MiNK Therapeutics, Inc. (INKT) Earnings Call Transcript & Summary

Good afternoon, everyone, and thank you for sharing your afternoon with us, for MiNK's inaugural R&D Day, and this will be the first of many opportunities where you can hear of our advancing science and an opportunity to share with you some of the findings that our team has presented just this morning at the most prestigious Society of Immunotherapy and Cancer Conference that's being held in Boston in the conference center that you can actually see. Today, you're going to hear about a new generation of therapies actually. And in fact, we can probably call this a new class in some respect. As we, at MiNK, are leading the charge in advancing living medicines to patients, and we're also elucidating the science and the power of these cells as we're doing so. At the conference this morning, we actually presented data that is first of its kind about the properties of these cells, their function, their features and why these cells are considered the most powerful cell in immunity. We're going to talk a lot more about this today. I want to take a moment just to thank those who have made this possible. Our Board of Directors, our scientific advisers, Dr. Mark Exley is here as well, our courageous doctors here who are on the front line and spending their lives and saving others, and you're going to see the courage that has come about in delivering our therapies to the most severely sick patients and the most vulnerable on the front lines in the heart of the pandemic, and Dr. Terese Hammond is with us today to tell you about her experience. I'd also like to thank our friends and colleagues at Wolf Greenfield, our host this afternoon and our partners and trusted advisers every day. I'm really grateful for your sage advice and helping us to get here. And of course, our best-in-class scientists who are joining us today, you are as persistent as you are brilliant and you work tirelessly to help not only discover and advance our novel off-the-shelf allogeneic invariant natural killer T cell therapy, but also to deliver them to patients who need them most. I want to take a moment also to thank our patients and their families. They join us in this effort of advancing science and they do so at defining moments in their lives, the most vulnerable for most of them, and we're very grateful for their contributions. Now today, the immune system is at the forefront, and it hasn't always been the case. Not only do we speak about antibody effectiveness, immune vulnerability in the sick and elderly, but one of the most sophisticated cancers -- conferences that I just spoke about, the SITC conference is being held here in Boston is boasting threefold increase in attendance, because we're seeing that immune therapies tuning the immune system is going to be necessary to combat some of the most widely tractable diseases that we're facing that includes cancer, autoimmunity, infections, sepsis, lung diseases and we're really excited to be a major part of this. This conference and participation underscores that while the pandemic has brought immunity to our daily conversation, significant progress in developing therapies to actually address diseases to immunity and eliminating diseases has ensured a future of designing immune-tuning therapies to combat these problems and it meant we believe that the cell therapy specifically iNKT cell therapies will lead the field and immune-tuning treatments, and here's how. Today, you're all sitting here and you're carrying around living medicines, living medicines within you. Dr. Hammond calls these cells sort of the 911. These are one of the most potent and quick-to-act cells in immunity. They're also the rarest cell in your periphery. So they're very difficult to get access to. Mark actually is an expert in this field and he's going to tell you more about this. These cells have a very important function, several very important functions. When you think about immunity, you have two arms of immunity: natural innate immunity that which you are born with, that which is very quick to respond to impending threats; and then adaptive immunity, that which you effectively develop responses to combat diseases like COVID-19 is how we think about this most. These cells are one of the most potent cells, and we believe the most powerful in actually modulating both arms of immunity. They not only choreograph how the immune system both arms innate and adaptive should be working, they have the ability with the natural engineering, we call them nature's CAR-T in some ways. They have an engineered TCR, and that's common in all of us. That allows not only these cells to function, they actually go to the site of disease when that ligand is upregulated naturally, without any engineering, without any complexity, just the cells in and of themselves. Once they get there, they have the ability to directly function. They can kill. They can lice tumor cells independently. They can clear infections. They can prevent secondary infections. This is particularly important in patients who are in the ICU. They also can do something very important. They can recruit other cells, T cells and NK cells to the site of action. And what you're going to hear from our scientists today, we're the first to report that these cells also can take exhausted T cells, CD8 T cells, which are commonly known as one of the most prominent cells in immunity and critical for eliminating diseases like cancer. Those cells get exhausted after treatment, common treatment after a lot of exposure to antigens or the disease. When you administer iNKTs and our scientists will tell you this, you actually change that existence. You can reinvigorate CD8 T cells. You can make them fight