Agenus Inc. (AGEN) Earnings Call Transcript & Summary

[Audio Gap] what we're doing and how we're doing it. And so you'll hear from a number of speakers, and I'll go over some of them. There'll be 4 speakers who are experts in their field. Some have been experts for a long time. Some are new kids on the block, not that new, but young kids like Bree Wilky, who have become experts instantly. Now they will include our good friends, Mike Atkins, who was the winner of the Lifetime Achievement Award. But Mike probably goes back in history in the journey of immuno-oncology for a very long time, the mid-80s before several years before, I woke up to my conviction that immunology would be the only way to cure cancer. That was in the very early '90s. And when I met Mike in the early 2000s, he told me something that was very memorable. He said, this is way before the approval. He said CTLA-4 works. It was, I think, in 2003 or 2004. So he is a man of conviction that has persisted in this journey for a long time. Dr. Larry Norton, who I've known since the late '90s, I met him at a session at Memorial Sloan Kettering, when he had a beautiful model, mathematical model to show that when you treat patients with chemotherapy or some patients, at least, or when you don't treat them at all, they die at about the same point, but the trajectory of disease progression is very different. And of course, quality of life would be different as well. Then we have Dr. Alexander Eggermont, who is one of the -- again veterans of immuno-oncology, Lex and I met, we were developing our cancer vaccine, individualized cancer vaccine in the early days. And Lex is a man of conviction who will call it the way it is. And I will not mince his words were times that we had some negative developments on the cancer immunology front with vaccines. And in fact, there were some experiments where vaccines seemed like they were hurting people. And of course, we're kind of a long ways from that as well. And Dr. Bree Wilky, as I told you, has done an incredible job. She had a brilliant presentation today, plenary presentation at SITC. And so we are where we are. Now in addition to those 4, adviser, experts, clinicians. We also have 2 of our own. And 2 of our own have joined us from treating patients only a short while ago. Dr. Steven O'Day, our Chief Medical Officer; and Dr. Joseph Grossman, both of them literally [indiscernible] Agenus from the patient bedside and have done a phenomenal job of advancing our programs. So they will be speaking. In fact, they'll do a deep dive into our data, and Dr. O'Day will do a deep dive into what is coming beyond just botensilimab. One thing that I may point out to you all is that, yes, we have been around for 28 years. We haven't wavered at all. This is not a product of serial entrepreneurship. In fact, if anything, it's anti serial entrepreneurship. It's not a product of making a quick buck with venture capital backing and having an exit strategy. It takes people with tremendous results people who love what they're doing, people of conviction, people of trust that allows a project like this to get to the maturity level that we have achieved right now. Now botensilimab, according to the experts, and you'll hear more about it, has achieved remarkable data. And people ask me, like my friend, Tyler Curiel, who is an expert in his own right. He says, what's taking so long for people to get this? And I should say it's not taking a long time for the experts in the field of medicine to get this. It perhaps is taking a little longer, and we can analyze the pathology, the anatomy of that for people who are in the money camp to get this. But they will, we're convinced of that. But one thing that I should point out is botensilimab is not a product that came about by chance. It was a product specifically designed to perform in a particular way. And there are a number of other products and cell therapies in our portfolio and our MiNK portfolio well that are also designed to perform in a specific way. And Dr. O'Day will speak to that a bit. Then we have the real newcomers, real newcomers to the company, not in real newcomers to the field. These are newcomers to Agenus. And they include Dr. Todd Yancey, who is an expert, not just in drug development, but also commercialization with a particular set of knowledge for international markets; and Dr. Patricia Carlos, who is the Chief of Regulatory, Quality and Compliance, now at Agenus. And they will tell you how we will move these portfolio of products towards the finish line. And why are we moving them to the finish line? Well, One very simple reason, to get the patients what they deserve. Now if we do that well, making money will be a side effect and we'll take that side effect and reinvest it wisely to advance our portfolio and to do other good things. So with that, I will invite Dr. Todd Yancey, who is there is no real introduction because he's going to introduce himself, and I take my hat off to him. Dr. Todd.

Thank you. Well, I think it goes without saying it's a tremendous honor to be here today and to be in the presence of such an esteemed panel of experts. We've been asked and everyone will be asked today to share a little bit about their own personal journey today. So I thought I would take a moment to talk a little bit about my background. For me, my background in terms of today began when I was 5 years old, when I was a kid, a big kid and my father was a military officer and people used to say, he's going to play football, and he's going to join the Army. Well, around age 5, I figured out, I better take control of the situation. And so I started to say, when people would ask me what are you going to be? I would say, I'm going to be a doctor. But before that, I would say -- and I'll tell you what I'm not going to be. I'm not playing football and I'm not going to join the Army. So ironically, I had my first -- been -- I started medical school 40 years ago. I had my first clinical trial patient in 1988, and a lot's changed in those many years. I entered the industry 22 years ago. I've always been in biotech and almost entirely an international biotech, having begun my career at Amgen, working at the time on [indiscernible] Neulasta and supporting the development of a field medical team initially in the United States and then subsequently in the 25 countries in Europe for Amgen. At the time did business. And was recruited and had an opportunity to leave Amgen to go to Genentech in clinical development to work on 2 important drugs, Tarceva in lung cancer and pancreatic cancer and; Avastin in everything, as was the case for us at Genentech in those days. And then I got a phone call from a friend of a friend to talk to them -- talk to him about a potential opportunity at a really small company at the time called Onyx, to work on a drug called Nexavar. And I went from Genentech to Onyx. It was my first C-Suite job in 2006, and to build a global safety organization, global medical affairs organization and then ultimately take over clinical development, working with our partner, Bayer, on the expansion of Nexavar including the registration of Nexavar in hepatocellular carcinoma. And then in addition, I was tasked by my CEO at the time to identify an opportunity for us to work on a hematologic malignancy. And with the work of the team, we identified a company, a very small company in San Francisco called Proteolix for a drug, which at the time was called carfilzomib, which is now called Kyprolis. And we acquired that company, and I led the team to the completion of the first registration intent clinical trial for that drug. This was about 12 years ago and I thought, gosh, I might need to retire. And I tried that, lasted 3 months. I got a phone call from a colleague at Medivation, which was about 100 people at the time before XTANDI was approved, to work on the clinical development of that drug. And then subsequently, when we had our first approval for the drug enzalutamide in a time post chemotherapy-treated patients with advanced metastatic castration-resistant prostate cancer. I took over an accountability to build out a global medical affairs organization once again, working with Astellas to launch XTANDI. Spent 5 years at Medivation and had an opportunity that I felt I had to take [indiscernible] to work on a PARP inhibitor. I worked on rucaparib at Clovis for 2 years. And then spend a couple -- spent about half a year working in rare diseases because I was interested in understanding how small targeted patient populations could have drugs brought to them in an accelerated fashion and to support the commercialization of that effort. So I had a global medical affairs position working at BioMarin and got a call from friends of friends. This is always the case, I think, in this world, about another small company at the time. And ask to take on the accountability to build a clinical development team for a company, which is called BeiGene. I went to BeiGene about 6 years ago. There were 250 people working at BeiGene. When I left BeiGene, there were 7,000 people working. I think there are now 9,000 people working at BeiGene. So I was an Executive at BeiGene. I built out the clinical development program for atezolizumab and Pamiparib the registration programs that you see coming to fruition now. We're built by my team. And across the course of the many years that I was at BeiGene, John -- as John Oyler, our CEO asked me to take on a variety of additional accountabilities, including once again, can you build out a global medical affairs organization, which I did. And then this case for 100 markets. But also to take on accountability for figuring out a path to accelerate access for patient populations internationally that are grossly underserved. I took on an accountability for a new function at BeiGene, which is called the new market development function and launch with a team of team members, professionally and internationally, registration intent plans and commercialization planning for 60 markets, which included all of ex-China APAC, all of Latin America, Mina, Israel, Turkey, Russia and Commonwealth. John knew I was going to retire and I had a plan to do so at the end of last year, and I did so. However, I received a phone call again a friend of a friend, asking me if I would take a call with Garo and Jen. And I said, sure. So I got on the phone with them. And we had a long conversation and I was struck, very struck by the focus of the conversation. It was on advancing these products to patient population throughout the world as fast as possible. They had heard that I had an experience set in that area, and they wanted to know if I would help. And I said, well, there's good news and there's bad news. The bad news is I'm retiring. But the good news is, I think morally I have to help you. So I put the rocking chair to the side after some agreement and discussion at home, and I've come back to help. And I think what really drove that was botensilimab. I've never seen anything like this. I've worked on a lot of fantastic products, been very blessed to work on those over 22 years. But we have a drug here that is active in cold tumors. We have not seen that before. It is a drug that is combinable with I-O. It combinable with cytotoxic chemotherapeutic agents. It's combinable with cellular therapies. It obviously has an opportunity to be effective in warm tumors. And I think we can go very quickly to earlier lines of therapy and begin to address the population that Dr. Wilky highlighted for us during the plenary session today. The 60% of patients who have no response to IO-based therapies. And by the way, the 40% that do the majority unfortunately relapse. So we are looking at an opportunity that extends internationally across all of those populations and critically in my observation, may have an opportunity for children who largely do not respond to these therapies. And so -- with that, I have made a decision to return and help out. So I'm going to moderate today's discussion. And again, it is a tremendous pleasure to be here. So I'm going to begin the program by asking Dr. O'Day to introduce Dr. Mike Atkins and then I'll be around. So thank you very much. Appreciate it.

Thank you, Todd, and you'll hear from me shortly. But -- and I know Garo gave a partial induction to Mike Atkins. But I thought I should give a little deeper flavor just for my personal deep relationship with Mike over 30 years now. Mike is the Deputy Director at the Lombardi Cancer Center in Georgetown. He is also Professor and Vice Chair of the Department of Oncology. And he really has led SITC from a very, very early stage. This meeting is extraordinary. It's 7,000 people. Pre-COVID, I think it was 2,000 at its maximum. But we go back to several hundred at best. So Mike was a previous past President of SITC, the Board of Directors, and this year was given a lifetime achievement award. But my biggest a sense of connection with Mike is much deeper than awards or titles of academia. Mike has been at the forefront of I-O, and I've emulated him, and we've worked closely together over almost 30 years. I think what most -- the community of experts really admired by Mike as he's scientifically rigorous secondary to none. But equally, he gets patients and what impacts in the clinic are material to patients. And I think he's led us in so many ways around those 2 areas. And I admired about him deeply. And so Mike, thank you for coming to join us. He's going to share some of his deep insights into I-O space over the course of his career and I appreciate it.

