We're gonna have a very full session today. A full session that's not just going to be about us, but about cancer, about immunology of cancer, about patients, and a little bit of a sprinkle of what we're doing and how we're doing it. You'll hear from a number of speakers, and I'll go over some of them. There'll be four 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 Breelyn Wilky, who have become experts instantly. Now, they will include our good friends, Michael Atkins, who was the winner of the Lifetime Achievement Award. Mike probably goes back in history in the journey of immuno-oncology for a very long time, the mid-1980s, you know, 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 1990s. 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." That was, I think, in 2003 or 2004. He's a man of conviction that has persisted in this journey for a long time. Dr. Larry Norton, who I've known since the late 1990s. 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. Of course, quality of life would be different as well. We have Dr. Alexander Eggermont, who is one of the, again, veterans of immuno-oncology. Lex and I met when we were developing our cancer vaccine, individualized cancer vaccine in the early days. Lex is a man of conviction who will call it the way it is, and he'll not mince his words. There were times that we had some negative developments on the, cancer immunology front with vaccines. In fact, there were some experiments where vaccines seemed like they were hurting people. Of course, we've come a long ways from that as well. Dr. Breelyn Wilky, as I told you, has done an incredible job. She had a brilliant presentation today, plenary presentation at SITC. We are where we are. Now, in addition to those four advisor experts clinicians, we also have two of our own. Two 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 whom literally flocked to Agenus from the patient bedside and have done a phenomenal job of advancing our program, so they'll 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 resolve, 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. 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?" 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. They will. We're convinced of that. 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. There are a number of other products and cell therapies in our portfolio, in our MiNK portfolio as well, that are also designed to perform in a specific way. Dr. O'Day will speak to that a bit. We have the real newcomers to the company, not 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. Dr. Patricia Carlos, who is the Chief of Regulatory Quality and Compliance now at Agenus. They will tell you how we will move these portfolio products towards the finish line. Why are we moving them to the finish line? For one very simple reason, to get to 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. With that, I will invite Dr. Todd Yancey, who deserves no real introduction because he's gonna 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 to today. 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 five years old. When I was a kid, I was a big kid, and my father was a military officer, and people used to say, "Oh, he's gonna play football, and he's gonna join the army." Well, around age five, I figured out I better take control of the situation. I started to say, when people would ask me, "What are you gonna be?" I would say, "I'm gonna be a doctor." Before that, I would say, "And I'll tell you what I'm not gonna be. I'm not playing football, and I'm not going to join the army." Ironically, 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 in international biotech, having begun my career at Amgen, working at the time on Aranesp and Neulasta and supporting the development of a field medical team, initially in the United States and then subsequently in the 25 countries in Europe where Amgen at the time did business. was recruited and had an opportunity to leave Amgen to go to Genentech in clinical development to work on two very important drugs, Tarceva in lung cancer and pancreatic cancer, and Avastin in everything, as was the case for us at Genentech in those days. Then I got a phone call from a friend of a friend to talk to him about a potential opportunity at a really small company at the time called Onyx to work on a drug called Nexavar. I went from Genentech to Onyx. It was my first C-suite job in 2006 to build a global safety organization, global medical affairs organization, and then ultimately to take over clinical development, working with our partner Bayer on the expansion of Nexavar, including the registration of Nexavar in hepatocellular carcinoma. In addition, I was tasked by my CEO at the time to identify an opportunity for us to work on a hematologic malignancy. 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. 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." 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. Subsequently, when we had our first approval for the drug enzalutamide, in at the 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 to work on a PARP inhibitor. I worked on rucaparib at Clovis for two years and then 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. I had a global medical affairs position working at BioMarin and got a call from friends of friends, as is always the case, I think, in this world, about another small company, at the time, and an ask to take on the accountability to build a clinical development team for a company which is called BeiGene. I went to BeiGene about six 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. I was an executive at BeiGene. I built out the clinical development program for tislelizumab and pamiparib. The registration programs that you see coming to fruition now were built by my team. Across the course of the many years that I was at BeiGene, 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. 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 launched with a team of members professionally and internationally, registration intent plans and commercialization planning for 60 markets, which included all of ex-China APAC, all of Latin America, MENA, Israel, Turkey, Russia, and the Commonwealth. John knew I was gonna 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, friend of a friend, asking me if I would take a call with Garo and Jennifer, and I said, "Sure." 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 populations 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. I said, "Well, there's good news and there's bad news. The bad news is I'm retiring, but, you know, the good news is, I think morally, I have to help you. I put the rocking chair to the side after some agreement and discussion at home, and I've come back to help. I think what really, 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 IO, 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. By the way, the 40% that do, the majority, unfortunately, relapse. 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. With that, I have made a decision to return and help out. I'm going to moderate today's discussion. Again, it is tremendous pleasure to be here. I'm going to begin the program by asking Dr. O'Day to introduce Dr. Mike Atkins, and then I'll be around. Thank you very much. Appreciate it. Thank you. Thank you, Todd, and you'll hear from me shortly. I know Garo gave a partial introduction to Mike Atkins, but I thought I should give a little deeper flavor just from my personal deep relationship with Mike over 30 years now. Mike is the Deputy Director at the Georgetown Lombardi Comprehensive Cancer Center. He's also professor and vice chair in the Department of Oncology. 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. We go back to several hundred at best. Mike was a previous past President of SITC, the Board of Directors, and this year was given a lifetime achievement award. My biggest sense of connection with Mike is much deeper than awards or titles of academia. Mike has been at the forefront of IO, and I've emulated him and we've worked closely together over almost 30 years. I think what most of the community of experts really admire about Mike is he's scientifically rigorous, second to none. Equally, he gets patients and what impacts in the clinic are material to patients. I think he's led us in so many ways around those two areas, and I admire it about him deeply. Mike, thank you for coming to join us. He's gonna share some of his deep insights into IO space over the course of his career, and appreciate it. Do I need this or can I just use this? No. Thank you, Steve, for those kind words. I have a bit of laryngitis and this is the second talk I've given today, so hopefully I can force my way through this one as well. I'm gonna talk about my journey, which pretty much is the journey of immunotherapy since it starts from the first effective immunotherapies. We really were in the wilderness in the beginning and we've moved towards the promised land, but we're not there yet. All cancers have mutations and therefore they look foreign to the immune system, and every successful cancer must therefore solve the challenge of overcoming the defenses erected by the host immune system. Many of those do that by disabling the immune system. When we use immunotherapy, we are actually treating the immune system so that it can treat the cancer. 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. The hallmark of an effective immunotherapy is therefore a tail on the KM Kaplan-Meier curve. 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. 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. It was this durability of the response that led the FDA to approve high-dose IL-2 for kidney cancer in 1992 and melanoma in 1997. When IL-2 was first announced as a new therapy, it was hailed as a cancer breakthrough in such noted medical journals such as Fortune Magazine. In the 2000s, it was actually looked at at the time when there was 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. I stuck with it because to me, these patients were being cured, and it was proof of principle that 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. We tried several approaches to try to improve on high-dose IL-2 and make it more applicable to the general cancer population. 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 were only seen with high doses. We tried to dissociate toxicity from efficacy. When we gave steroids, we eliminated both the toxicity and the efficacy. 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. We tried combinations with other therapies such as chemotherapy and what we call biochemotherapy or TILs or vaccines. 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 TILs exist, and therefore, for most patients, there was no need to vaccinate. They were already auto-vaccinated. 