again. Importantly and we're going to show you this visually that these cells not only can reinvigorate exhausted T cells, but they also can help those T cells get into the site of action. They actually bring them and show for them into the tumor, where they can then fight and deliver very specific anti-tumor activity. These features have long been spoken about, but they have never been demonstrated. And our team of scientists have shown this now and we will be presenting data to you with the esteemed panel that I'm humbled and honored to have here with us. These are oncologists treating solid tumor cancers, these are experts in pulmonary diseases, particularly those patients who are critically ill with critical care needs, individuals who have been studying these cells for their life's work. Dr. Lydia Lynch is with us today, and she's going to talk to you about how these cells stand up against others. Our scientists are going to talk to you about what we have been able to show not only by taking these cells in their natural form, at MiNK, we were the first to isolate these cells, we could manufacture them at scale, creating about 5,000 doses from a single donor that allows us immense development flexibility. It allows us to address major challenges in delivering effective medicines at the kind of logistically feasible and cost-effective approach of biologics. So our team and you'll hear from our head of manufacturing is able to actually from a single patient generate 5,000 doses that we can cryopreserve, we can demonstrate that the cells remain functional and we can distribute them all over the world where -- what we have done now on our international clinical trials, the cells are at the sites when the patient needs them. That's a major breakthrough. You're going to hear how we're doing that. I'm going to first start this meeting with the kickoff and I'm gonna introduce Dr. Manuel Hidalgo. Dr. Hidalgo is the Chief Hematology and Oncology at Weill Cornell Medical Center. He's been an advisor -- a strategic advisor to MiNK since its inception. And he's been in a position now to help us take these cells in the manufacturing form, in their native form as well as to identify ways in which we might want to leverage our engineering capabilities for super targeting and employ them in some of the most prevalent diseases. Dr. Hidalgo?

Well, good afternoon. Thank you very much for the invitation to be here. Today is a very important day, where many new data were presented this morning and thank you for attending the meeting. I'm going to briefly sort of provide brief summary of where we are at the moment in cancer treatment and what opportunities we have out there and what are the problems that sort of the most modern treatments are encountering. So these are my disclosures. So cancer is here to stay unfortunately for a while. These are data of cancer incidences and mortality projected to 2040. And as you can see many tumor types would continue to have increase in the incidence. And what is probably more dramatic is that the mortality remains basically flat. Some tumors were making progress known as small-cell lung cancer, for example, mainly because of smoking cessation, because of early diagnosis and because of the treatments that are more effective. But other tumor types, the ones that I treat in the clinic like colorectal cancer, liver cancer, pancreas cancer actually are increasing and will be the most important and most significant killers in 10, 15 years for now. So very, very important problem as you all know. What are we doing? We have done surgery, chemotherapy and radiation therapy and more recently the two newest therapeutic modalities, precision oncology and immuno-oncology and we will talk today mainly about immuno-oncology. But before I do that, I just want to mention that there is a very significant field of cancer genomics and targeting genomic aberrations, which is very important and likely at some point to be convenable with immunotherapy strategy, so this is one field that has a lot of merit on its own. And the field of immunotherapy, which essentially as Jen said before, we're talking now about two main modalities: one is the checkpoint inhibitors and we know that CTLA-4 inhibitors, PD-1 inhibitors, they're approved for -- in the clinic, they're used to treat many tumor types and they work by basically -- and reactivating T cells that have been sort of a quiet and are blocked from killing the tumor cell because of different ligands that the cancer produces and these antibodies, anti-CTLA-4, anti-PD-1 worked by these mechanisms. This was of significant revolution, Nobel Prize worthy and a couple of examples in the area that I work. Pembrolizumab in MSI colorectal carcinoma, perhaps one of the most sensitive scenarios in which these drugs work and you can see that is much better than chemotherapy, but there are problems not every patient responds as you see and some of the patients who respond initially eventually progress. So there is significant need to understand the mechanism of resistant to these drugs and to complement with other strategies like the one we will hear today about iNK cells, how we can make or synergize better with those immune checkpoint inhibitors. And in other scenarios, these drugs, they just don't work. So this is the disease that I treat in the clinic for most of the time, which is pancreas cancer. And this is a recent -- very recent trial, combining chemotherapy with chemotherapy plus double it checkpoint inhibitors both that I mentioned before CTLA-4 and PD-1. As you can see, there is basically -- there is -- there are no differences. And perhaps the reason is that these tumors have a very rich human microenvironment that produces ligands that is excluding T