain clean molecular signatures that are predictive of what will occur in actual tumors. Just zooming out a little bit, VISION is a preclinical research platform that is designed to help develop and de-risk Agenus' broad Io portfolio.
I'm sure you're all very familiar with this type of figure at this point, showing how, in order to mount an anti-tumor response, we need to have recognition of the tumor, we need to have immune cells localized to the tumor, and they need to have the ability to mount a durable response against the tumor.
Agenus has a differentiated and intentional approach of developing targets that address aspects of this entire cycle. The reason for that is, what we've accomplished and where we're going, some of the key catalysts over the impending 12 months. Many of the members of our management team are well known to you. They were the inventors, developers, and supported the approvals of immune agents, starting back with Humira, and then more recently, supported the breakthrough designation accelerated approval for some of the recent PD-1 molecules.
Today, you're going to be hearing from Dr. Anna Wijatyk. She's our head of clinical development and operations, she's going to give you an overview of where we are in the clinic. Through Agenus, we have created a company that is as innovative as it is efficient in an era where the pace of drug discovery must keep pace with the exponential growth of scientific knowledge to truly deliver high-impact therapies for patients with cancer. We have set up a company to do that, we've obtained and achieved some unprecedented outcomes in the past three and a half to four years. This includes making strategic acquisitions, developing formal collaborations, executing on those collaborations, and delivering from first in-man now to trials that are designed for BLA path, which we believe are on track to file next year.
The reason we were able to set up a company of this magnitude, and while it's small in size, we have about 300 people, it's mighty, with three sites producing from antibody discovery to full GMP manufacturing, as Garo mentioned. We were able to set up this company because we knew what was necessary to deliver high-impact therapies. We've been in this field for 20 years in the autologous space, delivering patient-specific vaccines and seeing curative benefits in some patients with highly refractory cancer. Here you see a patient with metastatic melanoma. These data were published in 2002, and what we have learned since that time was in addition to an immune education approach, the need, the necessity to actually expose the enemy, expose the tumor, so that the immune system could do its job.
Once you had that capacity with the vaccine, the tumor starts shutting down the immune's ability to effectively fight the tumor. We now later became to know the checkpoint blockade, and we now have a full suite of tools to address this as well. In addition to data that we had seen in patients with metastatic melanoma, we also observed in a study that we were running with our vaccine on top of standard of care radiation and temozolomide, that patients who had less elevated PD-L1 expression, so perhaps the tumor was less effective at shutting down the immune blockade, we saw some profound responses in patients with glioblastoma. These data led to a collaboration that's funded by the NIH, run through the Brain Tumor Trials Collaborative in collaboration with Merck, with PD-1 in combination with our PD-1 and vaccine in a randomized trial.
The trial is ongoing, we're anticipating data over the next 18 months. Garo mentioned through the acquisition of 4-Antibody, we saw a transformation of what we could actually do for patients, taking a multitude of combination approaches and being able to efficiently deliver those to patients. That we'll have a toolkit in-house in order to treat cancers in many different immune contexts. Although it is a challenge to develop such a diverse set of drugs, we have a good focus on making sure that our preclinical research capabilities and technologies can support the development of this diverse pipeline. In particular, what VISION enables us to do is, in a number of different physiologically relevant contexts, to very quickly and at scale screen our toolkit to predict mechanisms of action in vivo.
Specifically, the platform to this point has been focused on improving durability of PD-1 responses, particularly in light of our expected BLA filing next year. We're using it also to gain even more information on how anti-CTLA-4 therapy works and the benefits of AGEN1181. Finally, we're using it to maximize the potential of many of our next generation of reagents, some of which have not been disclosed. Also what you'll hear about right now, which is our iNKT allogeneic cell therapy platform. Thank you.
Thank you very much, Cailin. Very good.
First, let me thank everybody for staying for the last lecture of the day. We didn't do that in college, but you are to be congratulated. I have to do this, huh? AgenTus Therapeutics is a company that was developed by Agenus, and is a wholly owned subsidiary. I have just joined three weeks ago, and so I am proud to have a role in this company. It was established in 2017. It's co-located with Agenus in Lexington and has offices in Belgium and in England as well. I have a 50-year career spanning academic medicine and the business of medicine, culminating in nearly 15 years at Paul Capital Partners, a platform that I was proud to have developed within the partnership. Some of the senior folks that are worth pointing out may not be known to you.
In the top row, Andy Hurwitz was previously a principal investigator in the Cancer and Inflammation Program at NCI. He's responsible for preclinical evaluation of TCR candidates. Marc, with a C, to separate Mark with a K, in the top right, leads the platform for developing and design of TCRs and CARs. He had a tenure position in immunology at the University Medical Center in Utrecht. Mark with a K was on the faculty at Harvard, and has been a central element in the development of our programs. That's the highlights of the subset of the team. Agenus is leading with a new generation of cell therapies, and it was a nice segue from Cailin ending with the introduction. I would add to that wonderful one, two, three, four, five slide where you kill cancer cells, that we kind of swoop in from the left.