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. He had developed hypothyroidism after treatment in conjunction with these halo around his subcutaneous melanoma metastases associated with disease regression. He remains alive today. We published in the New England Journal of Medicine 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 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. We spent a lot of time thinking about this, and it was through great science by people like Jim Allison and Tasuku Honjo, who showed us that there were molecules inside the tumor microenvironment, such as PD-1 and PD-L1, that prevented those T cells from 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. When those 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. 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. When we gave a combination of anti-CTLA-4 and anti-PD-1, we saw that both in progression-free survival and overall survival, there was a 5%-7% increase in the tail of those overall survival and progression-free survival curves in patients with melanoma. We saw also improvements in patients with kidney cancer and lung cancer. What lessons have we learned from working with these checkpoint inhibitors over the past almost 20 years? Well, 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 was 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 mixed combinations. This is data from our MedStar Georgetown database looking at toxicity in melanoma patients getting immune therapy. The patients who have toxicity shown here in red have better overall survival than the patients who didn't have toxicity, shown in blue. 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. This allowed for what we call treatment-free survival or TFS. We looked at this in studies such as the melanoma study to see how much TFS we're actually creating. As you can see in the dark blue, in patients getting Nivo/Ipi, about 1/3 of their time for the average patient receiving Nivo/Ipi was spent in treatment-free survival. That was greater than what we could see. A very little bit of that time was actually seen here in the light blue in treatment-free survival with significant residual toxicity. What does treatment-free survival allow? Well, it's turned my melanoma clinic from a very sad place into, just as the 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. How can we get treatment-free survival? Well, one of the reasons why immune therapy works, and you can see these tails on the survival curve even after treatment stops, is 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? We did the DREAMseq trial. What the DREAMseq trial showed when we randomized patients to targeted therapy first, followed by immunotherapy, versus immunotherapy followed by targeted therapy, that the immunotherapy first treatment resulted in a 20% improvement in 2-year overall survival, meaning that the immunotherapy worked best when given first. Therefore, we wanna figure out how 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. At two years, these triplet regimens. The PFS curves are already below where the PFS curve for Nivo/Ipi is at five 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. The same thing is 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. When we look at these IO, non-IO combinations, I always look at them with caution. IO is different than tumor-directed therapy because of its ability to produce treatment-free survival and cures. Combinations that improve median PFS or median overall survival without producing TFS may sacrifice that potential of IO while contributing toxicity, inconvenience, and tremendous extra cost. I wanna see not only A + B being better than A - B or B - A, but treatment-free survival and cure being maintained in order for such combinations to fully be embraced. Clinical trials with IO agents, I think, need to look at IO 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. 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 TFS for as many pan-cancer patients as possible, is critical to achieving that goal. You're gonna hear from other speakers about some really impressive treatments that can actually do this. I'm gonna just close by acknowledging all my colleagues at Dana-Farber/Harvard Cancer Center, at Georgetown Lombardi Comprehensive Cancer Center, some of whom are actually in the room, and others from around the IO sphere and my funding sources. Finally, my family with my two sons 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 our grandson. Thank you very much. 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 member of the Office of the President. He's a Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering and our honored guest. Thank you. Thank you. I have another title, too, I think, which is relevant to this. 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. Although I did actually play in high school. I was a running back in high school. You know, 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 the Vietnam War a left turn, and I ended up going to medical school, and I got stuck. Here I am now. Music and math kind of go together, and so I've always been interested in mathematics. I've been working on mathematics really, you know, from high school age, whatever. I think that is relevant. Obviously, I'm gonna 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 Deputy Director of the Cancer Center, the NCI-designated Cancer Center for Clinical and Translational Research. I kind of overview all of the clinical and translational research in Memorial Sloan Kettering, which is a lot. 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. I found mathematics to be an 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 toward the future. That is an introduction. This is my topic. Why is it so hard to cure cancer? You've heard Michael present this and, you know, we have a real problem in doing this, and I'll talk about this in a second. If there is a problem with curing cancer, what can we do about it to actually make it better? 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, an abundance of tools to evaluate cancer. We have lots of drugs. Matter of fact, almost every drug that actually works its way into our therapeutic armamentarium in the laboratory shows some great efficacy. Usually the great efficacy is eradication of the cancer cells or a very profound effect on the cancer cells. Then we put it 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. Our ability to cure cancer is really impaired, and this is in marked distinction between what with what we're actually seeing in the laboratory. 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 to 16 and so on. It keeps growing. When we apply antimitotic 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 very clever science, which are attacking the cell division in one form or another of the cancer, they regress exponentially. If you regress exponentially, you move rapidly towards zero. If you get below the volume of a single cell, you've got disease eradication. Then we take these drugs, and we put them in the clinic. The reason I think, again, looking at this, an overview, and I can give two or three hours of lecture on this to make a convincing case, but I'm just gonna 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, in the proceedings of the Royal Society of Medicine in London. It's called the Gompertz curve, which is an S-shaped curve. It starts off sort of looking exponential, but then progressively slows down, and eventually, theoretically, if you look at it long enough, it'll reach plateau size. The benign tumors, the fibroadenomas of the breast and benign tumors that we see reach their 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 Gompertzian growth in the 1970s and started doing experimental models. I wasn't the first to notice that cancers in laboratory animals grew by Gompertzian kinetics. Others had seen that before, but I wanted to define the mathematics. In the 1970s, when I was at the National Cancer Institute, 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. It led to a clinical hypothesis, based on laboratory data, and the clinical hypothesis was that things that grow faster shrink faster, things that grow more slowly shrink more slowly, and therefore, if you wanna maximize the effect of your therapy, you should minimize the time of regrowth between cycles of treatment. Very, very simple kind of concept. That was in the mid-1970s. It took roughly 20 years before I could get it into clinical trial in the Cancer and Leukemia Group B in a breast cancer trial, and then another 20 years before this paper in 2019, which is from the worldwide overview, the Early Breast Cancer Trialists' Collaborative Group in Oxford. We're analyzing 26 randomized trials with almost 40,000 randomized patients, showing that the therapy that was derived from understanding this S-shaped Gompertzian curve actually improves cancer cure rates, reduces recurrence. The blue line is what's called dose-dense 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 'cause deaths without cancer is not increased, and all-cause mortality is in fact decreased. In fact, there's actually a decrease in the contralateral breast cancer incidence rates from these particular regimens 'cause we may be actually curing microscopic cancers that are not apparent or cold cancers in the opposite breast by this particular maneuver. I'm just presenting this to you as a bottom line of 40 years of work just to emphasize the fact that the math works and Gompertzian growth is true. You can use Gompertzian growth to make better cancer therapies. 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 curing cancer? The big breakthrough on this was it was my work with Joan Massagué, a great scientist now at the Sloan Kettering Institute at Memorial Sloan Kettering, who, working with colleagues, made the observation that you can actually derive a metastatic line called 4175 of MDA-MB-231 cells, which is a breast cancer model that has a very high probability of going to the 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 of lung metastases. The mystery was that these tumors in the lung, also in the mammary fat pad, grew faster. 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 the ones that were growing faster also went to the lung with the same percentage of dividing cells, and caused the death of the animals in that particular way. 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 cells was not greater. The hypothesis that we made in 2006 was maybe it was growing faster because not only it was metastasizing to the lung, but it was also metastasizing back to itself. Pathway C is to the lung, growing a lung metastasis. Pathway B is to go into the circulation and come back to the primary tumor and grow as a separate nodule. If you have three things, in this case, growing at rate X each, they'll grow 3x faster than one thing growing at rate X. So that if you measure the percentage of dividing cells, it's not any different, but the growth rate would be faster. This actually explains Gompertzian growth. Is it true? Well, good animal experimentations, finally published by me and Kim, in Cell 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. 