cells from the tumor microenvironment and basically just not for -- the T cells don't get to the tumor, for that reason, they just don't work. So how can we do better? Well, understanding the mechanism of resistant to these drugs and complementing them, as I said before, is an important strategy and we'll hear today how iNK cells cancer, we program these cells that are being exhausted to become then again effective against the cancer and how these cells can be engineered to target very significant components in the tumor microenvironment that are linked to the resistant to existing immunotherapy. So combination is a big thing. Now the other major strategy in the cell -- in the immuno-oncology field is the cell therapy. Cell therapy is not new. We have been using them for sometime in the clinic. The new aspect is sort of the engineered T cells, CAR-T cells, TCR engineer that have been developed and continue to be very aggressively developed with a very significant engineering sort of activity to make these cells more effective. And in some scenarios, there are quite effective. This is in multiple myeloma, relapse refractory myeloma. And as you can see, these cells targeting BCMA have a very, very important response rate and resulting in overall survival and they're approved. But the same concerns that I mentioned before about the checkpoint inhibitors apply. They don't work in some patients. Some patients eventually become resistant and there are many tumor types that are just intrinsically resistant. And cell therapy, as we know it today, is not an easy therapeutic area. It's not easy to manufacture these cells. They are autologous. It takes time. They are expensive. There are all kind of reasons why they just don't get into the tumor. They don't recognize the tumor. They don't permeate into the tumor microenvironment, and for that reason are not effective, and they are associated with significant toxicities. So it has been a tremendous revolution but one that still we can improve upon. So what was presented this morning and we will discuss today's new version of cell therapy, the iNK cells, iNKT cells, invariant iNKT cells that actually can address many of the problems that I mentioned before and we will see how these cells are able to kill tumors by different mechanisms. One is by blocking immunosuppressive signals in the tumor microenvironment, very important in some patients like pancreas cancer, by directly engaging and killing tumor cells, and as Jennifer mentioned, by recruiting, reprogramming and reactivating T cells that were once active but now have been exhausted. So going through the areas that we will hear today in the presentations that were presented this morning, we have basically 5 major topics. We'll be talking about agenT-797 Phase I clinical trial data, both alone as well as in combination. The efficacy and ability of these cells to help patients with severe distress respiratory syndrome caused mainly by COVID, but likely also applicable to other conditions. And then the data that they're able to sort of reprogram T cells that are exhausted in the tumor microenvironment for reactivation and killing again. And these cells can be used naive, but they can also be engineered. And we will see a couple of strategies to engineer iNKT cells want to produce or to attack FAP-expressing mesenchymal cells in the tumor microenvironment. This is a very attractive approach to sort of block signals that are excluding T cells from the tumor microenvironment in diseases like pancreas cancer. This is probably the most relevant mechanism by which these tumors are resistant to checkpoint inhibitors. We have attempted to sort of overcome this by different approaches. We did significant work, for example, targeting a cytokine, which is very important called CXCR4, which is activated or produced by these FAP-positive cells, those drugs that have not sort of shown significant activity yet. But going and eliminating the source of these negative ligands is a very cool strategy. And then as I showed the BCMA-CAR-T cell, we can improve upon that, and you will see data of reengineered iNK cells to target these important antigen, but with different engineering and different engineering that can probably hopefully make them more effective. So this will be sort of the topics for the day. I'm going to stop here. Jennifer, you want to take the podium? Thank you very much for your attention.

Thank you very much, Dr. Hidalgo. I think a couple of points I'll just emphasize here, the ability to address some of the current limitations of CAR therapies, not only the manufacturing and logistic problems, but then also identifying ways in which we can super target. So BCMA is a well-known target addressing multiple myeloma, but it's largely difficult to manufacture, and it hasn't shown a significant amount of durability of response. And we think that we may have found a way to improve upon that durability by armoring BCMA-CAR-T therapies. And it's a program that we're in active discussions with and contemplating strategic collaborations for. To go into a moment of the science of the iNKTs, we have a world leader, Dr. Mark Exley, who is -- has been working with these cell types, I think, for -- since 1996. He'll talk with you about the biology of the cells and why we believe we're seeing what we're seeing. Mark led our scientific efforts. First, he was a professor at Harvard, leading his lab and pioneering the science, also demonstrating ways in which he could take these cells and apply them in the clinic, showing some of the first-in-man data with these cells in different types of formats, including vaccines. He was leading our scientific charge for many years and now the leader of our Scientific Advisory Board.