Well, thank you Steve for those kind words. I have a bit of laryngitis and this is a second talk I've given today. So hopefully, I can force my way through this one as well. And I'm going to talk about my journey, which pretty much is the journey of immunotherapy since it starts from the first effective immunotherapies. And we really were in the wellness in the beginning, and we've moved toward the promised land, but we're not there yet. So all cancers have mutations and there are they look foreign to the immune system, and every successful cancer must therefore solve the challenge of overcoming the differences erected by the host immune system. And many of those do that by disabling the immune system. So when we use immunotherapy, we are actually treating the immune system so that it can treat the cancer. And because the activated immune system can target many tumor antigens simultaneously and deepen and broaden over time, it can eliminate the last cancer cell and cure patients with metastatic cancer. It's pretty much the only thing that can do that. And the hallmark of an effective immunotherapy is therefore a tail on the KM, Kaplan-Meier curve. And I noticed that in our early days with high-dose IL-2 in the 1980s, which produced responses in about 10% of patients with metastatic melanoma or kidney cancer. And if you were still responding at 2.5 years, you tended to never relapse as shown here out to 10 years in patients with melanoma and kidney cancer. And it was this durability of the response that led the FDA to approve high-dose IL-2 for kidney cancer in 1992 in melanoma in 1997. When IL-2 was first announced as a new therapy, it was held as a cancer breakthrough in such noted medical journeys -- journals such as Fortune Magazine. But in the 2000s, it was actually looked at in the time when was the less interest in immunotherapy as a case study for what was wrong in cancer clinical development. It was uncontrolled, no target, no target population. Toxic had to be given as an inpatient, and there were no correlates for who would benefit. But I stuck with it because to me, these patients were being cured and it was proof of principle. And if we could find the right treatments to activate the immune system and apply them to the right patients. We could cure patients with solid tumors. So we tried several approaches to try to improve on high dose IL-2 and make more applicable to the general cancer population. And we learned some lessons from that experience that I think are applicable to our current era. We tried to give lower doses of IL-2, and we learned that complete responses we're only seeing with high doses. We tried to dissociate toxicity from efficacy. When we gave steroids, we eliminated both the toxicity and the efficacy. And when we gave inhibitors of TNF and IL-1 receptor. We were able to still see efficacy, but also toxicity. We tried treatment selection, and we saw that IL-2 worked better in patients with inflamed tumors and in patients who had immune-related adverse events. And we tried combinations with other therapies, such as chemotherapy, in what we call biochemotherapy or TILs or vaccines. And we saw that most of the immune effect was lost with concurrent administration of chemotherapy or other things that inhibited the immune response and that tumor reactive kills exist. And therefore, for most patients, there was no need to vaccinate, they were already auto vaccinated. So this is one of the first patients that we treated back in 1986 with high dose IL-2. And you can see this mass here in his neck, which even medical oncologist was able to recognize as a goiter, and he had developed hypothyroidism after treatment in conjunction with these halo around his subcutaneous melanoma metastases associated with disease regression. And he remains alive today, and we published in England Journal in 1988 that response to immune therapy was associated with activation of the immune system against other organs, particularly the thyroid gland. We tried to combine IL-2 with chemotherapy. And although we saw advances in terms of response rate and median PFS when we compared it to chemotherapy alone. There was no difference in overall survival. We lost all the IL-2 benefit when we gave it with chemotherapy. We looked at giving -- taking T cells out of the tumor and giving them back together with IL-2, and we saw that even in patients who didn't respond to high-dose IL-2, in 20% of patients, we could produce durable complete responses when we gave them their T cells from the tumor with IL-2, which suggested to us that there were T cells there doing something, and we wanted to look at what was preventing those T cells from working. And we spent a lot of time thinking about this, and it was through great science by people like Jim Allison and Tachio Hangzhou, who showed us that there were molecules inside the tumor microenvironment, such as PD-1 and PD-L1 that prevented those T cells working and molecules at the antigen presenting stage in the periphery such as CTLA-4 that were shutting off the immune system from becoming too active. And when those were -- antibodies were developed to block CTLA-4 such as ipilimumab. We saw given to patients with melanoma that there was a tail on the overall survival curve now at the 20% level. And with anti-PD-1s, we could see a tail that was even higher than what was seen with the anti-CTLA-4s somewhere in the 40% level. And when we gave a combination of anti-CTLA-4 and anti-PD-1, we saw that both the progression-free survival and overall survival, there was a 5% to 7% increase in the tail of those overall survival and progression-free survival -- in patients with melanoma. And we saw also improvements in patients with kidney cancer and lung cancer. So what lessons have we learned from working with these checkpoint inhibitors over the past almost 20 years, but we've seen a relationship between immune-related adverse events and benefit similar to what we saw with IL-2. We saw that stopping therapy what's possible and that could create a treatment-free survival. We saw activity in patients with brain metastases. We saw sequencing with standard therapies, and we saw some issues related to these mix combinations. So this is data from our MedStar Georgetown database, looking at toxicity in melanoma patients getting immune therapy, and the patients who have toxicity shown here in red have better overall survival than the patients who didn't have toxicity shown in blue. And furthermore, if you have toxicity and you treat that with steroids or steroids plus an immunosuppressive agent, those patients even have better overall survival, indicating that how well you activate the immune system may be associated with benefit. We also saw with these treatments that they met the patient's needs where the treatment would end, but the benefit would persist. And this allowed for what we call treatment-free survival or TFS. And we looked at this in studies such as the melanoma study to see how much TFS we're actually creating. And as you can see in the dark blue in patients getting nivo/ipi have about 1/3 of their time for the average patient receiving nivo/ipi was spent in treatment-free survival and they stop. And that was greater than what we could see. And very little bit of that time was actually seen here in the light blue in treatment-free survival with residual toxicity. So what is treatment-free survival allow? Well, let's turn my melanoma clinic from a very sad place into just as a patient you heard a virtual travel agency, where patients are traveling the world, checking off items on their bucket list being unleashed from their oncology clinic and also attending milestone events for their family that they never thought they would be able to attend. And so how can we get treatment-free survival? One of the reasons why immune therapy works and you can see these tails on the survival curve even after treatment stops, is that it also works in the brain. You can see activity in asymptomatic CNS mets that's similar to what we see systemically. And that was not the case with any of the prior treatments we use for melanoma, where we saw isolated CNS relapses even in clinical responders. We wanted to know, should we give immune therapy first in patients with BRAF mutations or should it be given after treatment with BRAF mutations? So we did the DREAMseq trial. And what the DREAMseq trial showed when we randomize patients to targeted therapy first followed by immunotherapy versus immunotherapy target by -- followed by targeted therapy that the immunotherapy first treatment resulted in a 20% improvement in 2-year overall survival, meaning that the immunotherapy work best when given first. And therefore, we want to figure out to get immunotherapy in the front line whenever possible. When you combine immune therapy with targeted therapy, we don't see these tails on the survival curve. In 2 years, these triple regimens have the PFS curves are already below where the PFS curve for nivo/ipi is at 5 years, and therefore, we're losing some of the immunotherapy benefit when we leave out ipi and when we combine it with drugs that may inhibit the immune response, such as a MEK inhibitor. And the same thing was true with VEGF receptor TKIs combined with anti-PD-1 where you don't see yet a tail on the survival curve compared to ipi/nivo. So when we look at these I-O, non-I-O combinations, I always look at them with caution. I-O is different than tumor-directed therapy because of its ability to produce treatment-free survival and cures in combinations that improved median TFS or median overall survival without producing TFS may sacrifice that potential of I-O while contributing toxicity inconvenience and tremendous extra cost. So I want to see not only A+B being better than A2B or B2A, but treatment-free survival and cure being maintained in order for such combinations to fully be embraced. And clinical trials with I-O agents, I think, need to look at I-O endpoints such as landmark PFS and OS, complete or near complete response rates, response duration, time to initiation of subsequent therapy, treatment-free survival or cure and overall quality of life and overall value. So our goal when we're developing immune therapy should not be to simply turn cancer into a chronic disease, we should strive to make cancer a curable disease using agents or combinations that maximize the antitumor response and raise the plateau and enable PFS as many pan-cancer patients as possible is critical to achieving that goal. And you're going to hear from other speakers about some really impressive treatments that can actually do this. So I'm going to just close by acknowledging my colleagues at the FHSC, at Georgetown Lombardi, some of whom are actually in the room and others from around the I-O sphere and my funding sources. And finally, my family [indiscernible] here who rode in our big bike ride, which included many of my melanoma and kidney cancer patients who rode 25, 50 and 100 miles, showing what it means to be a cancer thriver, not just a cancer survivor as well as my daughter, son-in-law and my grandson. Thank you very much.

Thank you, Dr. Atkins. Thank you, Dr. Atkins. We appreciate all of your perspectives and your contributions over decades. I'd like to invite to the podium Dr. Larry Norton, Memorial Sloan Kettering Cancer Center. He's the Senior Vice President and a member of the office of the President. He's a Medical Director of the Evelyn H. Lauder Breast Cancer Center at Memorial Sloan Kettering and our honored guest.

Thank you. Yes. I have another title too, I think, which is relevant to -- thank you for the introduction, which is I think relevant to this, by the way, I never contemplated a career as a professional football player. I just want to make this [indiscernible]. Although I did actually had to play in high school, I was running back in high school. But I'm still recovering from the injuries and I've decided to move on. I was a musician, and I took around the time of [indiscernible], I took a left turn and I ended up going to medical school, and I got stuck. So here I am. But music and math kind of go together. And so I've always been interested in mathematics, and I've been working on mathematics from high school age, whatever. And I think that is relevant. Obviously, we present some of this stuff to you today, and I think it's relevant to what we're talking about. The other job that I have at Memorial is I'm Director of the Cancer Center, the NCI-designated cancer center for clinical and translational research. So I kind of overview all of the clinical and translational research in at Memorial Sloan Kettering, which is a lot. And what I've learned in that job over the years is to look at big picture things. And not necessarily focus in each individual scientist, each individual clinical investigator is focused in on their particular work and is a world expert at what they do. My job is to kind of weave it together and make sense out of all of it and put it together in some kind of context, so I can have people work together in collaborative ways. And so I can direct things in ways that could be maximally productive. And on mathematics to being extremely useful way of doing this and have learned things very, very specific about cancer that's been relevant to cancer therapeutics, but also, I think, towards the future. So that is an introduction. This is my topic. Why is it so hard to cure cancer? And you've heard Mike present this [indiscernible] we have a real problem in doing this, and I'll talk about this in a second. And if there is a problem with curing cancer, what can we do about it to actually make it better? So the reason why this is a puzzle is because it's extremely easy to cure cancer in the laboratory. We have lots of animal models, lots of cell cultures and abundance of tools to evaluate cancer. And we have lots of drugs. As a matter of fact, almost every drug that actually works its way into our therapeutic armamentarium in the laboratory shows some great efficacy. And usually, the great efficacy is eradication of cancer cells or a very profound effect on the cancer cells. And then we put into the clinic, and the results are much more modest. In fact, as presented, we often get stable remissions, partial remissions, complete remissions after a while, and then the disease becomes refractory therapy grows and the patient dies. So our ability to cure cancer is really impaired and this is in mark distinction between with what we're actually seeing in the laboratory. And the reason is, there's a very simple reason is that when you grow things in the laboratory, they grow exponentially. We choose models that give us exponential growth. Exponential growth is to go from 1 to 2 to 4 to 8, 16 and so on, and it keeps growing. And when we apply anti-mitotic therapy, therapies that kill dividing cells, one way or the other, all of our chemotherapies almost every targeted agent that's being developed now and with a very cluttered science, which are attacking the cell division in one form or another of the cancer, they regress exponentially. And if you regress exponentially, you move rapidly towards zero. And if you get below the volume of a single cell, you've got disease eradication. And then we take these drugs, we put them in the clinic. And the reason, I think, again, looking at this an overview, and I can give 2 or 3 hours of electro on this to make a convincing case, but I'm just going to give you the bottom line is that clinical cancers do not grow exponentially. They grow by a pattern that was originally discovered by Benjamin Gompertz, published in 1825, the proceedings of the Royal Society of Medical London. And so it's called the Gompertz curve, which is an S-shape curve. It starts off sort of looking exponential, but then progressively slows down. And eventually, theoretically, if you look at it long enough, it will reach a plateau size. And are the benign tumors, the fibroadenomas of the breast, the benign tumors that we see reach that plateau size and never cause another problem. Malignant tumors are malignant because their plateau size is larger than the size that's compatible with the life of the host. I started delving into Gompertz growth in the '70s and started doing experimental models. I wasn't the first to notice that cancers and laboratory animals grew by competing kinetics. Others had seen that before, but I wanted to find the mathematics in the '70s when I set the National Cancer [indiscernible]. I started defining the mathematics of this Gompertzian process and finding some very fundamental things about it that looked very intriguing from a theoretical point of view that we're still trying to pursue. But also it led to a clinical hypothesis based on laboratory data and the critical hypothesis was that things that grow faster, shrink faster, things that grow more slowly, shrink more slowly. And therefore, if you want to maximize the effect of your therapy you should minimize the time of growth between cycles and treatment, a very, very simple kind of concept. That was in the mid-70s. It took roughly -- took roughly 20 years before I could get into clinical trial in the cancer leukemia group B in a breast cancer trial. And then another 20 years for this paper in 2019, which is from the worldwide overview, the early breast cancer trials collaborative group in Oxford. Analyzing 26 randomized trials with almost 40,000 randomized patients showing that the therapy that was derived from understanding this S-shape Gompertzian curve actually improves cancer cure rates, reduces recurrence. The blue line is what's called dose end sequential therapy, which is the therapy that was derived from this kind of mathematical thinking. Recurrence rates are reduced. I'm not progressing. All right, cancer mortality is reduced. There's no increase in toxicity to the host because death without cancer is not increased and all-cause mortalities in fact, decreased. In fact, there's actually a decrease in the contralateral breast cancer incidence rates from these particular regimens because we may be actually curing -- curing microscopic cancers that are not apparent or cold cancers in the opposite breast by this particular maneuver. So I'm just presenting this to you as a bottom line or 40 years of work, just to emphasize the fact that the math works. And growth is true. You can use on protein growth to make better cancer therapies. But it leaves the big question is what is going on, Why do things grow in a Gompertzian fashion? And how can we exploit that to actually improve cancer therapeutics and overcome our barriers to securing cancer? And the big breakthrough on this was it was my work with Joan Massagué, a great scientist. Now the Head of Sloan Kettering Institute at Memorial Sloan Kettering, who working with colleagues made the observation that you can actually derive a mass line called 4175 of MDA-MB-231 cells, which is a breast cancer model, that has a very high probability of going to lung and forming lung metastases, as you see here. the gene expression profile of this tumor is dramatically different than the gene expression profile of the parental line with a much lower incidence a lung metastases. And the mystery was that these tumors in the lung, also in the mammary fat pad grew faster. And yet when they measured the percentage of dividing cells, the Ki-67, it was not higher in those tumors than the tumors that didn't go to the lung, but not the ones that were growing faster also went to be lung with the same percentage of dividing cells and of course, the animals in that particular way. And the mathematical puzzle that I was confronted with was how come you can have a tumor that is metastatic also grow faster when the percentage of dividing sales was not greater. And the hypothesis that we made in 2006 was maybe it was growing faster because not only it was a metastasizing through the lung, but it's also metastasizing back to itself. Pathway C is to a lung going with lung metastasis, Pathway B is to go into the circulation and come back to the primary tumor and grow as a separate module. And if you have 3 things in this case growing at rate x each, they'll grow 3x faster than 1 thing growing at rate x. So that if you measure the percentage of volume cells, it's not any different, but the growth rate would be faster. This actually explains competing growth. Is it true? Well, good animal experimentations, finally published by Myeong Kim in [indiscernible] 2009, showed that it was true because if you implant tumors with metastatic potential on different flanks of the animal with different fluorescent proteins, they will spread from one side to the other. And indeed, you can see this here, where the red tumor on the left now has attracted green cells from the right, the green tumor on the right is attracting red cells from the left. And this exchange of tumor cells from the one side to the other, which we call seeding or self-seeding, is a big factor in the growth of these tumors, an unexpected factor before doing this work every I thought growth was all mitosis and some mobility nothing to do with the process. It may have to do with the process of metastases formation, but didn't have to do with the process of growth. But actually, growth is promoted by the seeding process as well as -- as well as the elution of the individual cancer cells. Now interestingly enough, all right, that when these cells come in, they bring cells with them. They bring their own stroma. Marrow-derived blood vessel precursors causing angiogenesis, as you see on the left, and as you see on the right, white blood cells, leukocytes are brought in, in a plentiful fashion as a process of this growth by self-seeding. So now we're bringing in the to microenvironment in meaningful way. It explains the Gompertzian growth pattern because if the cells are coming in from the outside in, they will stick on the outside of the tumor. And the outside of the tumor, the ratio of the outside of the tumor to the inside of the tumor goes down as things get bigger. Because the outside is roughly related to the square of the diameter, whereas the volume is related to the cube of the diameter, square something over the cube of something as the numbers get bigger, that ratio drops, which is -- so I'm sure you're going to remember this, why mice [indiscernible] and elephants aren't. All right, because mice are small, so they have a very big surface there related to their volume. They have trouble holding the heat in. Whereas elephants have a very little surface area to volume ratio their trouble is getting rid of heat. All right. And you notice that great big people don't have to wear big, heavy coats in the winter, like those small people do. And therefore, that's why your children -- that's why your children or you have to really bundle them up in the winter, they can lose their temperature very rapidly, whereas adults can be more comfortable. It's all related to the ratio of the surface to the volume, and it explains Gompertzian growth if you're growing mostly on the outside as you get bigger you slow down your growth process. The only thing you're going to remember from my talk is mice and elephants. That's it, right? Again, thank you. People have come to me 10 years later and say, you were talking about mice and elephants, weren't you? All right. So further work has gone on this -- this is a little bit [indiscernible] myself who've done a great deal of further work on this particular process. As you see, the primary tumor is up there on the left. It goes into the circulation. It can go to the bone or the brand long metastatic sites. But what was not appreciated is that it can circulate back to the tumor. It could also come from metastatic sites back to the tumor. And all of this has been proven and it's easy to prove now with single cell sequencing. We have a lot of work and her colleagues have actually done a lot of work to show this is going on. And each time these cells come in, they bring white cells with them, and those white cells are important. Not only to defend against the tumors or even mentioned, but also to some extent to support the cancer cells. And so you have this yin-yang that's going on with the tumor and its microenvironment. So the growth of the cancer is 2 components. It's mitosis and it's also geometry, the relationship of the cells to the microenvironment. It doesn't -- it should not surprise anybody that if all you do is develop a mitotic drugs, you are not taking care of the whole cancer problem. You're only taking care of the cell division. And in fact, the reason that Gompertzian cure cancers are not cured by the same anti-mitotic therapy that cures exponential cancers in the laboratory is because of Gompertzian growth. The top you saw already in the lab, I got exponential growth, and I give an anti-mitotic therapy, and I drive it down to 0. If I take a Gompertzian tumor and I take the therapy anti-mitotic therapy, with exactly the same efficacy in terms of killing cancer cells, it will just, it will just reach a new Gompertzian plateau at a lower level. And so the geometry is determining this. And this is what we see every day in the clinic. We see patients achieving some -- is below level kind of appreciation to complete remission. Usually, it's a partial remission. There's some tumor present, the patient goes on for a long period of time while they're going on, cells are dividing. They're mutating, they're developing drug resistance and eventually, you've got pan-resistant cells and you have inability to control the cancer of the patient goes on to die. So this is basically the process. So what we're here today really celebrate this whole meeting to see this whole meeting and is to celebrate the fact that for the very first time in history, we're developing an effective armamentarium that could do something else, which is that it can be anti-mitotic but can also change the geometry of the tumor and its relationship to white cells that are there. The yin-yang of the white cell supporting the cancer and attacking the cancer, which hundreds of presentations over the last few days, we really -- have talked about. And that is why this is really a big change in the history of cancer therapeutics because if we can combine the appropriate anti-mitotic therapy certainly not anti-mitotic therapy that kills white cell, as you just heard about, that would be a mistake. If we can combine the right anti-mitotic therapy with the right anti geometry therapy or anti microenvironment therapy, that's when we can drive this down. And these are not theoretical curves, by the way, these are actually mathematical models that have been corroborated in the laboratory that actually showed that this is the pattern and this can really apply just like the simple Gompertzian growth can apply to design of badgering chemotherapy and give you the results that I showed to earlier in my talk. So combinations of anti-mitotic therapies and therapies that address the tumor microenvironment of which immunotherapy is the best lead that we currently have. You can talk about anti-angiogenic therapy, too. That's a whole other kind of topic. And it has not given us the kind of profound results so far that we've really seen with immunotherapy. And that's why I'm basically betting my future on addressing the immunotherapy component in combination with the anti-mitotic component. But to do this, we're not curing cancer why? It's Gompertzian. And to do this, what we need is to expand the activity of our effective immunotherapy. First of all, to work against tumors that have not so far been helped by it. I frankly don't really think that such a thing as a cold cancer. I think there's just various degrees of hot, all right? And if it's below the level of current therapy, you need a better treatment and Bree will talk about that very shortly to actually make that work. So we have to make our agents better. We have to combine them better. We have to combine immunotherapies better. We also have to combine it with anti-mitotic approaches in a very intelligent and creative fashion. And I think you can hear a lot about the thoughts in this regard as we proceed. Because if we can actually do this and utilize that effective therapy against the tumor microenvironment to zeroing in on the white cells and combined it with anti-mitotic treatment, I think it's going to take both that I think we're seeing the end of cancer by all the indications that we have. And math really doesn't lie. I mean math really gives a way forward. I think we just have to catch up with the math and develop the agents that could duplicate what we see in the mathematical models. Thank you all very for listening.