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. This exchange of tumor cells from both, other, one side to the other, which we called seeding or self-seeding, is a big factor in the growth of these tumors. An unexpected factor before doing this work. Everybody thought cell growth was all mitosis, and cell mobility had nothing to do with the process. It may have to do with the process of metastasis formation but didn't have to do with the process of growth. Actually, growth is promoted by the seeding process as well as the cell division of the individual cancer cells. Interestingly enough, 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. Now we're bringing in the tumor microenvironment in a 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. 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. 'Cause the outside is roughly related to the square of the diameter, whereas the volume is related to the cube of the diameter. The square of something over the cube of something as the numbers get bigger, that ratio drops. I'm sure you're gonna remember this, why mice are furry and elephants aren't. All right. 'Cause mice are small, so they have a very big surface area 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. You notice that great big people don't have to wear big heavy coats in the winter like little small people do. That's why your children are 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 explains Gompertzian growth. If you're growing mostly on the outside, as you get bigger, you're gonna slow down your growth process. The only thing you're gonna remember from my talk is mice and elephants. That's it. All right. I guarantee it. People will come to me 10 years later and say, "You were talking about mice and elephants, weren't you?" All right. Further work has gone on this. This is Elizabeth Comen with Joan Massagué and 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 lung or the brain with 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. All of this has been proven, and it's easier to prove now with single-cell sequencing. We have a lot of work and other colleagues that have actually done a lot of work to show this is going on. Each time these cells come in, they're bringing white cells with them, and those white cells are important, not only to defend against the tumor, as I already mentioned, but also to some extent to support the growth of the cancer cells. You have this yin yang that's going on with the tumor and its microenvironment. The growth of the cancer has two components. It's mitosis, and it's also geometry, the relationship of the cells to the microenvironment. It should not surprise anybody that if all you do is develop antimitotic drugs, you're not taking care of the whole cancer problem. You're only taking care of the cell division. In fact, the reason that Gompertzian cancers are not cured by the same antimitotic 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 antimitotic therapy, and I drive it down to zero. If I take a Gompertzian tumor, and I take the therapy, antimitotic therapy with exactly the same efficacy in terms of cancer killing cancer cells, it will just reach a new Gompertzian plateau at a lower level. All right. The geometry is determining this. This is what we see every day in the clinic. We see patients achieving sometimes it's below level clinical appreciation, 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. The patient goes on to die. This is basically the process. What we're here today to really celebrate, this whole meeting 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 antimitotic but can also change the geometry of the tumor and its relationship to the white cells that are there. The yin yang of the white cells supporting the cancer and attacking the cancer, which hundreds of presentations over the last few days really have talked about. That is why this is really a big change in the history of cancer therapeutics. Because if we can combine the appropriate antimitotic therapy, certainly not antimitotic therapy that kills white cells, as you just heard about, that would be a mistake. If we can combine the right antimitotic therapy with the right anti-angiogenic therapy or anti-microenvironment therapy, that's when we can drive this down. These are not theoretical curves, by the way. These are actually mathematical models that have been corroborated in the laboratory that actually show that this is the pattern, and this can really apply, just like the simple Gompertzian growth can apply to the design of adjuvant chemotherapy and give you the results that I showed you earlier in my talk. Combinations of antimitotic therapies and therapies that address the tumor microenvironment, of which immunotherapy is the best lead that we currently have. You could talk about anti-angiogenic therapy, too. That's a whole other kind of topic. 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 antimitotic component. To do this, we're not curing cancer. Why? It's Gompertzian. 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 there's such a thing as a cold cancer. I think there's just various degrees of hot. All right. If it's below the level of the current therapy, you need a better treatment, you know, and Breelyn Wilky 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 antimitotic approaches in a very intelligent and creative fashion. I think you're gonna 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, with us zeroing in on the white cells and combine it with antimitotic treatment, I think it's gonna take both, then I think we're seeing the end of cancer, by all the indications that we have. Math really doesn't lie, you know? I mean, math really gives a way forward, but 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 much 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. Todd, 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. It was Steven's patient on botensilimab, an 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 him, and he said, "This is very exciting, and I think I may know what's happening." 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. My journey and my road taken actually has brought me to Agenus. 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. 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. 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 gonna 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. 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. That's a very important and disruptive change in drug development and something that I'm really honored and proud to be a part of. How did I get here? I actually started my journey in large pharma and largely uninspired by a somewhat insular approach to 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 rate of therapies and still a burgeoning and developing high unmet need for patients. I sought and found an entirely different approach to 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 vaccine, and Agenus was the pioneer to actually take and industrialize the taking 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 knew, well, now we know, but we thought at the time, hypothesized, 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 gonna be talking about in just a moment. We built a structure that was different than what anyone else had done. In a five-year period, we delivered more than 17 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 molecules that was subject of Dr. Breelyn 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 in delivering a pipeline that is designed to address the limitations that currently exist and 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 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. What's necessary now? You're gonna 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 calling them less hot tumors from now on. 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 murine 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. Last year in October, we launched MiNK Therapeutics. MiNK Therapeutics. We just held an R&D Day on Thursday, which is available to all of you. MiNK Therapeutics presented five presentations at SITC Conference this year, which included three 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 in a hospital-based control dataset. Dr. Terese Hammond presented that data at SITC earlier this week. 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 'cause I trained at Dana-Farber in 1991 to 1994. SITC has come back here, and botensilimab's at a plenary session at new immunotherapeutics. I have all this wonderful team around me at Agenus. You're gonna hear more about them, and you've just heard some of the great pioneers, Dr. Norton, Dr. Atkins. You're gonna hear Lex Eggermont, my dear friends, through the. I feel very fortunate to be here. I wanna tell you a little bit about my story and the road I've taken. You know, after training in hematologic malignancies as a transplanter, I was enthralled with leukemia/lymphoma, the curative potential, the dramatic sort of taking someone from death to life. That was deeply ingrained in my head. I had many mentors at the Farber, but Emil Frei III, 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. Seriously, Emil Frei III had all that success, but he pivoted his career towards the end to solid tumors. To Larry's point, Larry knows very well, you know, this. The thought was, at that point, maybe we could pivot 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. Emil Frei III would spearheaded what we call the STAMP program at the Farber, Solid Tumor High-Dose Therapy. Unfortunately, it failed for many of 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 died. Emil Frei III told me, he said he knew I was, like, all into hematologic malignancies. He goes, "You're interested in immunotherapy. My best friend and colleague, Donald Morton, who's 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. It's a perfect sort of disease type to really develop immunotherapy. I went, he said, "Go to Morton. He'll teach you melanoma, then come back and we'll start a melanoma program at the Dana-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. He 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. What he was most wanting to know before he died, and I saw him very shortly before he died, was just beginning to understand the checkpoint revolution. He said, "I wish I were younger because the future is in front of us." He couldn't have been more true to the word. My career, like Mike's done a lot of my heavy lifting because those early days in melanoma, 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 a small number with non-specific cytokines that were like nuclear bombs on patients. Then, you know, we tried biochemotherapy and chemo plus and I spent a good decade. In about 2000, so about 23 years ago, I got to treat the first patients with Ipilimumab. This was a little company called Medarex. You know, I thought, you know, one more negative immunotherapy trial. We started to put it into patients, and there was 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 brake that prevents autoimmunity and cancer surveillance. CTLA-4 is really, you know, teleologically designed. Once you clear a virus in 48-72 hours, then you want to put your T cells back into memory so that you don't cause autoimmunity and other things. It's good to spare the species, you know, create, allow people to procreate. As you age, your T cells get, you know, not as effective. Cancers develop, and once cancer is established, you don't wanna turn off that switch too early, or the T cells never have a chance. We started to see these remarkable responses in a hot tumor like melanoma that were durable. We spent about 10 years. I wanna pay tribute to the group of investigators for before PD-1, 'cause think of PD-1 as sort of a second revolution, and it certainly was well-deserved. It took 10 years really to understand the paradigm shift from cytotoxics to IO. Mike was involved in that. I was in the trenches. Jeff Weber, Jedd Wolchok, Steve O'Day. We had to really change the paradigm and stand boldly against our oncology colleagues who wanted to see rapid responses, didn't wanna wait for duration of response, didn't wanna watch for plateaus. They loved medians. They. The kinetics of the response, they were impatient with CTLA-4. It actually took CTLA-4 longer to work, three months on average as a single agent. This was an eternity for medical oncologists. There was a lot of lessons learned. How does toxicity relate to efficacy? To this day, I'm so tired of hearing about IO 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. 