Great. Well, nice to be here and surrounded by my colleagues here, who've got some really great data, we want to get to as soon as we can, so that it will be the background on iNKT cells that we've been talking about. So they're quite unusual. They're rare cells, as we just heard. And that's one of the reasons why we know less about them and very few people have studied them. And also, it's been intimidating to be able to work with them because they're so rare, especially in people. A lot more common in animal models, which a lot of the data has come out of. But as Jen also mentioned, they really link the innate and adaptive immune system, the 2 halves of the immune system. And they do this by -- they have their own inherent activity. And this can be directly antitumor. It can be antipathogen. It can be immunoregulatory in a very profound way. But they also have the ability to activate other immune cells. They're very good at activating NK cells, other T cells, B cells, and they also mature antigen-presenting cells, myeloid cells of various types and they can really help shift the balance in favor of protective immune response, which has been really profound in a lot of early clinical studies. Yes, sure. Is that better? A little bit closer. How is that? Is it better? Even better? Okay. So amongst other features, they respond like innate cells, so although they are T cells at subset, T-cell receptor, they nonetheless behave very rapidly and they respond very rapidly like an NK cell would or another innate cell. So they have that ability to stimulate immune response. They produce a lot of cytokine per cell basis, so compared to conventional T cells. So this means that they have more profound effects locally and further afield. And there are also an unusually easy platform to work with as we've discovered in a number of ways. First of all, they expand very rapidly. Unlike other T cells that exhaust very easily, they will expand exponentially for a long period of time, so we can grow them and we'll hear from manufacturing Joy and the team about progress for manufacturing as well. So although you start off with a very few of these cells, you can get to very large numbers very quickly. So that makes a huge difference. So it basically overtake the T cells another populations that start off with much larger fractions, but could take a lot longer to get to the high levels. And another feature of this because they're so rare in each of us right now because they're so powerful, we don't need a lot, normally. There's a huge therapeutic window. So there's a big opportunity when you add, increase them and stimulate them and increase their numbers. Because they're so few, it's much easier to have a big therapy window than with NK cells or other cell populations, in which we already have a lot of much traction. So next slide looks at some of the particular features, which are involved in their antitumor activities that have been defined over the years, and this comes out of a lot of work in models, animal models, but also a lot of very good studies in humans that many colleagues as well as our lab have been involved with over the years. And again, it shows that they can reprogram immune responses into a more Th1 like responses. It's critical for anti-tumor responses. So that means they also produce more interferon gamma. They're able to stimulate IL-12 production. They're able to stimulate antitumor, the cytotoxic T cells and we'll hear about again how they prevent T cells from exhausting or they can re-energize T cells that have been exhausted. So that makes them potentially very attractive in their ability to maximize the immune benefits of the immune system against cancers. So they can affect the tumor microenvironment as well as the immune system systemically and this can include their ability to kill tumor-associated macrophages, for example, which we know are tumor promoting. So they have a number of different features that allow them to really benefit the immune response in cancer. This is just some data from others confirms the data we have from internally, that iNKT cells can work better, for example, as CAR carriers on the left there, in terms of compared to conventional CAR-T cells. And again confirming data that we have internally, others independently have shown that they also can work better as antitumor carrier cells populations than NK cells, and they do this partly by activating NK cells and T cells as well as their own inherent activities. So they provide that extra benefit in that way. So they -- not only do they have antitumor activity, but not surprisingly, given that the similarities between antipathogen and antitumor immune responses are very similar in the Th1 flavor and the reduction of the immunosuppressive M2 macrophages and so on, the whole Th1 thing is really important, the antiviral responses as well, anti-pathogen responses in general. I think T cells can do this in a number of different ways. They're activated by ligands, lipid ligands, which can be produced by bacteria and fungi, but they can also respond to viral infections in a number of different ways, including upregulation of CD1d in terms of its target for the iNKT cell receptor. We also have other ligands and receptors on them that can pick up other stress ligands like NK cells, they share with NK cells. So we have the additional benefit of being NK like as well as being -- having their own T cell receptor of its own activity. So all of these things benefit antiviral response as well. And again, we'll hear not only about antitumor activity that we're seeing clinically as well as preclinically, but also potential antipathogen effects. They're having in patients with COVID and ARDS, so really profound potential benefit there as well. And of course, they have the ability to be engineers. We're going to also hear to make them even more active, and that's one of the next stage of our process that we're developing in the clinical progress that we'll move into soon. So finally, a slightly provocative slide, but we compare a lot of people who are working with various other populations subsets for T cells and K cells, gamma delta T cells. And all of them have their benefits. Some have their limitations in different areas. But one of the nice things about iNKT cells, we've been able to use them in the absence of lymphodepletion, which is a huge potential benefit. So far, the other populations have used almost exclusively and certainly clinically with lymphodepletion, which is very real contraindication, a limited number of patients you can treat and also reduces the potential benefit of the rest of the immune system because of it, obviously, lymphoid depletes potentially good cells. And so those are examples of how they can have these multifaceted benefits which extend out into the rest of the immune system.