Thank you, Dr. Norton. I'd like to invite to the podium Dr. Jennifer Buell, who is the President and CEO of MiNK Therapeutics, the former COO and President of Agenus, to talk a little bit about the path that Agenus is on with regard to curing cancer.

Thank you very much, and what an honor to be able to follow such giants in the field. I'm thrilled to be here to talk about my Road-Taken. I think it exemplifies actually what I think to be some of the most powerful and exciting components of Agenus. Before doing so, I think that the most recent stops in my journey though, have led me into more time with Dr. Norton and as well as Dr. Atkins on the development of botensilimab. We had contacted Dr. Norton when we saw our first patient ever treated with Stephens patient on botensilimab in endometrial cancer patient who actually had a complete response. We called Larry and he said, "Why are you calling me about this patient, I'm a breast cancer guy." We went through the data with them and he said this is very exiting, and I think I may know what's happening. And we've launched a very exciting collaboration with him to help understand what could be happening, and you'll be hearing more about that as we move into botensilimab. But my journey and my road-taken actually has brought me to Agenus. And the thing -- the item and the component and the culture of Agenus that I think is most compelling, is their commitment to -- our commitment to rethinking the way that drug development is done. And that's not only with fully integrated capabilities, drug discovery capabilities and the ability to have fully integrated manufacturing that allows us to go from an IND clinical-grade material to now full commercial production of our own molecules and owning that supply chain, but also to have a fully-owned yet independently operated and funded CRO capabilities that allow us not only to identify the best investigators to be advancing our programs, but also to have the highest quality data, the operational capabilities and the speed that's necessary to move our programs very, very quickly. We have a Phase I facility that I'm going to speak about in just a little while in Hamburg, Germany and then a late phase international CRO capability, operating in Eastern Europe and with a footprint all over the world. So the most important part of these capabilities is that we share them with others, our collaborators, our partners and even some of our competitors that allow us to bring these molecules, our molecules and other effective molecules to patients as quickly as practical. And that's a very important disruptive change in drug development and something that I'm really honored and proud to be a part of. So how did I get here? I actually started my journey in large pharma and largely uninspired by somewhat insular approach, the development of therapeutics, an approach and a structure that I thought was far too cumbersome and quite bulky and led to what I think is the problem that we're facing now, which is just a high obsolescence rates of therapies and still a versioning and developing high unmet need for patients. I sought and found an entirely different approach how we were going to be advancing therapies and that was at Agenus, I joined just out of my fellowship. And at the time, the company was a single product company with 50 employees and it was a cancer value Agenus was the pioneer to actually take and industrialize the uptaking a patient's tumor, manufacturing that and distributing it to patients all over the world. Those early data that we generated in thousands of patients actually showed remarkable benefit in a number of patients, but what we learned is that some patients with disseminated or extensive diseases needed more than just a vaccine. We sought and tried to get access to checkpoint modulating antibodies that we thought and new. Now we know, but we thought at the time, hypothesize that they would be very important in bringing durable curative benefit to patients. That was 15 years ago, and it was really hard to get access to those molecules, and it's no less hard today. If you do not have access to combination agents in your own portfolio, it is nearly impossible to develop products, first clinically develop them and then commercialize them and then be able to price them so that every patient who needs them accesses them. What we actually have done now is we decided as a result of our frustration to build and internalize all of our own capabilities, and we did so through a series of strategic acquisitions, including antibody discovery platforms and partners, and building our homegrown and expanding our homegrown capabilities as well. I was the Head of R&D operations and working with Dr. Stein, who's joining us today as well. We were just so thrilled to have the pipeline now in a series of companies that I'm going to be talking about in just a moment. But we built a structure that was different than what anyone else had done. And in a 5-year period, we delivered more than 70 new discoveries to the clinic generated, nearly $1 billion in partnerships and milestones and went through a full BLA filing process including successful FDA inspections of our manufacturing facility in that time period. Our perfective process also gave rise to an enviable pipeline that includes the molecule that was subject of Dr. Bree Wilky's plenary presentation at SITC today, and that's botensilimab, you'll be hearing much more about botensilimab in the next coming talks. What I'm most proud of though is when you take a look and dig into this pipeline, you actually see that we've not only outpaced industry and delivering a pipeline that is designed to address the limitations that currently exist in those that Dr. Atkins and Dr. Norton spoke to you about just moments ago. The Agenus pipeline though boasts something else that is largely underappreciated and that is the high success rate of our programs. All of our discoveries are still in active clinical development, many of which are in late-stage development. I think that, that is something that very few others can say. This also includes a commercially available adjuvant. Our QS-21 Stimulon adjuvant is in the commercially available Shingrix vaccine from GSK as well as others. Typical success rates in the industry are really much lower than this at about 8% of clinical success in advancing through a pipeline here. So what's necessary now? You're going to be seeing some very provocative data of a molecule botensilimab that is generating responses and we call them cold tumors, but now we'll be them less hot tumors now on. And those -- that molecule, we are seeing some very interesting features across a host of different tumors. We believe that we may be able to combine that, and we've demonstrated in preclinical models that when you take botensilimab, you combine it with PD-1 in models that largely represent metastatic disease, secondary to melanoma. You see very good benefit in [indiscernible] models. However, when you add invariant natural killer T cells, that is a very powerful subset of T cells, you see complete eradication of tumor. That sets us up for a very exciting time as we develop. And last year, in October, we launched MiNK Therapeutics. And MiNK Therapeutics as we just held an R&D on Thursday, which is available to all of you. But MiNK Therapeutics presented 5 presentations at SITC conference this year, which included 3 clinical programs showing some very interesting early signals of iNKTs in solid tumor cancers alone as well as in combination with KEYTRUDA and OPDIVO. We're also seeing very remarkable dramatic benefit of survival in patients who are severely sick, mechanically ventilated elders on getting the cells. These patients were suffering from viral ARDS, and we're seeing a 75% response rate compared to about a 10% observation at hospital-based control data set, and Dr. Terrace Hammond presented that data at SITC earlier this week. So without further ado, I'm going to turn the presentation over to Dr. Steven O'Day, and he's going to kick off the main event on botensilimab.