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-1's resurrected T cells in the tumor where they're not circulating. There was less toxicity with PD-1 than CTLA-4, but CTLA-4, there was something special about that from early days. You could give one, two, even three 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. There was something very special about CTLA-4. The field then tried to get rid of it. We tried to say, "Oh, it's too toxic." In fairness, the problem with CTLA-4 was not the toxicity, but it didn't prime well enough across solid tumors. It was a limited drug, mainly to melanoma. We tried to look at it as a single agent, and it didn't respond. 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. Botensilimab, you're gonna see, is broad and effective, and that's what excites me. The field move, we went from CTLA-4 alone, and then we were curing half the patients with melanoma today. Mike brought up a very important point. With high-dose cytokines, the brain was still a sanctuary. For whatever reason, when you stimulated T cells with cytokines, they didn't eradicate brain subclinical brain mets. 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. That's where you saw the major change in survival curves. That, you know, now diseases where I would see 4-6 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 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 'cause the old ones aren't dying, and they're traveling and they're off treatment. Really an extraordinary experience. That's the background that led up to this. My focus in the last 10 years as a Cancer Center Director in Los Angeles was, could this happen in other solid tumors? The field has worked hard to exclude CTLA-4 from the discussions. LAG-3, which has made it barely in melanoma, but we're all very pleased with that target. There are a lot of other targets that failed. IDOs, oncolytic viruses, bempeg more recently, you know, just terrible failures with big trials where curves overlapped. 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. In the data you're gonna see, 125 patients with tumors that have no business being in the response rate of the first revolution of IO are absolutely responding to this combination. It's a pretty phenomenal situation. That's my story. And why Agenus? Well, actually, I'm a Care Center Director. I'm in charge now of solid tumor IO. I'm still seeing my patients in the clinic, and I'm, you know, doing all the usual combinations, and I'm waiting for a CTLA-4, and not much is going on. Then Daniel Von Hoff, another great mentor, said, "You need to talk to Agenus and get on their Scientific Advisory Board." I did. Jen tells the story about like, I see this pipeline. I'm like, "Is this Merck? Is this BMS?" I mean, you've got 17 INDs, you're partnering, have a lot of drugs, but you're keeping drugs. They were trying to show me all the things that I was just focused on, this next-gen CTLA-4. I said, "Yeah, I like the other stuff, that's great, but would they let me be the PI in the clinic for the first-in-human next-gen CTLA-4? There was an art to that story, I will admit, having been the first to dose Ipi, the thought of dosing this. I did dose the first patient, ovarian cancer patient, that had 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 onto this trial as the first patient at just 0.1 mg. Her disease, over the course of a whole year that had previously been growing, stopped growing. Her lymph nodes actually fluctuated, got hot and cold and painful, regressed. There was this battle going on. She finally, after a year, progressed. We went up to a higher dose of Ipilimumab, and added Nivolumab, the data you're gonna see, and a rapid response. I remember her CA-125 went from the thousands down rapidly. I was convinced. 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 the first gen, and my dreams started getting really activated in my mind. Agenus made me an offer I couldn't refuse two years ago, and I've been sort of watching this develop, trying to stay, as Mike would say, you know, measured. What's the data? Stay controlled. Keep looking for what the next best scientific experiment. We've got a team that's just. You know, Joe Grossman was here actually before I did. We call him GI Joe. You're gonna hear him. The guy keeps. You know, I wanna go to melanoma with this. He's like, "You know, colon cancer." I'm just telling him, "No, no. Let's go to melanoma. We know it can work there." To Joe's credit, he's really spearheaded, you know, a vibrancy and optimism and soaked in all the IO stuff. Jaymin Patel has come, and I'm just so privileged to have these young, really inspired young oncologists that are smart and we're working together as a team. You're gonna hear about our regulatory and other areas. Certainly with Todd, we're very serious about getting the team in place to get this forward. I think I'll just finish with. I think there's one slide I have, right? I just wanna 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 IO or if they had the disease that had an IO approved, had already failed that. I think Mike, you said this at one point to me when you looked at some of the early data. There's three phenotypes to this graph. There's obviously the early deep progressors, which is the hallmark of CTLA-4. There's also the early progressors, obviously the primary resistance. Then you have this middle ground, and I think Mike told me, "Don't assume in cold tumors that you're gonna be able to reproduce these phenotypes that you've seen in hot tumors like melanoma." I think the reason this is important is 'cause survival, which is the critical endpoint, depends on deep, durable responses. It also depends on stopping disease in its track for prolonged periods of time or minor reductions in tumors. These curves really reflect that in tumors that all of these lines should be going to the ceiling, historically. It's early days, but it's remarkable days. It's been received by the community today in endorsement of this data at the plenary session, where they put in, it's both a 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. I think I'll end there and let the next team go. I'm delighted to be here and happy to answer questions as the day goes on. Thank you, Steven. 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 for Clinical Research. Thank you very much for being here. Thank you. Thanks, everyone. It's a pleasure to be here. In 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-Stalinist modern piano stuff and tried to learn Russian. It was a disaster. 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. I think it's a nice balance to kind of keep us focused and ensure that, you know, that we remain not just people of data, but sort of looking at the human side and the other side of this as well. Anyways, my journey, my road taken. I'm a sarcoma doc, and when most people hear about sarcomas, if you actually know what they are, you just go, "T hat's scary." I was a first-year fellow. My very first rotation at Johns Hopkins was the consult team. I remember getting a call for a patient with an angiosarcoma in the spleen. 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 really sick. I remember going, knowing I was gonna round with the queen of sarcoma at Johns Hopkins, and googling and pulling up NCCN guidelines and all the things a good fellow is supposed to do and realizing, oh my gosh, well, there's nothing to do. Like, the NCCN guidelines were like, here are some therapies that might help. You know, I met with my attending, and she's like, "Yeah, we're gonna try this chemotherapy," and it worked. Like, we gave it to her, and her disease melted away, and I was like, "I've just cured my first cancer. This is awesome." For like three months, and then it came back, and she died within, you know, a couple months after that. That's what we call visceral angiosarcoma, and that was sort of my first encounter. I remember thinking, you know, there's breast cancer, there's GI cancer, there's all of these different cancers out there. How am I gonna actually make an impact? I saw my sarcoma patients, which ages 15 - 18, even younger, pediatrics all the way to, you know, to 100-year-olds, and no one, everybody can get these diseases. There's 100+ different types, right? If I could make any impact whatsoever, even the littlest thing, I felt like it would pay off for this particular group of patients. I guess the bar was low. Like, no one wanted to deal with them. I'm like, "Okay, well, that's what I'm gonna do." I went on to take my first attending job at University of Miami with a guy named Jonathan C. Trent, who'd been at MD Anderson for years. Another guy named John Goldberg, who was pediatric hematology oncology at Miami at the time. 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 just sort of like everybody was talking about it. I put a few patients on, you know, Chuck Drake's immuno trials. I'm like, it was intimidating. I'm like, "I just don't see how this is gonna be a way forward for sarcoma." You know, these things change. Anyways, this is sort of a snapshot of my life. Like I said, 100 different types of bone and soft tissue tumors, collectively only 1% of adult cancers. We say when in doubt, cut them out, which that's what we try to do. If you can't remove them surgically or they come back, in a metastatic setting, it's quite devastating. 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. 