Thank you very much, Mark. And we take you back to David. So the question is, why are we the first ones to be advancing these therapies if they're so good? And I'm going to see if there's an answer in the audience. Manufacturing has been a major roadblock, and that's why we really are the first company that's been able to address this problem. And part of that is because we have proprietary reagents that allow us to take a sample of blood from individuals and isolate the iNKT cells to nearly 100% pure. We have then a proprietary process that allows us to activate those cells and then administer them to patients. That's been a major impediment to progressing these cells that now we've been able to overcome. So presenting now is Dr. David Einstein. He's been Chief Partner, Lead Investigator of our Phase I study looking at these cells in a native form in patients with solid tumor cancers. David?

Thanks so much. Thanks to the whole MiNK team for the opportunity to speak here tonight and for the opportunity to be involved with this really exciting project. And thanks also to Marc van Dijk for some really hard work on data analysis up to the last minute. So I see patients with prostate, bladder, testicular, kidney cancers, which are among some of those immune therapies that Dr. Hidalgo spoke about are part of our standard armamentarium. But we clearly need to do a lot better. And so I think that there are some previous data out there in small subsets of patients looking at this concept of iNKT therapies. And most of these have used autologous iNKT, so you're actually freezing up the patient's own cells and trying to expand them ex vivo and then reinfuse with the idea that cancer patients generally have sort of a depletion of their iNKTs and also some dysfunction of those iNKTs. And limited numbers of patients, but there's some exciting data. I think that the head and neck report was one of the most interesting, where they had a number of patients that had really 50% tumor reductions through the strategy, sometimes a combination of autologous iNKTs plus some additional adjuvants, but it hasn't gone too much farther, as Jen mentioned. These are some data that have been generated internally kind of looking preclinically at models in this case of melanoma and looking at different immune-based strategies for trying to prevent metastasis. And so you can see here various combinations. We talked about checkpoint inhibitors. We talked about cellular therapies, can we put them together? And what you see here is sort of additive effects or even synergistic effects as you add more combination therapies in the amount of tumor control. And so certainly, there's the potential for combination therapies that would be very synergistic with the agents pipeline here. This is the Phase I trial that I've been fortunate to be involved with. And this is a kind of standard dose escalation design initially with monotherapy. And then in combination with standard of care PD-1 inhibitors in patients who have already developed progression on those. So as with the typical Phase I trial, we're looking primarily at kind of PK data, safety data and dosing tolerability, really. But I think there's some key questions that we're going to get to are sort of where do these cells go? Do they persist in the periphery? Do they traffic to tumors or other sites? And then also certainly some exploratory end points about the immune effects of all of this. So we've completed that dose level 1, no DLTs. We were able to move quickly on to dose level 2. Also no DLTs and then going on to Part 2 at the dose level 1 combination with other therapies. I want to just take a moment here and point out that this trial has been open since May. It's now about a half year later to have 40 patients accrued across a handful of sites as the fastest I've ever seen. So really credit to the CRO and the sites involved in all of this. So this is some basic data summarizing those patients who have been treated. And fairly typical Phase I population with pretty treatment refractory multiple lines of therapy types of patients. The clinical data here is limited by our median follow-up of only 18 weeks. So again, this is a rapidly accruing trial. We're still waiting for a lot of that really good clinical data, but I think what we have to share tonight is really about the safety and tolerability. So what we see here on the left is what we call swimmers plot. So this is showing individual patients who have been treated at these different dose levels or in combination, and the combination is shown in purple. The 2 dose levels as monotherapy are blue and green. And you're seeing patients, the duration that they're on treatment. Arrowheads indicating ongoing follow-up and dots indicating coming off for progression of disease. What's interesting here is not a waterfall plot, and that would show you actually reductions in tumor size. Those data are still very immature. So we're not ready to build that yet. But I think that across the limited number of patients that we are able to evaluate, we are seeing some reductions in some target lesions on scans. And we want to be able to