Thank you, Jen. I feel like it's a perfect storm that I'm back in Boston because I trained at Dana Farber in 1991 to 1994, and SITC has come back here and botensilimab is at a plenary session at new immunotherapeutics. And I have all this wonderful team around me at Agenus. You're going to hear more about them. And you've just heard some of the great pioneers Dr. Norton, Dr. Atkins, you're going to hear Alex Eggermont, my dear friends through the -- So I feel very fortunate to be here. But I want to tell you a little bit about my story and the road I've taken. After training and hematologic malignancies as a transplanter, I was enthralled with leukemia lymphoma, the curative potential, the dramatic sort of taking someone from death to life. So that was deeply ingrained in my head. And I had many mentors at the Farber, but Tom Fry, who you may know is one of the giants of medical oncology, really developed the first childhood leukemia treatments with colleagues, Sidney Farber, with high-dose methotrexate combination chemotherapy, high-dose therapy and transplant to cure kids sequentially. Tom Fry had all that success, but he pivoted his career towards the end to solid tumors. And to Larry's point, Larry knows very well this -- the thought was, at that point, maybe we could pivot combination -- given the heterogeneity of solid tumors, combination cytotoxics directly at the cancer either in combination or in high doses could repeat the data from hematologic malignancies. And Tom Fry would spearheaded what we call the stamp program at the Farber solid tumor high-dose therapy. Unfortunately, it failed for many of the -- essentially the reasons Larry has outlined that you certainly couldn't get rid of that last cell. You sort of pissed off the cells ultimately and they grew back and they developed multidrug resistance and patients die. So Tom Fry told me, he said, he knew I was like, all into hematologic malignancy goes, you're interested in immunotherapy? My best friend and colleague, Don Morton, who is in Los Angeles, knows more about melanoma than anyone in the world. And solid tumors, we need to stop thinking about the cancer cell and more about the T-cell. He said, now there's anecdotal evidence in melanoma that there's some relationship with the immune system and no chemo works. So it's a perfect sort of disease type to really develop immunotherapy. So I went -- he said, go to Morton. He'll teach you melanoma then come back and we'll start a melanoma program at the Farber. Well, that was 30 years ago. I never left Los Angeles because I was really enthralled with a career that was developing with Morton's mentorship, a great pioneer -- surgical pioneer, who, again, all the accomplishments in surgery, and Lex knows this in terms of debulking metastatic disease and then using vaccines to prevent recurrence. These were all great instincts. You just didn't have the tools in terms of effective vaccines. But his instincts were good, sentinel lymph node staging transformed the world in terms of understanding pathways of spread from the primary to regional nodes. But what he was most wanting to know before he died. And I saw him very shortly before his death, was he was just beginning to understand the Checkpoint revolution. And he -- I wish I were younger because the future is in front of us. And he couldn't have been more true to the word. And so my career, like Mike's done a lot of my heavy lifting because those early days in melanoma. We were -- I was working side-by-side with surgeons. We were resecting all this metastatic disease, trying to give vaccines. We were trying to use high-dose IL-2. And we did cure small number of with nonspecific cytokines that were like nuclear bombs on patients. And then we tried biochemotherapy, and ChemoPlus. And I spent a good decade. And then in about 2000s, so about 23 years ago, I got to treat the first patients with ipilimumab. This was a little company called Medarex that said, I thought one more negative immunotherapy trial. We started to put it into patients, and there were some phenomenal -- this was the first time outside of an ICU like with IL-2 or bio chemo that had to be given in the hospital. We could actually give outpatients a monoclonal antibody that was targeting not the cancer but the T cells. It was releasing this very primal early break that prevents autoimmunity and cancer surveillance. And CTLA-4 is really teleologically designed once you clear a virus in 48 to 72 hours, then you want to put your T cells back into memory, so that you don't cause autoimmunity and other things. But it's good to spare the species create -- allow people to procreate. But as you age, your T cells get not as effective, cancers develop. And once cancer is established, you don't want to turn off that switch too early where the T cells never have a chance. So we started to see these remarkable responses in a hot tumor like melanoma that were durable. And we spent about 10 years. I want to pay tribute to the group of investigators for -- before PD-1 because think of PD-1 as sort of a second revolution and it certainly is well deserved. But it took 10 years really to understand the paradigm shift from cytotoxics to I-O. And Mike was involved that. I was in the trenches, Jeff Weber, Jed Walchuk, Steve Hody we had to really change the paradigm and stand boldly against our oncology colleagues who wanted to see rapid responses, didn't want to wait for duration of response, didn't want to watch for plateaus, they love medians. The kinetics of the response, they were impatient with CTLA-4 that actually took CTLA-4 longer to work, 3 months on average as a single agent. This was an eternity for medical oncologists. So there was a lot of lessons learned. How does toxicity relate to efficacy. To this day, I'm so tired of hearing about I-O trials where there's -- they love to say there's no toxicity. And then you look for efficacy and there's no efficacy. IDO is a great example. No single agent activity, no toxicity, no efficacy. I'd much rather have a toxic, relatively, reversible toxicity that correlates with T cells actually getting rid of cancer cells permanently by moving through the body, causing some inflammation as they go, a natural correlate. And that's what we see with most effective therapy, CTLA-4 more so than PD-1 because the T cells are primed in the periphery as opposed to the tumor. So they're moving around more than PD-1s resurrected T cells in the tumor, where they're not circulating. So there was less toxicity with PD-1 and CTLA-4. But CTLA-4, there was something special about that from early days that you didn't -- you could give 1, 2, even 3 doses and patients were cured. We didn't see that with PD-1. We got back into a cytotoxic model of treat till death with PD-1, and we're backtracking from that. But there was something very special about CTLA-4. The field then tried to get rid of it. We try to say, it's too toxic. And in fairness, the problem with CTLA-4 was not the toxicity, but it didn't prime well enough across solid tumors. So it was a limited drug mainly to melanoma. We tried to look at it as a single agent that didn't respond. So that was the problem. It wasn't that it was producing cures or long-term survival. It had manageable toxicity. It just wasn't enough. In botensilimab, you're going to see is broad and effective. And that's what excites me. So the field move we went from CTLA-4 alone and then we were curing half the patients with melanoma today. And Mike brought up a very important point. With high-dose cytokines, the brain was still a sanctuary. For whatever reason, when you stimulate the T cells with cytokines, they didn't eradicate brain subclinical brain meds. But these in vivo antibodies that were manipulating T cells like PD-1 and CTLA-4. They were moving in and out of the CNS compartment. And essentially, that became another organ site, not a privileged site. And that's where you saw the major change in survival curves. So that -- so now diseases where, I would see, 4 to 6 metastatic patients a week that were in their 40s and 50s with young kids, to Mike's point, that had 6 months to live on average and none were alive even a year or 2 years, very, very rare. Now half of those patients are cured. Our clinics are filling up. Melanoma doctors don't actually have to take new patients as often because the old ones aren't dying and they're traveling and they're off treatment, really an extraordinary experience. So that's the background that led up to this. But -- but my focus in the last 10 years as a cancer center director in Los Angeles was -- could this happen in other solid tumors. And the field has worked hard to exclude CTLA-4 from the discussions LAG3, which has made it barely in melanoma, but we're all very pleased with that target. But there are a lot of other targets that fail, IDOs, oncolytic viruses, bempeg more recently. Just terrible failures with big trials where curves overlapped. So I think the field now is starting to come back to combinations of driving sort of early T cells that have memory and cytotoxicity in combination with a PD-1. It's certainly a better combination of the data, you're going to see 125 patients with tumors that have no business being in the response rate of the first revolution of I-O or absolutely responding to this combination. So it's a pretty phenomenal situation. So that's my story. And why Agenus? Well, actually, so I'm a care center director, I'm in charge now of solid tumor I-O. I'm still seen by patients in the clinic. And I'm doing all the usual combinations, and I'm waiting for CTLA-4. And not much is going on. And then Dan Van Hoff, another great mentor said, you need to talk to Agenus and get on their scientific advisory board. So I did. And Jan tells, sorry but, I see this pipeline. I'm like, is this Merck? Is this -- you've got 17 INDs. You're partnering had a lot of drugs, but you're keeping drugs. And they were trying to show me -- I know, I remember, they were trying to show me all the things that I was just focused on this next-gen CTLA-4. And I said, yes, I like the other stuff, that's great. But would I -- would they let me be the PI in the clinic for the first in-human next-gen CTLA-4. So -- and there was an art to that story, I will admit. Because haven't been the first to dose ipi, the thought of dosing this. And I did dose the first patient -- ovarian cancer patient that it failed platinum, bevacizumab. She'd actually been on a trial that I had with KEYTRUDA and a PKI inhibitor had failed that. And then came on to this trial as the first patient at just 0.1 milligrams. And her disease over the course of a whole year that had previously been growing stopped growing. And if her lymph nodes actually fluctuated, got hot and cold and painful, regressed so there was this battle going on. And then she finally after a year progressed. We went up to a higher dose botensilimab and added balstilimab, the data you're going to see and a rapid response. I remember. CA 125 went in from the thousands down rapidly. So I was convinced. Then I started treating some GYN, some sarcoma patients. And I just couldn't believe what I was seeing. It was like these patients have missed the boat with first drug and my dream started getting really, really activated in my mind. So then Agenus made me an offer I couldn't refuse 2 years ago. And I've been sort of watching this develop, trying to stay, as Mike would say, measured, what's the data, stay controlled, keep looking for what the next best scientific experiment. And then we've got a team that's just Joe Grossman was here actually before I did. We call him GI Joe, you're going to hear him. But the guy keeps -- I want to go to melanoma with this -- he's like colon cancer. I'm just telling them -- No, no. Let's go to melanoma. We know we can work there. But to Joe's credit, he's really spearheaded a vibrancy, an optimism and soaked in all the I-O stuff. And [indiscernible] come. And I'm just so privileged to have these young, really inspired young oncologists that are smart and are being -- we're working together as a team. You're going to hear about our regulatory and other areas -- and certainly with Todd, we're very serious about getting the team in place to get this forward. So I think I'll just finish with -- I think there's one slide I have, right? I just want to remind people, this is a spider plot of 125 patients who got this combination in diseases that were all either diseases that have never shown any significant activity with an I-O or if they had the disease that had an I-O approved had already failed that. And I think Mike, you said this at one point to me when you looked at some of the early data. There's 3 phenotypes to this graph. There's obviously the early deep progressors, which is the hallmark of CTLA-4. There's also the early progress. There's obviously the primary resistance. And then you have this middle ground. And I think Mike told me, don't assume in cold tumors that you're going to be able to reproduce these phenotypes that you've seen in hot tumors like melanoma. And I think the reason this is important is survival which is the critical endpoint depends on deep, durable responses. But it also depends on stopping disease and its track for prolonged periods of time or minor reductions in tumors. And these curves really reflect that in tumors that all of these lines should be going to the ceiling, historically. So it's early days, but it's remarkable days. It's been received by the community today, an endorsement of this data at the plenary session where they put in a -- it's called an high educational scientific session but also a session that they put a few abstracts that they think are very meaningful, and they put this into the session today. So I think I'll end there and let the next team go. But I'm delighted to be here and happy to answer questions as the day goes on.

Thank you, Stephen. Thank you very much. That was a tremendous presentation and an unbelievable transition. I'd like to invite Dr. Breelyn Wilky to the podium who had the plenary session earlier today. She's at the University of Colorado Cancer Center, where she's the Director of Sarcoma Medical Oncology and a Deputy Associate Director Clinical Research. Thank you very much for being here.