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 6-7 months, and the overall survival for most metastatic sarcomas is somewhere between 12-18 months, maybe a little bit longer now that we've gotten a couple more agents approved. This is a high bar. What about immune therapy? For those of you that have looked back, remember back in the days of Coley's toxins. I mean, it was actually sarcomas that he theoretically cured with his toxins. For a long time, you know, 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. What's interesting is that even though most sarcomas will 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 can still do remarkably well. It kind of gives you this question of could the immune system be playing some sort of suppressive role, and making this happen? Back to my days in Miami. John Goldberg there, you know, he actually had wound up abandoning University of Miami. He's about 2 years in to go work for this company called Agenus. He, the HemOnc, academic, and he came over to be the CMO for these guys. I just remember him calling me and being like, "Hey, you know, we're about to kick off this trial with zalifrelimab," which was AGEN1884 at the time, which is a CTLA-4 inhibitor. "Do you guys wanna open this?" Of course, you know, baby attending, I'm like, "Sure. Let's do it. That sounds great. We opened, and we actually put the first patient on. This was like the baby dose escalation. Her dose was 0.1 mg per kg of CTLA-4, 100-fold less than what we thought would have been active. This lady 60 years old, and she had this horrible, awful disease that you can see here on her face. This is what's called cutaneous angiosarcoma. Compared to my spleen lady in fellowship, these tumors can occur usually in the elderly in sun-exposed areas. You know, you can do surgery, and we've tried to cut these things out, but you know, they're usually in bad places where you can't get good margins, and they just keep coming back. She had had a dozen different treatments, cytotoxic chemotherapy, targeted therapies. We put her on, a Notch inhibitor phase I. We cut her nose off. We did definitive radiation. Like, we had tried everything, you know, and she just kept coming back with this awful, horrible thing. We put her on AGEN1884, and at about day 12, you can see this tumor explode. This is all immune cells. I mean, this is basically pus and sort of inflammation here, granulation tissue. She just kept on responding, and she kept on responding. About a year and a half in, we did a biopsy, after seeing a complete radiographic response of her tumor that's now gone, and she had a path CR. No more cutaneous angiosarcoma. That was February of 2018 that she hit pCR, and she's still cured today. Like, this never came back. It's nuts. It turns out after this amazing response, we actually teamed up with Agenus to do some beautiful correlative work on her tumor we got in biopsies. Others have found that cutaneous angiosarcoma has a UV signature, so similar to melanoma, sun-exposed areas, high mutational burden. We were like, "Oh, that's gotta be, you know, that's gotta be why she responded so well." But she actually didn't. 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, you know, I saw this, I was hooked. I'm like, "Wait a minute. Like, we just fixed this lady that couldn't be fixed." 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, that kind of resembles melanoma. It's got a conserved translocation with TFE3, and basically a group of transcription factors that had some similarities. This kid, or this disease presents in young and healthy adolescents and adults with 0% chance of response to chemotherapy. We had pitched this study to Merck for an IIT of pembrolizumab plus a VEGF inhibitor 'cause that was the one thing that was somewhat active for ASPS. In sarcomas, there's some activity of VEGF located in TKIs as well. We did this. Merck bought it. I don't even know how that happened. It's all serendipity is the theme of my story today. 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. This lady up here at the top was 23 and had had multiple recurrent ASPS. Again, she's one of these long-term cures, right? Like, we got rid of her disease with immunotherapy. Now, of course, the rarest disease on the planet is now the most popular disease for immunotherapy. 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. 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. 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? I'll show you why. We have worked really hard to catch up to the rest of the field in combining with various, agents, including CTLA-4, macrophage-targeting agents, chemotherapies, and we're still stuck at about 20% for most sarcomas. The reason, I think, and what most people think, is that there's a continuum of hot and cold. This is transcriptomic data of about 700, of the three most common sarcoma subtypes. What you see here is a heat map of gene expression related to various immune signatures. You can tell, outlined in the bright green box, is that about 20% of these tumors have very high immune expression. We think these are sort of the hot tumors. What about the other 80%? What do we do about them? I'll just go through this. Basically, you know, just to, 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." I wound up taking a job at University of Colorado, where I partnered with a PhD immunologist named Eduardo Davila, who you may know. We've basically put together a basic science, translational science, and then clinical trials focused on working on cold tumors and trying to improve microenvironment. When I got to Colorado, my dear friend Dr. Jennifer Buell 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." We did, and we've been able to put a bunch of patients on this amazing trial. Lo and behold, here I am with all of you today, and now I gave a SITC plenary of this beautiful work. Serendipity. This is the summary data that you may have seen already, but that Dr. Hodi just showed you. This represents 125 patients, 19 different solid tumor types. This is all of the data. Within those 125 patients, we presented on four different disease-specific expansion cohorts. 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 IO refractory tumors here. Most of these responses are ongoing. The median duration of response has not yet been reached, and the disease control rate's 66%. Tremendous stabilization of disease here as well. We have a 12-month overall survival rate of 66% in a heavily pretreated phase I population. We went forward, and we looked at four specific disease expansion cohorts. Again, Dr. Joseph Grossman's gonna 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. Durvalumab and tremelimumab was 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, impressive stabilization of disease as well. Dr. Grossman will go through, but these are not snuck in accidental MSI colorectal cancer patients. There's no tumor mutation burden when we checked in patients, and only one of seven was PD-L1 positive. Ovarian carcinoma, same thing. We heard a story about Dr. O'Day's ovarian patient. 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 outcomes, the hardest to treat. We have a response rate of 26%, including a complete responder that was durable to almost or to over 90 weeks and is still ongoing. Disease control rate, again, 63%. It keeps going and going. Sarcoma, my tumor of choice. What did we do? We have 12 patients, mostly angiosarcomas. I showed you know, angio's got its 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, and they don't respond to chemotherapy either. 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 a DDLPS liposarcoma patient who had progressed on at least 4 or 5 other things. I mean, this is real. These are real responses and so exciting and so promising. Finally, non-small cell lung cancer. These are previously refractory patients to IO therapy. These are retreated with IO. We've got now a fifth adenocarcinoma patient, who has a confirmed partial response. 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. Very exciting. The last thing I'll just say is that I've been so excited to be partnered with Agenus from the very beginning, with the, you know, with those patients, and it's totally changed my career, right? Like, I never would have seen myself doing this. 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? We combined initially zalifrelimab, so traditional CTLA-4, and balstilimab with doxorubicin in patients first- or second-line with metastatic soft tissue sarcomas. We've completed the first two stages of this study. About 30 patients give or take, and we're hoping to have data for ASCO. What I'm really excited is we're opening imminently in the next couple of weeks an expansion cohort where we're subbing in botensilimab. This is the first time, to my knowledge, that we're actually gonna have a study with chemotherapy and IO here. Next-gen IO, promising for cold or not so hot tumors. I think the future's incredibly bright and just so excited to see where this goes. 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. Joseph 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. Hey, thank you so much, Todd. Wow, Dr. Wilky, that was inspiring and a hard act to follow. Keeping with the theme of the road taken, I wanna tell you a little bit about how I got here. Another common theme, I was also playing music and writing plays. About a 10-year detour before I went to medical school. 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. Hidalgo, who's 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. I wanna 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. 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. 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. I would describe to the patient the possible benefits or first, usually the risks of chemotherapy for treatments like FOLFOX and FOLFIRI. I would talk about they might have 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. 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 gonna come back, and it's gonna take their life probably within a year. As you can imagine, this could be depressing and difficult, but like most oncologists, I'm an optimist, or I wouldn't be doing it. For each patient that sat in front of me, I like to think, "Okay, maybe this one's gonna be different, right? Things are gonna turn out differently 'cause we're gonna figure something out. Maybe it's on a clinical trial, and that checkbox that we checked is gonna be wrong." 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 Michael 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 Traveler's Clinic because he was getting postcards from Machu Picchu. That's what I wanted to do for my patients. That is why I came to this company two years ago because I thought that, wow, here's a chance to actually do this for cold and IO-refractory tumors and do it quickly. I'm gonna try to move along. To give some context, about the patients that we're talking about today, that Dr. Wilky presented on so eloquently, patients with microsatellite stable colorectal cancer, which is about 95% of patients with colorectal cancer in the metastatic setting for which there is 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 are regorafenib and TAS-102, treatments with about a 1% response rate and, median overall survival improvement of about a month and a half. 