confirm that and apply the usual RECIST criteria to come up with an overall response rate. I think the other thing that's intriguing, of course, is disease stabilization. Certainly, with some I/O therapies, we don't always expect tumor regression, but sometimes stabilization over the long term is a very good correlate for overall survival. And so there are some patients here who have had stable disease for many, many weeks. This is a little bit about our safety data. It's pretty boring because there's not a lot happening here. That's very good, okay? So there's really no treatment-related adverse events Grade 3, I think, when reported, but no irAEs and importantly also no cytokine release syndrome, which is a real problem with some cellular therapies. And so we're talking now about the toxicity of the drug itself or the product itself. But I think that it's also worth sort of coming back on something that Dr. Exley mentioned, which is the lack of lymphodepletion, which is a major, major barrier to rolling out CAR-Ts across solid tumors. So really favorable toxicity so far. We also see no increase in the typical cytokines related to cytokine release syndrome. And finally, are these cells active? Well, yes, it seems so. So on that second day, you can see a little spike in interferon gamma, which is a key cytokine that drives a lot of anti-tumor cytotoxicity and antigen presentation and recruitment of more immune effectors. So that's good to see. This is a parallel trial Phase I in multiple myeloma. I was not involved with this, but I will share the data, similar design with increased dose levels as monotherapy and similar endpoints, albeit with myeloma clinical endpoints, not solid tumor ones. So these are the patients who have been treated so far on that trial. A couple of stable disease patients, including one who had kind of an interesting decrease in the, what we call, paraprotein, which is kind of the abnormal protein. That's the problem in myeloma is what the abnormal plasma cells are cranking out. And so that decrease while on therapy eventually progressing, but with a nice response initially and some stabilization in those abnormal plasma cells in the bone marrow. So more to come. Again in the myeloma patients, a very similar safety profile. So no immune-related adverse events, no cytokine release, no increase in the cytokine release syndrome cytokines. So to put all this together, I think that we have some very promising data as far as tolerability both as monotherapy and in combination. We've been able to dose escalate with no DLTs and no cytokine release, no neurotoxicity, no immune-related adverse events. And I think that there's some exciting science that we're going to hear a little bit more about what could be going on. But I think clearly, we want to continue expanding this effort and we're planning some further specific dose expansion cohorts in specific tumor types, both alone and in combination. And I think that thinking broadly in terms of future trial development, in my mind, there's sort of 2 directions, and one is sort of circling back on that melanoma data and thinking about how this could be combined with other checkpoint inhibitors in the pipeline. I think that, that's both justified based off of preclinical data and safe to do based off the tolerability, unlike, say, combining ipi/novo and CAR-Ts, which would be quite toxic. And then I think that the other thing that allows us to do is to think about moving into earlier disease spaces, where the immune microenvironment could be significantly less immunosuppressive. So this is disease spaces like first-line therapies or adjuvant therapies or early recurrence based off of circulating markers. And those are situations that you would never want to base a patient with something like a CAR-T, but this, I think, is a much more reasonable proposition. So with all that, I thank you for your attention, and I turn it over to our next speakers.

Thank you very much, David. Actually, this is going to be one we're going to try to elucidate some mechanisms now with some flash presentations from our scientists at MiNK, who are going to give you a very brief overview of the data that were presented at the SITC conference today. I think importantly, based on the data observations that we're seeing, we will continue to advance these cells and mature the data and looking forward to providing in updated upcoming conferences. The solid tumor data, as they mature, we expect, we'll be able to better understand the potential of these cells as we have more mature time on study from these patients. Multiple myeloma is an indication in which again, as I mentioned earlier, still is an unmet need. And what we will be doing is we've now demonstrated that we could administer the cells without lymphodepletion. And now we have an opportunity to look at super targeting with an armored BCMA CAR therapy, which Eleni is going to tell you about. First, Dr. Sapana is here. She's a superstar, and she is the pioneer of the data that actually has now elucidated that these cells may reinvigorate partially exhausted T cells that return them to tumor killing. Sapana?