Thank you. Thanks, everyone. It's a pleasure to be here. And keeping with the icebreaker questions, I did not think about football in high school either. I was a musician, however, and so kind of went through the great debate in undergrad. I did my thesis in St. Petersburg, Russia. Studied post [ hellenistic ] modern piano stuff and try to learn Russian, that was a disaster. But -- at the end of the day, I came back, went to med school and have sort of kept the music piece of it on the side. But I think it's a nice balance to kind of keep us focused and ensure that we remain not just people of data, but sort of looking at the human side, and other side of this as well. So anyways, so my journey, my road taken. So I'm a sarcoma doc. And so most people who hear about sarcomas, if you actually know what they are, you just go -- oh, that's scary. And I was a first-year fellow. My very first rotation at Hopkins was the consult team. And I remember getting a call for a patient with an angiosarcoma in the spleen. And she was 27 years old, couldn't eat, had a tumor that's about the size of a watermelon in her spleen, TPN, like the works like this woman was -- this woman was really, really sick. And I remember going -- knowing I was going to round with the queen of sarcoma at Hopkins. And Googling and pulling up NCCN guidelines and all the things that good fellow is supposed to do and realizing, oh, my gosh, there's nothing to do. Like the NCCN guidelines are like, here are some therapies that might help. And I met with my attending and she's like, yes, we're going to try this chemotherapy. And it worked like we gave it to her and her diseases melted away and I was like, I've just cured my first cancer. This is awesome. For like 3 months, and then it came back and she died within a couple of months after that. That's what we call visceral angiosarcoma and that was sort of my first encounter. So I remember thinking, there's breast cancer, there's GI cancer. There's all of these different cancers out there, how am I going to actually make an impact? And I saw my sarcoma patients, which ages 15 to 18, even younger, pediatrics all the way to 100-year-olds. And no one -- everybody can get these diseases. And there's 100-plus different types, right? So if I could make any impact whatsoever, even a littlest thing, I felt like it would pay off for this particular group of patients. And I saw, the bar was low, like no one wanted to deal with them. And so I'm like, okay, well, that's what I'm going to do. So I went on to take my first attending job at University of Miami with a guy named John Trent, who's been at MD Anderson for years. Another guy named John Goldberg, who was pediatric hematology oncology at Miami at the time. And that's sort of where my journey started. Incidentally, I will say that at Hopkins, we had the first patients on what would become nivolumab, on the floor when I was a fellow, pneumonitis and sort of like everybody was talking about it, and I put a few patients on [ check TriKE's ] immuno trials and like it was intimidating. I just don't see how this is going to be -- this is going to be a way forward for us, but these things change. But anyways, this is sort of a snapshot of my life. Like I said, 100 different types of bone soft tissue tumors, collectively only 1% of adult cancers. We tried -- we say went out cut them out, in which -- that's what we try to do. But if you can't remove them surgically or they come back in a metastatic setting, it's quite devastating. And so this is just sort of a summary of the past 40 years of work where we've tried to prove that anything, any combination, any new drug, anything could be better than single agent doxorubicin. And no, it's still for metastatic soft tissue sarcomas, doxorubicin monotherapy, is still the standard of care. The median progression-free survival for doxorubicin is somewhere about 6 to 7 months, and the overall survival for most metastatic sarcomas is somewhere between 12 to 18 months, maybe a little bit longer now that we've gotten a couple of more agents approved. But this is a -- it's a high bar. But what about immune therapy? So for those of you that have looked back to -- to remember back in the days of Coley's toxins, I mean it was actually sarcomas that he theoretically cured with his toxins. And so for a long time, there have been people thinking that sarcoma might have some way to be targeted by the immune system, not just from this but with vaccines or with natural killer cell therapies, just because of the way that they've behaved. And what's interesting is that even though most sarcomas would do poorly, there's about 10% of patients where if you can take out all their disease, you give them chemotherapy, which we know doesn't kill everything. They could still do remarkably well. And so it kind of gives you this question of could the immune system be playing some sort of suppressive role in making this happen. So okay, so back to my days in Miami. So John Goldberg there. We -- he actually had wound up abandoning, University Miami about 2 years in to go work with this company called Agenus. Pete, HemOnc, academic, and he came over to be the CMO for these guys. And I just remember him call being like, hey, we're about to kick off this trial with zalifrelimab, which was AGEN1884 at the time, which is a CTLA-4 inhibitor. You guys want to open this. And of course, baby attending. I'm like, sure, let's do it. This sounds great. So we opened -- and we actually put the first patient on. And this was like the baby dose escalation. Her dose was 0.1 milligrams per kilogram of CTLA-4, like fold less than what we thought would have been active. So this lady, 60 years old, and she had this horrible awful disease that you can see here on her face. So this is what's called cutaneous angiosarcoma. So compared to my spleen lady in fellowship, these tumors can occur usually in the elderly and sun-exposed areas. And you can do surgery and we've tried to cut these things out. But -- they're usually in bad places where you can't get good margins and they just keep coming back. So she had a dozen different treatments. Cytotoxic chemotherapy, targeted therapies, we put iron like a NASH inhibitor Phase I. We cut her nose off. We did definitive radiation, like we had tried everything. And so -- and she just kept coming back with this awful horrible thing. So we put it on AGEN1884. And at about day 12, you can see this tumor explode. And this is all immune cells. I mean, this is basically puss and sort of inflammation here, granulation tissue. And she just kept on responding and she kept on responding. And about 1.5 years in, we did a biopsy after seeing a complete radiographic response of her tumor. It's now gone. And she had a past CR. So no more cutaneous angiosarcoma. And that was February of 2018 that she hit past CR, and she's still cured today, like this never came back. It's nuts. And so it turned out after this amazing response. We actually teamed up with a [ general studies ] some beautiful correlative work on her tumor we gotten biopsies. Others have found that cutaneous angiosarcoma has a UV signature. So similar to melanoma. Sun-exposed areas, high mutational burden. And so we were like, oh, that's got to be why she responded so well, but she actually did. She didn't have a high tumor mutational burden. And you can pull the JITC article where we kind of went through some of these things. But I saw this, I was hooked. I'm like, wait a minute, like we just fixed this lady that couldn't be fixed. I mean I don't know why. The other thing -- that's her final -- the other thing that was happening at the same time again with John Goldberg's help at the time is that, I had met this kid who was 20 years old, who came into my clinic with this disease called Alveolar soft part sarcoma, and this is less than 100 cases per year in the United States. It's a disease. Again, it kind of resembles melanoma. It's got a -- it's a conserved translocation with TFE3 and basically group of transcription factors that had some similarities. And so this kid -- or this disease presents in young and healthy adolescents and adults with 0% chance of response to chemotherapy. And so we had pitched the study to Merck for an IIT of pembrolizumab plus a VEGF inhibitor because that was the 1 thing that was somewhat active for ASPS. And then sarcomas, there's some activity of VEGF located in TKIs as well. So we did this, and I -- Merck bought it. I don't even know how that -- how it happened. It's all serendipitous is the theme of my story today. But we got this IIT. We wound up putting 12 patients with ASPS on this study, and we're the first to show a response rate of greater than 50% in a disease that had absolutely no options. And I -- this lady up here at the top was 23 and had, had multiple recurrent ASPS. And again, she's one of these long-term cures, right? Like we got rid of her disease with immunotherapy. And now, of course, the rarest disease on the planet is now the most popular disease for immunotherapy. And you can see that basically, in just a few years since that trial close to 100, if not more, patients have been treated with various PD-1 inhibitors with ASPS across the world. And so it's just sort of one of these things. I'm using this to show that if you go after the little problems, you actually can make a big dent, even if it seems that's impossible and not feasible. Okay. Moving forward. So unfortunately, when you look at other types of sarcomas, the nutshell here is that we've tried to turn the cold tumors hot and now they're less hot, right? And I'll show you why. But we have worked really hard to catch up to the rest of the field and combining with various agents, including CTLA-4, macrophage targeting agents, chemotherapies and we're still stuck at about 20% for most sarcomas. And the reason, I think and what most people think is that there's a continuum of hot and cold. So this is transcriptomic data of about 700 of the 3 most common sarcoma subtypes. And what you see here is a heat map of gene expression related to various immune signatures. And you can tell, outlined in the bright green box is that about 20% of these tumors have very high immune expression. So we think these are sort of the hot tumors. But what about the other 80%? What do we do about them? So I'll just kind of go through this. Basically, so just again, with my Road Taken, I saw that my responses with immunotherapy, and I'm like, all right, that's it. I'm not an immunologist, I need to find an immunologist. And so I wound up taking a job at University of Colorado, where I've partnered with PhD, Immunologist named Eduardo Davila, who you may know, but we've basically put together basic science, translational science and then clinical trials focused on turning -- working on cold tumors and trying to improve microenvironment. So when I got to Colorado, my dear friend, Dr. Bill called me and said, hey, we got to get you on to C-800. We have to get this rolling with botensilimab and try to get you on the study. And so we did. And we've been able to put a bunch of patients on this amazing trial and lo and behold, here I am with all of you today. And now -- and I gave us -- the plenary of this beautiful work. So certainty. This is the summary data that you may have seen already, but -- and that Dr. O’Day just showed too. This represents 125 patients, 19 different solid tumor types. So this is all of the data. And within those 125 patients, we presented on 4 different disease-specific expansion cohorts. And so the spider plot and the waterfall plots here show you the responses and they show you the stability of disease. The overall response rate was 20%, and these are generally cold and I-O-refractory tumors here. Most of these responses are ongoing. The median duration of response has not yet been reached, and the disease control rate is 66%. So tremendous stabilization of disease here as well. And we have a 12-month overall survival rate of 66% in a heavily pretreated Phase I population. We went forward and we looked at 4 specific disease expansion cohorts. Again, Dr. Grossman is going to take on colorectal and dive into this in more detail, so I'll just show you initially. 22% in microsatellite stable colorectal cancer. This disease does not respond to immunotherapy. Durva and Treme 1 out of 119 patient response rate, right? We got 22% with botensilimab and balstilimab. Again, durable responses, no median duration of response reached yet and impressive stabilization of disease as well. And Dr. Grossman will go through, but these are not snuck in accidental MSI cancer patients. There's no tumor mutation burden when we checked some patients and only 1 of 7 was PD-L1 positive. Ovarian carcinoma. Same thing. We heard a story about Dr. O’Day's ovarian patient. So less than 10% response to traditional PD-1 and CTLA-4. Here's 19 patients, heavily pretreated more than 3 lines of therapy. Most of them are high-grade serous carcinoma, which is the worst histology, the worst outcome, the hardest to treat. And we have a response rate of 26%, including a complete responder that was durable to almost -- or to over 90 weeks and it's still ongoing. Disease control rate, again, 63%. It keeps going, going and going. And then Sarcoma, my tumor of choice. So what did we do? So we have 12 patients, mostly angiosarcomas. And so I showed you, angio's got it's unique things, but visceral angiosarcoma like my spleen lady I just told you about. Like my patient in the video that I'm not sure, if I'm allowed to tell you it was my patient, I forgot, sorry. That -- these people don't respond to checkpoint inhibitors. They don't respond to chemotherapy either. But we have 3 of 5 visceral angiosarcoma patients with deep, durable responses, 2 of them are for more than a year, including that patient. We have a response in additive liposarcoma patient who had progressed on at least 4 or 5 other things. I mean this is real -- these are real responses, so exciting and so promising. And then finally, non-small cell lung cancer. So these are previously refractory patients to I-O therapy, okay? So these are retreated with I-O. We've got now a fifth adenocarcinoma patients who has a confirmed partial response. So the updated response rate is 3% of 5% or 60%. Yes, it's early, but this is incredibly promising. These are PD-L1 negative responders. These are patients who had initially responded to chemo and pembro and then progressed. So very exciting. So the last thing I'll just say is that I've been so excited to get partnered with Agenus from the very beginning with the patients, and it's totally changed my career, right? Like I never would have seen myself doing this. And so what are we doing now? They have supported us with an even more ambitious investigator-initiated study where we're taking on single-agent doxorubicin, the 40-year standard of care, right? So we combined initially zalifrelimab, so traditional CTLA-4 and balstilimab with doxorubicin in patients first or second line with metastatic soft tissue sarcomas. And so we've completed the first 2 stages of this study, about 30 patients, give or take, and we're hoping to have data for ASCO. But what I'm really excited is that we're opening imminently in the next couple of weeks, an expansion cohort where we're selling in botensilimab. So this is the first time, to my knowledge, that we're actually going to have a study with chemotherapy and I-O here next gen I-O for promising for cold or not so hot tumors. And so I just -- I think the future is incredibly bright and just so excited to see where this goes. So sorry to be long-winded and lengthy. But again, it's been a joy to work with you, everybody, and thanks so much for the opportunity today.

Thank you so much, Dr. Wilky. I'd like to next invite Dr. Joe Grossman, who is our Vice President of Exploratory medicine to the podium to talk about botensilimab in a more depthful manner in MSS-CRC. Joe? Thank you.