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, single-digit responses and very little impact. Alongside of this, you can see both nivolumab and ipilimumab with a response rate now above 20%, and substantial disease control. That doesn't really tell the whole story, in terms of the clinical benefit that we're getting for these patients. That's what I'm gonna show you next. You've seen this 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 six months in a patient population where you expect most people wouldn't have lived six months. 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, durable 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. The point estimate for median overall survival at 12 months is already 60% with a median follow-up of 6 months. I wanna 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. That's microsatellite stable colorectal cancer, and there was nothing special about them. They're common patients who go on phase I clinical trials, who are heavily pre-treated. Two 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 one of the seven responders had any degree of PD-L1 positivity. If you look at the RAS and BRAF mutational status in this population, it's exactly what you would expect for a colorectal cancer population. Nothing unusual. I wanna 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. 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. There's 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 six weeks. The investigator thought it looks like the metastatic disease is under control, but I'm not sure what's going on with this primary. Took the patient to surgery, and lo and 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 responses ongoing. As you think about this activity that we are seeing in this very late line in MSS colorectal cancer and that we're seeing across so many other diseases that have historically been unresponsive to IO, 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. You're gonna hear more about that from Dr. Eggermont after myself. Thank you. 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 Chief of Regulatory, Quality, and Safety at Agenus, to talk about how we're gonna get there. Sorry, I have to move out of the way. First of all, welcome to all of you here. I really appreciate that you took the time on 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 wanna 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 startup 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. Moved to the San Francisco Bay area, where I start to work for Gilead Sciences. After my time at Gilead Sciences, I went to Medivation, where I also worked on the PARP inhibitor. I got a phone call similar to the phone call that Dr. Todd Yancey received about a small 250-person company called BeiGene. That was where I solidified my wonderful friendship and relationship with Dr. Yancey. 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 to doing everything I could to honor his beautiful, but very short life. Fast-forward. I made it through that pretty well. Give me the credit there. I moved on to another IO company. I worked at Arcus Biosciences. I had the great pleasure building out the regulatory quality and safety team. 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 wanna 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 a company right now?" He said, "No, no. I'm working with them to help them, and I think you should help them, too." I said, "Todd, I really appreciate the phone call. Very happy where I am. I'm enjoying my work." He said, "No. They have activity in cold tumors." He said, "Do you know what that means?" I said, "Yeah. I know what that means." I said, "I'll talk to them. I'll absolutely talk to them." Todd had said, "These pediatric tumors are very cold or less hot." Sorry, Dr. Martin. And I really wanted to see if there was something behind this. I flew out. I met with Dr. Buell, Dr. Armen, Dr. Grossman, Dr. Patel, Jen, Dr. O'Day. The only thing that was more compelling than the data were the commitment, the excitement, and the energy of these people who absolutely wanted to make a difference the way I did. Here I am. I decided to join. We're here at the crossroads now. We've got the road we've taken, but now we need the path to approval. We need to get this drug to the patients that need it most or the combination of drugs, absolutely. Two choices here. We can take the traditional phase III long-term study OS endpoint trial, or we can take the expedited path. I think that you would all understand from the data that you saw today that this is the path forward, the expedited path. How do we do the expedited path? 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. How are we going to ensure our success in this area? 'Cause 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, more than Europeans have this issue. We need to take this drug globally. 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. There are more than just the accelerated approval. We have lots of different paths. We have 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 standard comparators, a standard 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 1-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. We are currently designing phase III study that can then confirm exactly what we've seen in the phase I and the phase II. We also have a multi-pronged 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 from 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. Now the real question, which I'm sure a lot of you are 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. 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 and 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 of surgical oncology at the Erasmus University in Rotterdam and at Paris-Saclay University in France. Thank you, Dr. Eggermont. Thank you. I discovered that it's usual to start on a personal little note, and why not? Let's do that. I'm Dutch, and I never get called. I have to do the calling all myself. I'm a very fortunate person because in this iPhone, there are a number of very interesting numbers linked to very interesting people. One of those people is one of the rare uomo universalis intellectuals is Larry Norton. I'm so happy to see you again after five years not having seen you, Larry. Another number in there is what shaped my career, and that was my alma mater, Steven Rosenberg. I was exceptionally lucky to get a fellowship to be in his lab for almost two years. It drove my career into two directions, going to immunotherapy, become a melanoma specialist for the biology, and surgery is not so interesting there. For the fun of surgery, also become a soft tissue sarcoma specialist, right? Just for the pure fun of surgery. Of course, the next thing is that there are now new numbers in there that link me to Agenus, and there is a principle involved. The principle involved is the program interesting? Because if that first criterion is not met, you know, 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? Jennifer Buell, Garo Armen, Steven O'Day, and there's always Michael Atkins, because we are the same generation of early developments with the IL-2, and so on. I'm a very lucky person. I discovered that we have two great musicians here in the audience, Larry Norton. And you, Breelyn Wilky. You were at the conservatory of St. Petersburg. I spent many evenings when there were performances at the conservatory of St. Petersburg to listen to Russian piano, which I just adore. I play the piano also, but I can only entertain myself, not my neighbors. When I went to medical school and I went to live in a small room in Amsterdam, I immediately bought a guitar. Within half year, we created a band, bluegrass music, called Vitamin C, with the banjo, mandolin, guitar, bass, contrabass, and the fiddle. We actually toured in the United States in 1974, and we toured at 6 bluegrass festivals. I have very fond memories of that. One of the biggest hits was not the Orange Blossom Special, which we also played, but the Amsterdam Special. Good. Now we go into this song. 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. Anti-PD-1 is a core necessity as it protects CTL function at the tumor site. This is the Mozart molecule of modulating in innovative ways the immune system. Anti-CTLA-4 is another core necessity because priming T cells creates 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, the anti-PD-1, and the second one Bach. Anti-CTLA-4 is here to stay. This is a very important thing, an anti-CTLA-4 you need for the stabilization of the tail of your curves. Anti-LAG-3 prolongs CTL function but has less impact on T cell clone diversity power. For me, it's an interesting molecule, but it's not anti-CTLA-4. The anti-PD-1 ceiling is very hard to break and will be broken in new patient populations that we need to define. I will 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. 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-CTLA-4 and anti-PD-1 in seeing more cures, shorter treatment cycles, less surgery. We will need to insert this systematically in all our drug development programs also to learn more about your new agents. 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 in squamous cell carcinoma, and so on. These are sort of the themes so you feel what's coming. Here you see which is a landmark trial, the CheckMate 067. Monotherapy with anti-CTLA-4 is the bottom curve. This is treatment-naive melanoma metastatic patients. Monotherapy with anti-PD-1, five-year survival 44%. They have completely different mechanisms of action, and they should work together. You see 52% for the combo. There's already Mike. This is a landmark design for where there's very heavy competition for the BRAF-mutant melanoma patients. If you start with Nivo/Ipi, in this case, anti-CTLA-4 + anti-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. Now it's all immunotherapy in melanoma in first line, okay? Basically. Then there's a number of attempts to break the anti-PD-1 ceiling. This is not so easy. The agonistic monoclonal antibodies have basically uniformly failed because they're hard to develop in phase I, and you can create cytokine storms and all this. The Ipilimumab experience showed that we ran too quickly into too many phase III trials on too small a data set, where actually at that time we hadn't even realized that in treatment-naive advanced melanoma patients, their response rates on anti-PD-1 alone were quite a bit better than the initial data. What is also an observation is that the intratumoral treatments, so the MASTERKEY, pembro plus key fact versus pembro alone, or ILLUMINATE, tilsotolimod plus Ipi versus Ipilimumab in melanoma have shown that in terms of initiation of systemic immunity, the IT injections fall short. 