Hi, everyone. My name is Sapana Pokharel, and I'm a leading scientist in MiNK Therapeutics, leading the project with our unmodified aphthous cell allogeneic iNKT product, agenT-797 and how it interacts with other immune cells that are critical for antitumor responses. Like Dr. Hidalgo and Dr. Einstein mentioned in their talks earlier with current immunotherapy and immunosuppression that occurs in the tumor microenvironment, there is an unmet need which needs to be addressed using novel cellular therapies just like our iNKT. Okay. Today, I'm going to hear, so you, how we can use our unmodified iNKT product to target 3 key immune cell types that are present in the tumor microenvironment and how agenT-797 can improve antitumor functions in those immune cells. First, T cells, which are the primary effector cells; second, dendritic cells, which are also known as DCs and are the key antigen-presenting cells that are known to help the recruitment and activation of T cells; and thirdly, macrophages, where often associated with immunosuppression. Today, I'm going to show you how agenT-797 firstly can reinvigorate partially exhausted T cell enhancing their killing capacity. So for this, we performed the coculture of agenT-797 with partially exhausted T cells. That we generated using our exhaustion platform, where we saw that either with coculture of partial exhausted T cells with agenT-797 or supernatant from preactive agenT-797 that contains the soluble factors secreted by this iNKT, you see enhancement of killing of these partially exhausted T cells as shown in the graph on the left. Furthermore, we wanted to investigate if we can utilize agenT-797 to target myeloid cell in a way that you can improve the antitumor functions of this myeloid cells and then promote immunostimulatory effect. For that, we performed coculture of agenT-797 with dendritic cells. where you can nicely see in the panel in the middle here that agenT-797 was able to activate the DCs as shown by the enhancement of co-stimulatory molecule expression like CD80, CD86, which is associated with T cell activation. And not only the iNKTs, we're able to activate the DCs, but the DCs were also in turn able to act with iNKTs. Lastly, we wanted to address one of the major challenges that remains in the immunotherapy field, which is how do we reduce the suppression that happens to the immune cells in the tumor microenvironment. And for this, we performed the coculture of agenT-797 with pro-inflammatory M1 macrophages, which is actually beneficial to the antitumor function and immunosuppressive M2 macrophages, which actually is detrimental to the tumor macro environment. When we performed the coculture of agenT-797 with either of these macrophages, we're nicely able to saw as shown in the panel on the right, that agenT-797, we're able to selectively target immunosuppressive M2 macrophages, while preserving M1 macrophages with a pro-inflammatory effect. So altogether, our data nicely shows that agenT-797 can promote the antitumor functions of partial exhaust T cell by returning their killing potential, activating the dendritic cells and targeting the immunosuppressive M2 macrophages, altogether creating a hostile environment for tumor cells to grow. And next, you will hear from Xavier and Eleni on how we can further engineer these iNKTs to further enhance their antitumor functions. Thank you.

Thank you very much, Sapana. You've heard it first here. This is going to be really magnificent building on these mechanisms that we're observing now. And to tell you more about our capabilities is Dr. Marc van Dijk, our Chief Scientific Officer. Marc and I have been partnered together for about 13 years, where we had been working with Agenus, the parent company of MiNK. And Marc is a molecular biologist, technologist, who had delivered the antibody -- created the antibody discovery platforms at Medarex, at Genmab and later at Agenus, which has given rise to some remarkable molecules, including the subject of the plenary session at SITC on Saturday. So Marc is going to talk to you about how we've leveraged our tools and technology to now engineer these cells for super targeting. And you'll hear about two of our engineered CAR platforms that are advancing into IND-enabling studies now for first-in-man studies to start early next year. We'll hear from 2 of the lead scientists behind those platforms, and then we'll turn to the data -- the clinical data that we have in ARDS.

Thanks, Jen. Okay. I'm Dutch. I'm a little taller. So let's see if it holds up here. Okay. So pretty cool cells. Can we make them even better? Yes, of course. And why? Because solid tumors do present a formidable barrier for T cells and CAR T cells and also for cell therapy in general. And Manuel Hidalgo has laid out the field and actually shown that, yes, we have made a major difference with IO therapy. Still people progress. There's still also people that don't respond. And a lot of the reasons why they don't respond has to do with the work that we've heard resistance, immune suppression, the environment within the tumor that actually keeps T cells out. So what do you do with this? We actually think that cell therapy can actually make a huge difference in the paradigm by which we treat solid tumors. And we do this also by enhancing the cells in a way that actually makes them even better than the natural state. We have 2 platforms that I'm going to introduce you today, one for chimeric antigen receptors and one for bispecific iNKT cell engagers that are both intended to increase tumor homing and also activity within the tumor and make these cells even better at overcoming resistance than they already are, by nature. The big thing with the immune therapy is this resistance. So what do you need to do to actually overcome that is once you have to have a cell type that is able to, already by nature, counter some of the mechanisms that actually suppress the activity within tumors. And Sapana has very elegantly shown that we have evidence that these mechanisms by the cells themselves already are able to change some of the microenvironment in favor of actually an antitumor response. We also don't use lymphodepletion and that's important not just because it's easier for the patients, it's also better because you have more of the immune system around to then take over and actually get actively engaged when the tumor microenvironment changes. What else can we actually do to this strategy make this better is to add properties to these cells that make them even stronger. And that is actually by adding