Thank you so much, Todd. Well, Dr. Wilky, that was inspiring and a hard act to follow. But keeping with the theme of the Road Taken, I want to tell you a little bit about how I got here. Another common theme. I was also playing music, writing plays. About a 10-year detour before I went to medical school. And then about 2 years ago, I found myself at Beth Israel Deaconess Medical Center as a GI oncologist, treating patients primarily with colorectal cancer and pancreatic cancer. Thank you to Dr. [indiscernible], who is here in the room, who convinced me that, that was a good career path. I think I saw something in those diseases, which was a tremendous opportunity because there was so much room to do better than what we can do right now. So I want to take you into the room of a patient, a typical patient that I treated a couple of years ago before I came here. Most of the patients I treated had advanced or metastatic disease. So when I sat down with one of these patients, say a patient with colorectal cancer, we would have a discussion about the prognosis, about the diagnosis, and then about the chemotherapy treatment that we could offer. And part of this conversation was what we would call consent for therapy. It included a discussion of risks and benefits and a piece of paper, the consent form. And we've described -- I would describe to the patient the possible benefits -- but first, usually, the risks of chemotherapy for treatments like FOLFOX and FOLFIRI. I would talk about they might have the loss of feeling in their hands or feet. That might be permanent. They might have nausea, they might have vomiting, they might have diarrhea. They might get admitted to the hospital for a life-threatening infection because of low white blood cells. They may even die as a result of the chemotherapy. But the even harder part was to talk to them about the benefits of the therapy because we had to sit down and check a little box on the piece of paper that said the intent of therapy is palliative. Meaning that the best we could hope for is that the tumor might shrink for a period of time, but ultimately, it's going to come back and it's going to take their life probably within a year. And -- as you can imagine, this could be depressing and difficult, but like most oncologists, I'm an optimist, I wouldn't be doing it. And for each patient that sat in front of me, I like to think, okay, maybe this one is going to be different, right? Things are going to turn out differently because we're going to figure something out. Maybe it's on the clinical trial and that check box that we checked is going to be wrong. And I was inspired to think that, that might be possible by some of the people that you heard from today, from people like Steve O'Day, and Mike Atkins who took a disease called melanoma, which was a cancer that gave cancer a bad name. And as Mike said, he turned it into the travelers clinic because he was getting postcards from Machu Picchu. And that's what I wanted to do for my patients. And that is why I came to this company 2 years ago because I thought that, wow, here's a chance to actually do this for cold and I-O-refractory tumors and do it quickly. So try to move along. So to give some context about the patients that we're talking about today that Dr. Wilky presented on so elegantly, patients with microsatellite stable colorectal cancer, which is about 95% of patients with colorectal cancer in the metastatic setting, for which there was no immunotherapy option. What is standard of care for these patients? What might they get once they've progressed on standard chemotherapies like FOLFOX and FOLFIRI. The available standard of care treatments or regorafenib and TAS-102. Treatments with about a 1% response rate, and median overall survival improvement of about 1.5 months. For other patients that come on our trial, they've already progressed on these treatments, and they actually have no available treatments other than a clinical trial. Immunotherapies have been tried in this setting, PD-1 inhibitors, which have worked so well in warm and hot tumors have had virtually no responses. PD-1 inhibitors combined with non-IO treatments, single-digit responses, PD-1 inhibitors with first-generation CTLA-4 inhibitors. Again, single-digit responses and very little impact. Alongside of this, you can see botensilimab balstilimab, with a response rate now above 20% and substantial disease control. But that doesn't really tell the whole story in terms of the clinical benefit that we're getting for these patients. And that's what I'm going to show you next. So you've seen the spider plot before, and you've seen the waterfall plot. Every line is an individual patient, and you see many of these going out over a year with little green pluses indicating that the response is ongoing. As Steve described earlier, you see patients that are clearly responding. And then you see patients who have tumor shrinkage, patients who have tumor markers decreasing and patients who have prolonged stable disease out over 6 months in a patient population where you expect most people wouldn't have lived 6 months. So clearly, the clinical benefit that we're seeing goes beyond what the RECIST response rate describes, which is exactly what you expect for CTLA-4. That is the hallmark of CTLA-4 therapy. These deep dermal responses. In addition to the response rate of 20% and disease control of 73%, as Dr. Wilky mentioned earlier, with the durability that we're seeing, the median duration has not been reached. And the point estimate for median overall survival at 12 months is already 60% with a median follow-up of 6 months. I want to go into a little more detail on some of these individual patients. But before I do that, there's some common characteristics amongst the responding patients. None of these had biomarkers associated with response to immunotherapy. So they had a disease that doesn't respond at the microsatellite stable colorectal cancer. And there is nothing special about them. They're common, patients who go on Phase I clinical trials, who are heavily pretreated, 2 of them actually had prior immunotherapy because they had gone on clinical trials and that immunotherapy didn't work. All of them were microsatellite stable by design, the responders and none of them had a high tumor mutational burden. Only 1 of the 7 responders at any degree of PD-L1 positivity. And if you look at the RAS and BRAF mutational status in this population, it's exactly what you would expect for colorectal cancer population. Nothing unusual. I want to point out a couple of individual patients here. You can see one kind of in the middle marked with a symbol. This is a patient who had a metabolic complete response by PET scan and normalization of the tumor marker and a negative biopsy. So the cancer seems to be gone even though it kind of continues there on the CT scans. Just another example of conventional imaging, not really telling the whole story when it comes to immunotherapy. Another patient, you'll see here marked on the waterfall plot on the left side with the plus and the infinity symbol. This is a patient who -- after they were treated, the lung metastases started to shrink. But the primary tumor in the right colon seemed to be growing at 6 weeks. And so the investigator thought, it looks like the metastatic disease under control, but I'm not sure what's going on with this primary took the patient to surgery and lo behold, there was no cancer left in the primary tumor, even though it seemed to have grown on imaging. The common theme is starting to emerge. Again, from the waterfall plot, just like the spider plot, you see the depth of the responses and the green pluses with the majority of the response is ongoing. So as you think about this activity that we are seeing in this very light line in MSS colorectal cancer and that we're seeing across so many other diseases that have historically been unresponsive to I-O, it's exciting to think about the future about where we can go next, about treating patients in earlier lines of therapy, about adjuvant therapy and finally, about neoadjuvant therapy, which has the potential to cure so many patients. And you're going to hear more about that from Dr. [indiscernible] after myself. Thank you.

Thank you, Joe. Thank you really very much and also for your encouragement to the company to focus on what wouldn't have been expected to be a treatment responsive malignancy. It's turning out to be quite the opposite. I'd like to invite Dr. Patricia Carlos to the podium, who is Head Chief of Regulatory Safety and Quality at Agenus to talk about how we're going to get there.

First of all, welcome to all of you here. I really appreciate that you took the time this Saturday afternoon to attend. I would like to say, how absolutely honored and humbled I am to be able to stand here with such an amazing collection of physicians. I feel like I've arrived. This is a really great place to be. I want to bring you through my Road Taken. Canadian by birth. I've been in pharmaceutical development for almost 25 years. I started right, fresh off of college in a small start-up company that spun out of the University of Victoria on Vancouver Island. Then I went through a number of small companies where I realized that Vancouver Island was not going to be a hub of biotechnology. Beautiful place, just not a hub of biotechnology. And moved to the San Francisco Bay Area where I started to work for Gilead sciences. After my time at Gilead Sciences, I went to Medivation, where I also worked on the PARP inhibitor. And then I got a phone call similar to the phone call that Dr. Todd Yancey received by a small 250-person company called BeiGene and that was where I solidified my wonderful friendship and relationship with Dr. Yancey. And in the course of the time that I was there, we worked very closely on the clinical development program. Also during my time at BeiGene, cancer dealt, my extended family a difficult and critical blow. His name is Nathan Gibbons. He just turned 9 years old when he died. At that point, I made a commitment to devote the rest of my career, doing everything I could to honor his beautiful, but very short life. So fast forward, I moved through that pretty well. I give you the credit there. I moved on to another I-O company. I worked at Arcus Biosciences. I had the great pleasure building out the regulatory quality and safety team. And things were humming along it felt like I was working really hard, and I got another phone call from Dr. Todd Yancey. He said Patty, I have a company I want to talk to you about. I just started working with this company called Agenus. I said wait a minute, aren't you retired? How are you working with the company right now? He said, no, no, I'm working with them to help them. And I think you should help them too. And Todd, I really appreciate the phone call, very happy where I am. I'm enjoying my work. And he said, no. They have activity in cold tumors. So do you know what that means? And I said, yes. I know what that means. So I'll talk to them, I'll absolutely talk to them. As Todd had said, this pediatric tumors are very cold or less hot. Sorry -- and I really wanted to see if there was something behind this. So I flout, met with Dr. Buell; Carlos; Dr. Grossman, Dr. [indiscernible] Chand; Dr. O'Day and the only thing that was more compelling than the data or the commitment, the excitement and the energy of these people, who absolutely wanted to make a difference the way I did. And so here I am. I decided to join. So we are here at the crossroads now. We've got the road we've taken but now we need a path to approval. We need to get this drug to the patients that needed most or the combination of drugs, absolutely. So 2 choices here. We can take the traditional Phase III long-term study, OSN endpoint trial or we can take the expedited path. And I think that you would all understand from the data that you saw today, that this is the path forward, the expedited path. So how do we do the expedited path? This is -- I don't need to tell anyone in this room that there's been a lot of press about accelerated approval and expedited pathways and people that get it and people that don't and. So how are we going to ensure our success in this area? This is very important to us. The first thing I will tell you that we are and will continue to do is to engage early and often with global regulators. More than Americans have this issue or the Europeans have this issue. We need to take this drug globally. And so we've begun to do this. We've begun the early engagement, and we will continue to engage as often as we can and need to as we continue to grow the development program. The great news is there are expedited approval mechanisms for patients that have limited treatment options in very serious disease. Again, from the data Dr. Wilky showed you, these are very, very serious outcomes for the patients that don't have treatments. And there are more than just the accelerated approval. We have lots of different pass way, like accelerated approval. We have priority review. We have conditional approval. We have prime access. We are examining all of these in the context of balstilimab and botensilimab. The one thing that's very important in order to have an agreement to bring this forward for accelerated approval, you do need a comprehensive approach to safety and efficacy, optimal dosing is very key as well as a standard of care comparison. Our Phase II studies have been designed to address these issues, in addition to the issues of contribution of components, which are also important to some global regulators. We are combining information. This is not going to be a single one study approval. We are building a beautiful story with data from our Phase I study that goes all the way out to survival. You can have overall survival there. Data from our Phase II study, which will show our response rate, and duration of response. And we are currently designing a Phase III study that can then confirm exactly what we've seen in the Phase I and the Phase II. We also have a multipronged approach that we're hoping will lead to not only approval but reimbursement in multiple regions, simultaneously. We are not picking them off a list. We are going as quickly as we can in multiple regions. The other thing that we're really looking to do is leverage data for multiple studies to expedite the expansion of that label after we have the initial approval. So we can have indication and indication and indication in these tumor areas where you see we have the most need. So now the real question, which I'm sure a lot of you here have answered. First filing. If the data that we have seen in our Phase I study are replicated in our Phase II study, and we continue to enroll our studies as quickly as we have, you can anticipate that our first filing will be an MSS colorectal cancer in 2024. We are also planning for multiple, supplemental filings in the years that follow, and we will be expediting those as well. That's the big story. So I would like to, at this time, say, thank you all so much. Thank you for tolerating my quavering voice. And thank you for listening and supporting the work that is so very important to all of us.

Thank you, Patty. I'd like to invite Dr. Alexander Eggermont to the podium. Dr. Eggermont is Professor of Clinical Translational Immunology at the University Medical Center Utrecht, the Chief Science Officer at the Princess Máxima Center for Pediatric Oncology also in Utrecht, and a Board member of the Comprehensive Cancer Center in Munich. He's also an Emeritus Professor, surgical oncology at the Erasmus University in Rotterdam and at Paris-Sud University in France. Thank you, Dr. Eggermont.