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 gonna go back to IT protocols. Then there's another one, the cytokine protocol. I'm not gonna go further into that. We have two very strong Nobel Prize-winning discoveries, anti-CTLA-4 and anti-PD-1. They're both totally essential, but we also need something to solve the profound immunosuppressive environment that is mainly created by tumor-associated micro-macrophages, myeloid-derived suppressor cells, and CAF, cancer-associated fibroblasts. 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 have of course 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 the adjuvant setting. That's simply how you can look at your own program as well. That translation for anti-CTLA-4 + anti-PD-1 needs two more slides because something went well and something went wrong in that translation from the efficacy in advanced to the adjuvant setting. What went well is when you dose Ipi correctly, 3 mg every 3 weeks plus Nivo. 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-CTLA-4 + 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 two Lancet publications, and you see it's long-lasting. It's long-lasting, right? Now, here something went totally wrong. 2,000 patients in the CheckMate 915 trial, and what goes wrong there? Look in red. The anti-CTLA-4 was dosed at 1 mg and not per 3 weeks, but per 6 weeks. 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 mg per kilo. We never saw a responder at 0.3 mg per kilo. Sometimes you ask, where's the memory, right? If you dose Ipi below an activity level, yeah, are you going to see an effect? No. The answer is that no, you will not see an effect, right? 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 two milestones further. 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 to discover a number of niches of also approvals. It started all with palpable macroscopic Stage 3 melanoma, and that's where the whole series of lessons come from. Then it translated into MSI colorectal cancer, locally advanced cutaneous squamous cell cancer in the face. Then now we have all sorts of neoadjuvant trials in all sorts of tumor types. 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 them. 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. 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 two cycles of anti-CTLA-4 + anti-PD-1, or it's neoadjuvant first two cycles of anti-CTLA-4 + anti-PD-1, and then the surgery. Okay? 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. It shows the amplitude and the diversity of clones that were already present at the base level prior to ipi nivo and after ipi nivo. Then you see that in blue, all the bars are much higher, both in creating diversity of T-cell clones, 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. This is the recipe for cure. How does it translate into further observations? If you just work with anti-PD-1, not even with anti-CTLA-4 + anti-PD-1, if you just work with anti-PD-1 and you give the classic approved system, surgery first, that's the top, and then you give one 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 SWOG S1801 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 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. Neoadjuvant is not just alive, it is a necessity in what you need to do now to further develop. These are back now to the in-transit patients, and they had palpable nodal disease. Look at the green curve, look at the red curve. The green curve are 65%, let's say 2/3 of the patients who had a pathologic complete or near complete response. There were only two relapses in 64 patients, and one relapse actually was not a relapse. The patient died in a traffic accident and had no tumor on autopsy. We have never, ever seen these curves. Never, ever. This pertains to 2/3 of your patient population. This is where neoadjuvant therapy development is going to take us. This has been confirmed. Look, I'm just showing you now this panel on the left side of the slide by a consortium, pooling all the anti-PD-1 neoadjuvant-treated patients or the anti-PD-1 + 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. Look at the three top curves. You basically see no more relapses. This we have never, ever seen in melanoma. Now, if you have a BRAF-mutated melanoma, you could also do this with dabrafenib and trametinib, a BRAF MEK inhibitor combo as neoadjuvant therapy. We know durability in these targeted combinations, not so good. Look at this. All right. The superiority of immuno-oncology in melanoma is just like unbelievable. That is how strong it is. We promised more cures, data shown. We promised shorter treatment cycles, this trial. 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 + 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. Then in the 60% of patients, you don't do even lymph node dissection anymore because how did you find out it was a pathologic complete response? Because you only took out that node, little remnant, where the magnet was. 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 axilla, right? More cures, shorter treatment cycles, because look at the other yellow box where you were there, no more adjuvant therapy. Just two cycles of Ipi Nivo in this trial. This is changing the world to start with, I would almost say like always, in melanoma, but then the rollout into other tumor types. This is the last couple of slides. That means that, you know, you see 50% complete responses in bladder cancer with neoadjuvant anti-PD-1. 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. Two cycles of Ipilimumab prior to rectal resection. Response rate close to 100%. 95% or 92% pathologic complete or near complete responses. Whoa, 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 tract with advanced colorectal cancers. Advanced I mean T3, T4 tumors with positive lymph nodes. Look at this Niagara Falls, right? That's a waterfall plot we like to see. In the Netherlands, you must refer an MSI colorectal cancer patient to only one of six hospitals where you will not be operated, but where you will get Ipilimumab. We got the payers to pay for that because, you know, if you explain this to the payers, they say, "Yeah, well, in this case you may be right." Yeah. Okay. Otherwise, they never say that, right? New England Journal of Medicine paper in 70 advanced, locally advanced cutaneous squamous cell cancers in the face, you know, this type of disaster. Fifty-six point but, 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, fifty percent. These are now best medical practice findings. 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, yeah, great. Yeah, take my rectum out. I got the uneven number." No, no. This is not randomizable anymore. We need to go, and I already have an appointment with EMA because after this was presented, the colorectal data was presented, I went immediately to the President of the committee of EMA because I know him very well because he was at EORTC Data Center when I was President. I say, "Hey, butt out." Good. That's what we said. Now we see these neoadjuvant initiatives also in lung cancer. Just look at PCR rate for combo with chemo versus just chemo. 24% pathologic complete response rate to 2%. Something will pan out, right? This I find also, like, pretty unbelievable. 40 patients or 39 patients at UCLA and UCSF were randomized preoperatively for a glioblastoma multiforme relapse that was still operable, right? Okay. They are always immediately scheduled. You only have two weeks. They get one dose of anti-CTLA-4, anti-PD-1 in here. I mean, unexpected, but these are the findings. There was a doubling of PFS, and a halving of relapse rate, and there was a doubling in overall survival. I mean, 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 predictions slide where things will go very fast and where in yellow things will take some a little bit more time. I thank you for your attention. Thank you. Thank you, Dr. Eggermont. 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. Then following that, we're going to take questions from the audience and also from the folks on the phone. Thank you. Well, first of all, I thought it was an interesting series of presentations and nothing less was to be expected. What I find very interesting in your talk is that, Breelyn, is that you address a number of tumor types. The first one of which is the main cause of cancer death in the Western world is colorectal cancer. 95% of colorectal cancer is MSS colorectal cancer, and we never got anything to work. Actually, surprisingly, because we know that in the Immunoscore system 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. 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, you know, are new. Whereas to my understanding, the anti-PD-1 is a relatively regular type of anti-PD-1, right? How do we philosophize 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 the often cold metastases 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? A great question. I would actually pass this to Dr. Grossman, who is our colorectal cancer expert and can probably weigh in 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? I think that's the question mechanism-wise, what is botensilimab actually doing? What is it about the engineering that's making these that's changing the paradigm? Yeah. Sorry, Dr. Grossman, but my principle is always ladies first. Now you are. It's your turn. Thank you. Yeah, I will certainly answer and might even pass it along after to Dhan Chand, who's in the audience, if he wants to add anything kinda out of drug discovery. Certainly what we're seeing in the clinic with botensilimab is different as we described than what we've seen with first gen CTLA-4. Obviously something different is happening and what is it? 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. Essentially we believe that the Fc portion of an 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. Yeah. Thank you, Joe. 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 a Fc gamma expressing dendritic cell. We put 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. 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 with an antigen-presenting cell. We have solved that with botensilimab by creating a better bridge between that T cell and that antigen-presenting cell. I just wanna add, I was supposed to talk a little more of the pipeline in my presentation, so I think I'm gonna get called in for that. In addition to CTLA-4 and 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. 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. The myeloid compartment is also critical, and I think Lex commented on it. Jaden and I were at a Melanoma Conference recently with liver mets and certain histologies as well as ovarian obviously is one. Even within diseases, organ sites defend themselves differently. We saw some beautiful data at Edinburgh at SMR with liver mets and melanoma showing literally a myeloid wall around tumors. 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. 