The cell therapies that we are developing are designed to be safer and more effective. We have three programs underway at Agenus. Invariant natural killer T cells, iNKT is easier. Proprietary platforms that are designed to generate best in the class CARs and TCRs, and a series of proprietary neoantigen targets. The unique relationship with Agenus has the ability to design our allogeneic cell therapy platforms with checkpoint antibodies. This gives us a very nimble approach to accelerating and developing therapies. You are all aware of the first generation of cell therapies. At present, there are only two approved for cancer-based treatment. They are both autologous and therefore limited, long time to develop, and very expensive as shown. A little bit more about the details of these therapies is on the next slide. It gives you the positives, which they do treat cancer, the hurdles and the difficulties.
They're constrained by manufacturing hurdles, not the least of which is that they are autologous, and that implies the necessity to take from the patient, go through a long-term process, and return. Whereas what we are designing is something that will be off the shelf. Making cell therapies more effective requires a number of different steps and assets. This slide portrays the elements that are necessary. It is the combination of cell format, receptors, targets, and manufacturing capabilities that results in the achievement of safe and effective therapies. As you will see later, Agenus's powerful iNKT cells in an allogeneic format are naturally tumor tropic due to both endogenous homing mechanisms and thus have a significant advantage over other forms of cell therapy. Manufacturing agility in an allogeneic platform is a key in our strategy to outpace the competition.
Just as a reminder, we can't go all the way without a cartoon. This represents Jesus. Sorry about this, guys. You moved the slide. It's here. My notes are here. Anyway, two mechanisms of action of the iNKT, which are important to their cytocidal effects and how they home to tissues. A little bit more of the cartoon showing the reconditioned tumor microenvironment and other activities that lead to tumor cell killing. Where are we in our process? I'm pleased to say that we are developing an IND, which will be completed by this year for unmodified iNKT cells to be used in a phase I, first in human study relating to patients with multiple myeloma. The study will be performed at the Dana-Farber Cancer Center.
In 2000, we will add a second study looking at combinations and which exact combination is being discussed, but it could be a variety of the Agenus therapies that you have just heard about. It is designed to be developed in a broader base form of therapy, treating more forms of cancer at a lower price, and a quicker form of manufacture. It will be, in essence, an off-the-shelf form of allogeneic therapy. This is a compare and contrast. Our activities are up at the top with an allogeneic iNKT from healthy donors, fairly rapidly, four weeks, to an on-the-shelf product. Other allogeneic approaches take six or more weeks. Of course, the autologous approach is a longer and patient-specific approach, much more expensive. We are taking advantage of being able to manufacture allogeneic iNKT cells for the treatment of a broader number of cancers.
If there's one slide that summarizes everything that goes on at Agenus, this is it. If you look to your left under program one, those are the various clinical trial plans that are currently being developed to explore the various opportunities that we have. To the right are color-coded references to the various programs that we have in order to achieve our goal, which is safe, effective, and affordable therapies. I'd like to thank you for your time. It is our objective to become the killer iNKT cell program. Thank you.
Thanks very much, Walter.
What's next?
Your concluding remarks. Happy hour.
Happy hour next. Thank you, Walter. I think pretty much everything that needs to be said has been said. Just a couple of thoughts here. First of all, thank you everybody for your attentiveness. Thank you for our clinical experts for your wonderful talks and our team for having prepared their remarks and having worked so hard to get us to this point of execution for our programs. As our clinical experts alluded to, this is complicated. It's not simple. It's become fashionable over the last four or five years, it's attracted a lot of people because of fashion. We look at it differently because of our pedigree in the business, our history in the business. To tackle these challenges requires high science, I hope that you had a sampling of the level of high science that's conducted at the company.
By no means what you heard today is all-inclusive of our programs, but it gives you a sense of how we do what we do. The objective here is that over the next near term as well as coming years, we will perfect the art and science of combinations, timing of these combinations. We will be able to profile patients' immune system, profile specific diseases, which we're in the process of doing, by the way. This is not something that's destined to come in the future. Be able to be much more deliberate in our interventions. As Dr. O'Day and Manuel Hidalgo, and Dr. Monk said, I think the objective here is significant improvements in patient treatment, and also very importantly, not just measurable response rates, but response rates that are curative or very long-term durable. With that, we hope to see you again.
The aim is not to wait for another four years for our next R&D day. We will be hosting these things with some topical subjects being highlighted for each one. We will also be having these R&D days in other venues such as Europe and the West Coast as well. Thanks again. We are running only a few minutes beyond schedule, it's a big deal for an Armenian, actually. Armenians always run late, I think we've done a good job here, 11 minutes late. Thank you very much.