Thank you. So I discovered that it's usual to start on a personal little note and why not, let's do that. So I'm Dutch and I never got called. I have to do the calling all myself. But I'm a very fortunate person because in this iPhone, there are a number of very interesting numbers linked to very interesting people. And one of those people is one of the rare [ Foreign Language ] intellectuals. It's Larry Norton. And I'm so happy to see you again after 5 years, not having seen you Larry. Then another member in there is what shaped my career, and that was my alma mater, is Steve Rosenberg. So I was exceptionally lucky to get a fellowship to be in his lab for almost 2 years. And it drove my career into 2 directions. Going to immunotherapy, become a melanoma specialist for the biology and surgeries and that's interesting there. But for the fun of surgery, also become a soft tissue sarcoma specialist, right, just for the pure fun of surgery. And then, of course, going into immunotherapy development -- no. And then the next thing is that there are now new members in there that linked me to Agenus. And there is a principal involved. And the principal involved is the program interesting. Because if that first criterion is not met, that stops the buck right there. Second criterion is always -- do you like the people because who wants to go into a long-term type of project with people you don't like, right? So [indiscernible], Garo, Steve, and there is always, Mike Atkins because we are basically the same generation of early developments with the IL-2 and so on. So I'm a very lucky person. But I discovered that we have 2 great musicians here in the audience, Larry, and you Bree, and you were at the conservatory of St. Petersburg. And I spent many evenings when there were performances at the conservatory of St. Petersburg to listen to Russian piano, which I just adore. So I play the piano also, but I can only entertain myself, not my neighbors. Well, when I went to medical school, and I went to live in a small room in Amsterdam, I immediately bought a guitar. And within half year, we created a band, bluegrass music called Vitamin C, with the banjo, mandolin, guitar, bass, contrabass and fiddel. And we actually toured in the United States in 1974, and we toured at 6 Bluegrass festivals. I have very fond memories of that. And one of the biggest hits was not the Orange Blossom special, which we also played at the Amsterdam special. Good. Now we go into the start. So basically, what I want to do is take from the lessons learned in the melanoma field, some of the things that we should roll out, and I'll start with a couple of statements. So anti-PD-1 is a core necessity as it protects CTL function at the tumor site. So this is the [ mozart ] molecule of modulating in innovative ways, the immune system. And then anti-CTLA4 is another core necessity because primary T cells create also the diversity of T-cell clones and is the absolutely kicking start point to have something to work with. I would call that first mozart anti-PD-1 and the second one bach. So anti-CTL-4 is here to stay. And this is a very important thing and anti-CTLA-4 you need for the stabilization of the tail of your curves. Anti-LAG-3 prolonged CTR function but has less impact on T-cell clone diversity power. So for me, it's an interesting molecule, but it's not anti-CTLA-4. The anti-PD-1 sealing is very hard to break and will be broken in new patient populations that we need to define, and we'll give a number of examples. What is clear from melanoma is that what works in the advanced setting works almost at the same hazard ratios in the adjuvant setting. But then in terms of the future developments that are already ongoing. We are going to live in for 5, 6, 7 years, neoadjuvant immunotherapy that will change management of a whole series of tumors where anti-PD-1 is active and now where we will score with the combinations of anti-CTLA4 and anti-PD-1. In seeing more cures, shorter treatment cycles, less surgery. And we will need to insert this systematically in all our drug development programs also to learn more about your new agents. And as a general observation, the combination of anti-CTLA-4 and anti-PD-1 sort of double the pathologic complete response rates across a number of tumors, not just in melanoma, not just the squamous cell carcinoma and so on. So these are sort of the themes so you feel what's coming. So here, you see -- which is a landmark trial, the CheckMate 067, so monotherapy with anti-CTLA-4. The bottom curve -- this is treatment naive melanoma, metastatic patients, monotherapy with anti-PD-1, 5-year survival, 44%. And they have completely different mechanisms of action, and they should work together, and you see 52% for the combo. And this is already, Mike. So this is a landmark design for where there is very heavy competition for the BRAF mutant melanoma patients. And if you start with nivo, ipi, in this case, anti-CTLA-4 present at PD-1, you get by far the best results. And you don't spoil the durability that you will get which you might not get to the same degree if you give this combo in second line. And so now it's all immunotherapy in melanoma in first line, okay, basically. So then there's a number of attempts to break the anti-PD-1 ceiling. And this is not so easy. So the agonistic monoclonal antibodies are basically uniformly failed because they are hard to develop with Phase I and you can't create cytokine storms and all this. The [indiscernible] experience show that we ran too quickly into too many Phase III trials on too small data set, where actually, at that time, we hadn't even realized that in treatment naive advanced melanoma patients, the response rates on anti-PD-1 alone. We're quite a bit better than the initial data. And then what is also an observation is that the intratumoral treatments. So the master key, they have pembro plus T-VEC versus pembro alone or ILLUMINATE tisotumab plus ipi versus ipilimumab in melanoma have shown that in terms of initiation of systemic immunity, the IT injections fall short. And so when we are looking at the combination of: a, and now an improved anti-CTLA-4 molecule in combo with an anti-PD-1 molecule, we are not necessarily going to go back to [ IT ] protocols. And then there's another one, the cytokine protocol. I'm not going to go further into that. So we have 2 very strong Nobel Price winning discoveries, anti-CTLA-4 and anti-PD-1, both totally essential, but we also need something to solve the profound immunosuppressive environment that is mainly created by tumor-associated macrophages myeloid-derived suppressor cells and CAF, cancer-associated fibroblast. And so that is going to be another field where if we don't have a key master regulator to work with for that third compartment of the tumors, we somewhere are going to get stuck. I'm not going to talk about all the promises of cellular therapies and MiNK because I don't have time for that, but that should, of course, should have been at the bottom line that this is not only a discovery field for new targets, but there will be niches of exceptional efficacy to be discovered and also that's the future of immunotherapy. This is just one slide to show that whatever works in the new era, whatever works in the advanced setting in melanoma in treatment-naive metastatic melanoma patients works almost with the same hazard ratios in [ IgAN ] setting. And so that's simply how you can look at your own program as well. That's translation for anti-CTLA-4 plus anti-PD-1 needs 2 more slides because something went well and something went wrong in that translation from the efficacy and advance to the adjuvant setting. So what went well is when you dose ipi correctly, 3 milligrams every 3 weeks plus nivo. And if you do that in the highest risk population advanced melanoma after resection of resectable distant metastatic disease, you see that the top curve is anti-CTL-4 plus anti-PD-1 adjuvant. The green curve is monotherapy adjuvant anti-PD-1. The bottom curve is placebo. This is a German trial and it's to lancet publications. And if you see, it's long last. It's long lasting, right? Now here something went totally wrong. So 2,000 patients in the CheckMate 915 trial and what goes wrong there, look in red the anti-CTLA-4 was dosed at 1 milligram and not per 3 weeks, but for 6 weeks. And then if you go back to the first Phase I study on anti-CTLA-4, actually, you're very close. This is then relatively 0.5 milligrams per kg. And we never saw a responder at 0.3 milligrams per kg. So sometimes you ask, where is the memory, right? So anyway, so then if you dose ipi below an activity level, yes, are you going to see an effect? No, the answer is there. No, you will not see an effect, right? So now in the neoadjuvant immunotherapy, ongoing revolution, this is where so many things are to be discovered, to be developed, that will give us insights, that will really push forward immuno-oncology 2 milestones further. And with the diverse portfolio that you have, you need to explore for all those choices a neoadjuvant, learning 20 patients to make sure that you're not missing out on a very big opportunity to learn more than you could have ever learned out of 20 patients. And two, discover a number of niches of also approvals. So it started all with palpable, macroscopic Stage 3 melanoma and that's where the whole series of lessons come from. And then it translated into MSI colorectal cancer, locally advanced cutaneous squamous cell cancer in the face. And then now we have all sorts of neoadjuvant trials in all sorts of tumor types. And the principle is that when you look at the top of this slide, you see -- you do a lymph node dissection in patients. You leave very few infiltrating T cells behind then you come in with your anti-PD-1, but you have little things to work with. If you give your anti-PD-1 and anti-CTLA-4 upfront, you work with all the cells already present, you will create many more T-cell clones. And this is what you, therefore, should do. So look, in the left corner of this slide. The top of the slide was the first, and this is a landmark study. 20 patients randomized in Amsterdam with palpable nodal disease, melanoma. And it's either first surgery and then adjuvant 2 cycles of anti-CTLA-4 present at PD-1 or it's neoadjuvant first 2 cycles of anti-CTLA-4, plus anti-PD-1 and then the surgery, okay? And in the peripheral blood monocytes, what do you see? Look at the bottom. At the bottom, you see what you see if you have just adjuvant after surgery ipi/nivo in this case. And it shows the amplitude of [ NV ] diversity of clones that were already present at the base level prior to ipi nivo and -- after ipi/nivo. And then you see that in blue all the bars are much higher, both in creating diversity of T-cell [ plans ], especially in the neoadjuvant antigens, neoantigens, clones as well as per clone, always each amplitude, much higher. That means that you are going to work now with hundreds and hundreds of more different T-cell clones with an amplitude that each brigade is much bigger than you can ever achieve by just giving adjuvant therapy. So this is the recipe for cure. And how does it translate into further observations? If you just work with anti-PD-1, not even with anti-CTLA-4 plus anti-PD-1, if you just work with anti-PD-1. And you give -- if you give the classic approved system, surgery first, that's the top. And then you give 1 year of adjuvant pembrolizumab in this case. Or you do the bottom. You give the first 3 doses of anti-PD-1 before the surgery and then the 15 doses after surgery, right? This is the SWAC801 trial. That gives an additional 42% reduction of relapses. The adjuvant therapy that was approved already gave a 44% reduction of relapses. That means that by just bringing in and reorienting the only 3 doses of anti-PD-1, you actually, against placebo, you would have gotten a hazard ratio of 0.30, if you would have done this as the first trial. So neoadjuvant is not just a life, it is a necessity and what you need to do now to further develop. So these are back now to the Amsterdam patients. And they had palpable nodal disease. And look at the green curve, look at the red. The green curve are the 65%, let's say, 2/3 of the patients who had a pathologic complete or near complete response. And there were only 2 relapses in 64 patients, and 1 relapse -- actually was not a relapse, patient died in a traffic accident and had no tumor abduction. So we have never ever seen these curves, never ever. And this pertains to 2/3 of your patient population. So this is where neoadjuvant therapy development is going to take us. This has been confirmed. Look only, I'm just showing you now this panel, in the left side of this slide, but in a consortium pooling all the anti-PD-1 neoadjuvant treated patients or the anti-PD-1 plus anti-CTLA-4 treated patients together. First of all, look at the PCR, pathologic complete response rate for just anti-PD-1 20% and doubling by the combination with anti-CTLA-4. Now look at the 3 top curves. Here basically see no more relapse. This, we have never ever seen in melanoma. Now if you have a BRAF muted melanoma, you could also do this with dabrafenib and trametinib as BRAF inhibitor combo as neoadjuvant therapy. We know durability in these targeted combinations, not so good. Look at this. All right. So the superiority of immuno-oncology and melanoma is just like unbelievable. That is how strong it is. So we promised more cures, data shown. We promised shorter treatment cycles, this trial, and we promised less surgery. Here we go. Take you through this trial. Palpable nodal disease, you put a lymph node marker, let's say, you have palpable nodal disease in the neck, this is your biggest lymph node. You put a little magnet into that lymph node. It's the lymph node marker. You give 2 cycles of anti-CTLA-4 plus anti-PD-1. Follow the yellow box up there because this is where the whole story is. You get 60% of pathologic complete or near complete responses. And then in the 60% of patients, you don't do even lymph node dissection anymore because how did you find out it was the pathologic complete response because you only took out that node little remnant where the magnet was. And now no more disfiguring lymph node dissection. It's the end of those lymph node dissections in the head and neck area, the [ groin ] with 30% lymphedema and the [ eczema ] right? So more cures, shorter treatment cycles because look at the other yellow box where you were there, no more adjuvant therapy, just 2 cycles of ipi nivo, in this trial. So this is changing the world to start with, I would almost say, like always, in melanoma, but then the rollout into other tumor types. And so this is the last couple of slides. That means that you see 50% complete responses in bladder cancer with neoadjuvant anti-PD-1, but look at MSI colorectal cancer, because this is like the most sensational data. This was the first trial. Rectal cancers, to MSI cancers, right? That's essential, of course, 2 cycles of ipi/nivo prior to rectal resection. Response rate close to 100%. 95% or 92% pathology complete or near complete responses. So well, should we still do the surgery? I think not. I think not because you can do simply endoscopy, biopsies and MRI scans to follow up. The second trial colorectal cancers throughout the track with advanced colorectal cancers, advanced, I mean, T3, T4 tumors with positive lymph nodes. Look at this Niagara Falls, right? So -- that's a waterfall plot we like to see. And so in the Netherlands, you must refer an MSI colorectal cancer patient to only 1 of 6 hospitals where you will not be operated but where you will get ipi/nivo. And we got the payers to pay for that because if you explain this to the payers, they say, yes, well, in this case, you may be right. Yes. Otherwise, we never say that, right? So New England Journal of Medicine Paper in '70 advanced -- locally advanced cutaneous squamous cell cancers in the face, this type of disaster. [ 56 ] point -- so the pathologic complete response rate and major pathologic response rate was 63%. The pathologic complete response rate with just cemiplimab, just anti-PD-1 was already 50%. So these are now best medical practice findings. And in the face of that, I would say, EMA and FDA butt out because this, you must approve immediately because this -- how can you propose a randomized clinical trial with these findings? I mean which patient is going to say, oh, yes, great. Yes, take my rectum out I got the uneven number. So this is not randomizable anymore. So we need to go. And I already have an appointment with EMA because I have to -- this was presented the colorectal data was present. I went immediately to the President of the Committee of EMA because I know him very well because he was at [indiscernible] data center when I was President. I said, hey, butt out. Good. That's what we said. So -- and now we see these neoadjuvant initiatives also in lung cancer. But just look at PCR rate for combo with chemo versus just chemo, 24% pathological complete response rate to 2%. So something will pan out, right? And -- this I find also like pretty unbelievable. So -- 20 -- 40 patients or 39 patients at UCLA and UCSF were randomized, preoperatively for glioblastoma multiforme relapse. That was still operable, right? Okay. So they are always immediately scheduled. You only have 2 weeks. They get one dose of anti-CTLA-4 -- anti-PD-1 in here. I mean unexpected. But these are the findings. So there was a doubling of PFS and there was a relapse rate, and there was a doubling in overall survival. So the potency of neoadjuvant initiatives in this field are now a must, structurally to be involved whenever we discuss every pathway for whichever indication, this is what we need to do now. This is like a prediction slide where things will go very fast, and where in yellow things will take some a little bit more time. And I thank you for your attention.

Thank you. Thank you, Dr. Eggermont. Thank you. I'd like to invite our clinical speakers to the podium and Dr. Eggermont is going to take a few minutes to moderate a panel discussion, bringing all of the data sets and information as well as treatment concepts that we've discussed together. And then following that, we're going to take questions from the audience and also from the folks on the phone. Thank you.

So you'll give me a sign when we think can start.

Yes, ready to go. Thank you.

Well, first of all, I though it was an interesting series of presentations and nothing less was to be expected. But -- what I find very interesting in your talk is that -- is that you addressed a number of prototypes. The first one of which is the main cause of cancer deaths in the western world, it's colorectal cancer. And 95% of colorectal cancer is MSS colorectal cancer. And we never got anything to work actually, surprisingly, because we know that in the immunoscore, primary colorectal cancers. It is extremely predictive of outcome. What you have in T-cell infiltrates and how well the patients will do and you think actually we should have a field day in colorectal cancer in terms of immunotherapy development. And that has absolutely not been the case. And now you are with, therefore, very interesting data coming with both mono and combo therapy with a special anti-CTLA-4 because that has a number of aspects that is our new, whereas to my understanding, the anti-PD-1 is a relatively regular type of anti-PD-1, right? So how do we philosophy about the specialness of the anti-CTLA-4 involved that may unleash this because so far, we had a hard time finding out how we could be often cold metastasis of colorectal cancers although they may have a ring of infiltrate around them, but are often empty inside for T cells. What is your feeling, what's your observation? And do you have, in the meantime, any tumor biopsies or paired tumor biopsies observations that give you a clue of what is different?