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 pre-clinically as the ILT4 program as a myeloid checkpoint, but adds lymphoid checkpoint properties that the ILT4 doesn't have. We have that first in human just in the last two months. On the music theme, we're gonna have an orchestra here very shortly. We already have four different checkpoints, PD-1, next gen CTLA-4, CD137, and an ILT2 in clinic in humans right now. Obviously, speed is everything, and to Jen's points, the company's really trying to figure out a way in parallel to look at these combinations very quickly, both in metastatic settings. To Lex's point, the neoadjuvant setting is a perfect place to look at proof of concept for mechanism and pathologic response. We're actively, as a company, engaging KOLs all over the world across these diseases in early neoadjuvant studies. Well, Steven, you've made an excellent point about, you know, also treating the myeloid compartment of that tumor. You know, if you think of Dr. Norton's presentation, you take that beta part of the equation and treat the microenvironment. You know, 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. You can take myeloid cells, which, by the way, are the most abundant immune cell in cold tumors. You can actually activate those cells. You see increased ability to activate T cells. You take things like CD40, things like MHC, things like CD86, which you need to prime the T cell with, all increase through the Fc. Again, you know, with botensilimab, unlike that of the first generation, CTLA-4 has the ability to modulate both the innate and adaptive forms of the immune system, and of course, bringing in the rest of the pipeline would only help take that tail even higher. Larry. Yeah. I mean, yeah, I have so much to say, actually. Let's stay for another couple of hours. We'll have dinner sent in. We'll just, you know, just relevant to this point. I think something that Jen said is, like, really very important. All right. What I see is before me. I see an expert violinist, an expert viola player, you know, an expert cellist. You know, I see percussion. I see, you know, an ensemble of great musicians and great instruments. All right. If you just say, "Go," or, "Let's randomly put these things together," you're just gonna get noise. No matter how good the solos are, that's all you're gonna get with noise. That's what I mean. You've got to coordinate it in a way that makes sense. I think that's where, from my point of view, the mathematics comes in because no great advances have been made without engineering. Engineering is our basically mathematical rules for how things play together, you know, in a way. It's like, you know, airplane doesn't fly because just has a good engine. You know, it's got all the pieces have to work and 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, you know, a good drug A and a good drug B from different companies and design what is the appropriate clinical trial to actually maximize them. 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 equation is a parameter. So you have to manipulate the various parameters in such a way that should make the whole thing work. All right. If one parameter could be influenced by one company and another parameter by another company, you're never gonna get them to work together in a way that's gonna be maximum, 'cause they're gonna wanna show that their company, that their drug is better than everybody else, including, you know, the other company, even though they work together. I think what makes this particular moment exciting, what makes this meeting exciting for me, is the fact that we have all these instruments and all these musicians, and it's all together in the same orchestra. You put the right conductor in front of them, all right? Then all of a sudden you have music, and you won't have noise. Absolutely. I think this is what really is profoundly exciting. The fact that we have this incredible lead that Breelyn Wilky presented today, you know, to an audience that was sitting there with their mouths open, saying, "My God, everybody knows these cancers don't respond to immunotherapy." Everybody knows that. You see these waterfall plots with this responding is that, you know, it shows me two 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, you know, two different cell types together so that they actually can, you know, can work. None of these cancers... I mean, every cancer is just filled with mutations. Every cancer is aberrant. Every cancer is aberrant proteins. So it's just a matter of degree, and it's just a matter of they're not cold. They're just being treated with the wrong drugs to actually make them work in that regard. But I'm also seeing a lot of provocative ideas, you know, about the ways to put things together, including, you know, what is the timing of the intervention compared to the timing of surgery, you know, which is. What is the right timing between a cytotoxic agent that may actually affect mitosis and release of antigens and the immunotherapy component? This thing that's going on in our community, if A works, B works, let's just sort of chuck them together. For mostly what we do in medical oncology is we titrate to toxicity, you know. I mean, you know, we reduce the dose of things, so that we can actually give them together as if, as if God said, "You must use them together, or they're not gonna work." That's not necessarily the way that works. That, those curves that I showed you with the breast cancer, you know, that's sequential therapy. When that was originally proposed, you know, I was called criminally insane in public because everybody knows you gotta use them together. You can't just use them sequentially. If you use them sequentially, you actually do much better. Absolutely proven. You know, it's 40,000 randomized patients. If you do 'em, you know, with what we call dose density, you use them closer together in time. I was also accused of criminal insanity for proposing using them closer together in time because that would cause more toxicity. It wouldn't cause greater efficacy. They were wrong. No greater toxicity and greater efficacy. I'm seeing a very exciting thing going on here now, which is really very novel agents, a lot of novel ideas, and a pipeline that we can utilize to actually weave them together all under the control of one company so that we can do creative work together. I think this is a really exciting meeting. Mike, because you are the DREAMseq guy now. You're the DREAMseq guy. What is new, and what do you see as some of the next steps that you sort of 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. First of all, I wanna emphasize that what I think Dr. Norton said in his presentation is you can't cure most cancers with chemotherapy because of Gompertzian kinetics. When you give immunotherapy, you're not hitting just one pathway or two pathways or three pathways. You're machine gunning the tumor, so it can't escape. You can get rid of the last tumor cell. Immunotherapies 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 immunoresponsive disease, but we didn't have the right therapies. When you get a response in lung cancer from purely immunotherapy, you see that 60%-80% of those are durable, are cures. The goal is to get the response. 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. 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. That's what we need to do. Yeah. Very good. Thank you. It was as beautiful as Nessun Dorma. We can do that. Larry, you wanted to give a follow-up. I wish I gave a longer talk because there's so much to say here, but I think that this a very important point. If you looked at my curves, all right, you got a Gompertzian tumor, you do something and it shrinks, and then it plateaus. All right. If you're accomplishing that with chemotherapy, what's happening is you are gonna have continued proliferation and even proliferation under the pressure of an agent that actually may increase mutation rates like alkylating agents, and you get more mutations, eventually getting mutations so that the agent that you're giving is not gonna work 'cause you're gonna have drug resistance. If you achieve that same low dose plateau, a durable response with immunotherapy, and you develop more mutations, it'll make the immunotherapy work better. It actually, the same things that make it difficult to cure cancer with chemotherapy may make it more likely that we'll be able to cure cancer with immunotherapy because of that particular phenomenon. That I think that there's a lot to exploit there. I've actually never thought of it until Mike was just speaking. There's a lot to exploit there about these incredible durable responses. I have a patient I treated for breast cancer. She's a BRCA1 and BRCA2 heterozygote. She was treated for breast cancer, and she was cured of her breast cancer. Then she developed a lung cancer, and then she was treated with immunotherapy. That was, gosh, maybe a decade ago, and she still hasn't recurred. It's a you know just a remarkable thing. I think the BRCA1 and BRCA2 mutations might have increased mutation rates and might have actually made her. The same things that made it more difficult to treat the breast cancer might have made the immunotherapy work better. I think that weaving together a lot of these themes, we clearly are approaching a theoretical as well as a practical basis for actually making curative therapy using these particular tools. Very good. Yes, Garo. Lex, because we're running about 40 minutes late. Okay. What I'd like to do is give the last word to you. I wanted to thank our panelists and the audience for this really the most meaningful session on the subject of immunotherapy that I've experienced because of the depth and the breadth of expertise in our panel. Lex, the final word. Thank you for that privilege. Well, first of all, everybody here at the table and everybody here present, thank you for contributions and, well, congrats on a very dynamic and very promising program. I hope that what comes out of this session, that when you have assisted in it or when you have watched it on Webex, is that there are so many elements now that make us realize that although there has been an 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. That a leading pathway there will be a number of neoadjuvant approaches that will replace current approaches. We'll cure more people with less surgery and so on. That at the same time, we have now the tools and the whole Agenus story now with your anti-CTLA-4, anti-PD-1 actually shows that in a number of niches we see a breakthrough in what we considered, yeah, how do we make it work in MSS colorectal cancer? I mean, 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 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. I mean, I'm a surgical oncologist, soft tissue sarcoma. Who would say about soft tissue sarcoma that this was going to happen? Of course, it's going to happen first in niche one, two, three, and then we'll find a common denominator to make it stick. It's very hopeful and it's a very positive session, and I think rightfully 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 we'll always be available for those in a subsequent meeting or subsequent encounters. 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 appreciated.