Great question. I would actually pass this to Dr. Grossman, who is our colorectal cancer expert and he can probably weigh more on that. I would just say that I do think -- yes, the colorectal cancer story is exceptional. But to me, when I look at this data, what's so compelling is it's not just one tumor type, right? We are seeing this across the board in multiple tumors that have absolutely no business responding to immunotherapy, right? So I think that's the question mechanism wise, what is botensilimab actually do? What is it about the engineering that's making these -- that's changing the paradigm.

Sorry, Dr. Grossman, but my principle is always ladies first. But now, it's your turn.

Thank you. Yes, I'll certainly answer. And might even pass it along after to -- Dhan Chand is in the audience, if he wants to add anything about the drug discovery. But certainly, what we're seeing in the clinic with botensilimab is different as we described and what we've seen with first-gen CTLA-4. So obviously, something different is happening. And what is it? So the drug was designed for improved activity relative to first-gen CTLA-4 via what our scientists discovered regarding the Fc portion of the antibody, and there's a nice publication on this in 2018, cancer cell, which Dhan Chand can describe in more detail. But essentially, we believe that the Fc portion of the antibody is extremely important to the mechanism of action, not just the front end of the molecule. I'll hand it over to Dhan for more details.

Yes. Thank you, Joe. So what's different? Well, let's come back to what Dr. Atkins said in his talk, agents that maximize the antitumor response have the best chance of promoting curative responses. When we designed botensilimab, we observed that the ability to prime T cells requires you to create a synapse between a T-cell and Fc gamma expressing dendritic cell. So we could point mutations into our antibody to enhance binding to these activating Fc receptors that can bridge these dendritic cells to these T cells and promote better T-cell activation, which in turn leads to better memory formation. And what's remarkable is that you get a broadening of the T-cell response. you get an increase in diversity of T cells that can respond to that tumor. T cells that weren't there before, those T cells then have the ability to infiltrate and kill the tumor. Now when you think about what CTLA-4 does in the body, it limits the ability of a T-cell to communicate to antigen presenting cell. We have solved that with both encelimab by creating a better bridge between that T-cell and antigen presenting cell.

I just want to add, I was supposed to talk a little more of the pipeline in my presentation. So I think I'm going to get called in for that. But in addition to CTLA-4 PD-1 botensilimab, obviously, we have CD137 that hasn't been able to be an agonist has not really been able to be combined with potent checkpoint inhibitors because of liver toxicity with first-generation molecules. And our next-gen CD137 is performing well in clinic in terms of its toxicity profile and some early clinical activity that we will update further next year. But the myeloid compartment is also critical. I think Lex commented on it. [indiscernible] and I were at a melanoma conference recently with liver mets and certain histologies as well as ovarian, obviously, is one. But even within diseases, organ sites defend themselves differently. And we saw some beautiful data at Edinburgh SMR with liver mets in melanoma, showing literally a myeloid wall around tumors. And so we obviously are very cognizant of that. And one of the reasons I'm here is as a conductor of an orchestra of a pipeline is CD137, PD-1, botensilimab. But our ILT4, which we gave to Merck is performing quite well in the clinic and they're expanding a large program. Our scientists have put an ILT2, which has every bit as much we think, preclinically as the ILT4 program as a myeloid checkpoint but adds lymphoid checkpoint properties that the ILT4 doesn't have. And we have that first in-human just in the last 2 months. So obviously, we're going to have an orc on the music thing. We're going to have an orchestra here very shortly. We already have 4 different checkpoints, PD-1, next-gen CTLA-4, CD137 and an ILT2 in clinic in-humans right now. And so obviously, speed is everything. And to Jen's point, the company is really trying to figure out a way in parallel to look at these combinations very quickly, both in metastatic settings, but to Alex's point, the neoadjuvant setting is a perfect place to look at proof of concept for mechanism and pathologic response. So we're actively as a company engaging KOLs all over the world across these diseases in early neoadjuvant studies.

Well, Steven, you've opened an excellent point about also treating the myeloid compartment of that tumor. And if you think of Dr. Norton's presentation where he -- you take that beta -- that beta part of the equation and treated to a microenvironment, we've started to demonstrate that with our approach to CTLA-4 botensilimab, bridging those APCs and T cells, actually results in the activation of those APCs as well. So you can take myeloid cells, which, by the way, are the most abundant in immune cell cold tumors. You can activate those cells, you see increased ability to activate T cells, you like things of CD40, things like MHC I think like CD86, which you need to prime the T-cell at all increase through the Fc basket. So again, with botensilimab unlike that of the first-generation CTLA-4 has the ability to modulate both the innate and adaptive arms of the immune system and of course, bringing in the rest of the pipeline would only help take that tail even higher.

Larry?

Yes. I mean I have so much to say, actually, let's stay for another couple of hours. We'll have dinner sent in, and -- but just relevant to this point, and I think some of the gen set is like really very important. All right. What I see is before me, I see an expert violinist, expert violin player, expert cellist, I see percussion. I see -- an all time great musicians and great instruments, all right? If you just say go, or let's randomly put these things together, you're just going to get noise. No matter how good the solos are. That's what you can get with noise -- doesn't it. You've got to coordinate it, in a way that makes sense. And I think that's where, from my point of view, the mathematics comes in because no great advances have been made without engineering and engineering are basically mathematical rules for how things play together. In a way, it's like the airplane doesn't fly because just it has a good engine, it's got all the pieces have to work, they have to work together. What makes this moment very exciting, basically, is this extraordinary pipeline you have, is what Jen said, I mean, is that my whole life, I have been struggling to get a good drug A and a good drug B from different companies. And design what is the appropriate clinical trial to actually maximize them. And what I didn't present in the mathematics is that those -- I showed you figures, I didn't show you the equations. Each of those equations are parameter. So you have to manipulate the various parameters in such a way that you make the whole thing work, right? But if one parameter could be influenced by one company and another by another company, you're never going to get to work together in a way that's going to be maximum because they're going to want to show that their company -- that their drug is better than everybody else, including the other company, even though they work together. And I think what makes this particular moment exciting, what makes this meeting exciting for me is the fact that we have all these instruments, all these musicians and it's all together in the same orchestra. So you put the right conductor in front of them, all right? And then all of a sudden, you have music, you won't hear noise. And I think this is what really -- I think it's profoundly exciting. The fact that we have this incredible lead that we presented today to an audience that was sitting here with their mouth opened saying, my God, everybody knows these cancers don't respond to immunotherapy. Everybody knows that. And you see -- you see this [indiscernible] responding is that it shows me 2 things. It showed me what I said before is we're calling them cold but they're not really cold. They just need the right drug, right? And the right biology that brings the components together 2 different cell types together, so that they actually can work. So none of these cancers. I mean every cancer is just filled with mutations. Every cancer is bearing, every cancer is at bearing proteins. So it's just a matter of degree. It's just a matter, if they're not cold, it's just being treated with the wrong drugs. Actually make them work in that regard. But I'm also seeing a lot of provocative ideas about the ways to put things together, including when -- what is the timing of the intervention compared to the timing of surgery, which is, what is the right timing between cytotoxic agents that may actually affect mitosis and release of antigens and the immunotherapy component. This thing is going on in our community of A Works B -- sort of chuck them together. For mostly what we do in metro oncology, we titrate to toxicity. I mean, we reduced the dose of things so that we can actually give them together as if God said you must use them together, they're not going to work. That's not necessarily the way they work. Those curves that I showed you with the breast cancer, that's sequential therapy. When that was originally proposed, I was called criminally insane in public because everybody knows you got to use them together. You can't just use them sequentially. But if you use them sequentially, you actually do much better, absolutely proven. And it's 40,000 randomized patients. And if you do with what we call dose density, using closer together time, I was also accused of criminal on Saturday for proposing using closer together in time because that would cause more toxicity, wouldn't cause greater efficacy. They were wrong, no great toxicity and greater efficacy. So I'm seeing a very exciting thing going on here now, which is a lot of -- which is really very novel agents, a lot of novel ideas and a pipeline that we can utilize to actually leading together all under the control of one company so that we can do creative work together. So I think this is a really exciting meeting.

Mike, because you are the dream sequential guy now, you're the dream seek guy. What is new and what do you see as some of the next steps that you sort of then that you figure out that you would like to propose or that you are thinking about?

We'll see if I have a voice, when I speak. So first of all, I want to emphasize that what I think Dr. Norton said in his presentation is you can't cure most cancers with chemotherapy. Because of comforts in kinetics, but when you give immune therapy, you're not hitting just one pathway or 2 pathways or 3 pathways. You're hitting many pathways simultaneously, your machine gunning the tumor. So it can't escape. And so you can get rid of the last tumor cell. So immune therapies that cause a response, even if it's in what we thought previously was a cold tumor, when you see that response, it's going to be more durable than the responses you get with chemotherapy. There was a time when we thought that lung cancer was not an immune responsive disease, but we didn't have the right therapies. And when you get a response in lung cancer from purely immunotherapy, you see that 60% to 70%, 80% of those are durable, are cures. And so the goal is to get the response. So those responses in colon cancer, in sarcomas, in GYN cancers that are not seen typically with the immunotherapies we've had access to previously, will be durable. And we know how to move forward the development of drugs that produce responses to immune therapy. Because we've done that in melanoma, we've done that in kidney cancer. We've done that in lung cancer. They need to be moved to the front line as quick as possible. We have to figure out how to do that, then to the adjuvant setting and then to the neoadjuvant setting. And so that's what we need to do.

Very good. It was as beautiful as [indiscernible] -- we can do that -- Larry, you want to give...

I wish I get a longer talk because there's so much to say here. But I think that this is -- this is a very important point. If you looked at my curves -- you got a gun protein tumor. You do something and it shrinks and then it plateaus. All right? If it's due to -- if you accomplishing that with chemotherapy, what's happening is you are going to have continued proliferation and even proliferation under the pressure of an agent that actually may increase mutation rates like alkylating agents, and you need more mutations, eventually getting mutation so that the agent that you're giving is not going to work because you don't have drug resistance. If you achieve that same low dose plateau, a durable response with immunotherapy and you develop more mutations, it will make the immunotherapy work better. So it actually -- the same things that make it difficult to cure cancer with chemotherapy may make it more likely that we'll be at a cure cancer with immunotherapy because of that particular phenomenon. So I think there's a lot to exploit there. And I actually never thought of it until Mike was just speaking. But they had, there's to exploit there about these incredible durable responses on. I have a patient I treated for breast cancer. She's a BRCA1 and BRCA2 heterozygous. She was treated for breast cancer, and she was cured of her breast cancer and then she got the lung cancer and then she was treated with immunotherapy. And that was a cusp, maybe a decade ago, and she still hasn't recurred. And is a -- just a remarkable thing. I think the BRCA1 and BRCA2 mutations, but it increased mutation rates and might have actually made her, the same things that made more difficult to treat with the breast cancer might have made the immunotherapy work better. So I think that leading together a lot of these themes, we clearly are approaching a theoretical as well as a practical basis for actually making HER2 therapy using these particular tools.

Very good. Yes. Lex, because we're running about 40 minutes late. What I'd like to do is give the last word to you. And I wanted to thank our panelist and the audience for this really one of the most, I'd say not one of the most, but the most meaningful session and the subject of immunotherapy that I have experienced because of the depth and the breadth of expertise in our panel. So Lex, the final word.

So thank you for that privilege. Well, first of all, everybody here at the table but everybody here present, thank you for contributions and congrats on a very dynamic and very promising program. But I hope that what comes out of this session that when you have assisted in it or when you have watched it on the WebEx is that there are so many elements now that make us realize that although there has been a anti-PD-1 ceiling for a number of years that the number of tools to actually now break through the ceiling in the most successful tumors -- is going to be achieved and that a leading pathway there will be a number of neoadjuvant approaches that will replace current approaches, and will cure more people with less surgery and so on. But that, at the same time, we have now the tools and the whole edging the story now with your anti-CTLA-4 and anti-PD-1 actually shows that in a number of niches, we see a breakthrough in what we considered, yes, how do we make it work in MSS colon cancer. I mean -- and now we will actually find out what makes the difference, and then we'll find out what's the next step, and then we'll find out if you have to -- if you can have it preceded by immunogenic cell death chemotherapy, yes or no, or you could. Anyway, now the whole pathway is open to establish something that now you already know will work. But it will be stepwise improvements of what you know at this particular point in time. I think we all have that feeling. And I mean I'm an oncologists. So this is a -- so who would say about -- soft tissue sarcoma, that this was going to happen. But of course, it's going to happen first in niche 1, 2, 3, and then we'll find a common denominator to make it stick. And so it's very hopeful, and it's a very positive session, and I think rightfully so. And so thank you -- thank you, all.

Thank you. I'd like to also thank the people on the Zoom call. We've had several hundred people actually joining us. And unfortunately, we didn't have time for all the questions that have come in, but will always be available for those in a subsequent meeting or subsequent encounter. So -- thank you very much. everybody. Thank you, panelists that have traveled from all over the world actually to get here with some of the challenges. Very much appreciate it.