CAR, so chimeric antigen receptors that really enhance the activity of these cells, specifically within tumors and also by redirecting more of these cells to tumors with the bispecific antibodies. And we have 2 platforms for this. I'm going to focus today on our CAR platform, and I'll update everybody next year when we progress to mature the platform for iNKT cell engagers. But today, I'm focusing on our CAR platform. We call this CARDIS. It stands for CAR display for reasons that I'll actually show you in a few minutes. And what are chimeric antigen receptors just as a brief recap. There are custom-built receptors that actually have 2 parts. One part actually is what sticks out of the cell is the part that recognizes the tumor targets. It's an antibody part. And we actually engineered that to very specifically recognize tumor targets with a very specific binding strength. That's important. The solid tumors actually have targets that are very specific and overregulated on solid tumors, but they're also expressed on normal cells that you don't want to kill. So you have to really create that therapeutic window very, very specifically. And that's why we built the way we -- we build our platform, the way we build it. There is an obvious synergy between the top part that recognizes the tumor and the bottom part that actually conveys the signal to the iNKT cells when the tumor target has been recognized, and that you need to tune very carefully. So there is a synergy between the top and bottom part of a CAR. There's also a synergy between the CAR and the iNKT cells, in which we want these cars to act. And that's because the cells don't just react to the CAR you put in there, so the tumor target it recognizes, it actually also reacts to all the other ligands that these iNKT cells naturally recognize. The TCR recognizes CD1d and myeloid cells that actually are potent suppressors. The NK receptors react to stress ligands expressed on tumor cells and together, this integrated response actually starts a whole cascade that ends up not only killing the tumor cells, but also changing the environment and bringing in other cell types. And that's the reason why we think iNKT cells are such a good host. They're not just only able to directly kill tumor cells, they also change the environment, and we can beef up their activity by actually adding CARs to these cells and armor, which I'm going to talk about later. So how do we do this? How do make these CARs work very well together, the top and bottom part and also work very well in iNKT cells? We have our own platform. We have 2 platforms And for CARs, we use this long-standing experience we have with antibody-based drugs that Jen alluded to. We use the antibody parts to actually build the top parts of our CARs. And then we very cleverly have a technology that actually allows us to integrate this antibody parts with the signaling parts and really find the best goldilocks activity combination between the top and bottom part. So this is a typical screening funnel that everybody who does drug screening knows. You start with a huge amount of molecules. At the top, it could be small molecules. It can be antibodies. And then you work your way down through several steps to the ones that actually brings you the final candidate that you're going to put into your products. Traditionally, for CARs, most people stick with the antibody part for most of the journey. And only at the very bottom, you convert it into CARs and then you sort of look one by one what's going on. We think that's not good enough. You actually compromise on the numbers. You don't -- you really not able to pick the best CAR if you do this so late. We do this a lot earlier. So we have built a specifically value-added step in this process, which we call CAR display. The reason for that is that we are able to, very early on in the process, already put a lot of antibody pieces on CARs in specific reporter cells that we can then interrogate for the exact function that we're looking for. How do we do this? We actually have a special custom-built reported T cell that we can grow to large quantities, put a lot of different CARs in there. And at this stage, we're talking about up to 1 million different CAR molecules. Each cell has 1 CAR molecule with a specific antibody portion, and they're all together in one big library. What do we do with this library? We actually add tumor cells to this mix, incubate them for a while. And then those CAR cells, those library cells that actually have a CAR that responds to the tumor in the right way, they light up. And with this light signature, we can isolate them from the library, and we immediately have, also based on the strength of the light signal, the CARs that have the function we're looking for, that recognize the target we want to recognize and do not have background activity. That's important. And why that's important? Well, this is a bit of an example from our BCMA screening campaign, which Eleni will go over to later. It actually shows you in the red circle that only 1% -- less than 1% of the antibody binding portions that already recognize the tumor targets are able to support a functional CAR. And an even smaller proportion of this 1% is the CAR that you're looking for with the exact level of signal activity you're looking for, and that's crucial for solid tumors. As I mentioned, you need to know your therapeutic window. You need to pick the spot where you want the activity because you want to just kill the tumor cells and nothing else. So this is why we built our platform the way we built our platform. But we not only build these cells with CARs, we also armor them. And by the way, we actually put so much NGS and bioinformatics works in this process, they're not just armor trucks, they're actually cyber trucks by this time. So anyway, I'll have to get [indiscernible]. So this is what we do. We built a platform that allows us to build CARs for solid tumors, very effectively, very precisely, and we armor them. And in this case, we armor them with interleukin-15, which is a cytokine that's crucial not only for iNKT cells because it drives persistence, but it also recruits and activates NK and T cells that are already in the tumor that they can bring into the tumor. And this package is even better than a cyber truck, I would say. So -- and now we're going to talk about 2 of our programs. First, we're going to talk about MiNK-215. This is a solid tumor targeting CAR iNKT product that secretes IL-15, which targets fibroblast activating protein, which is really key to tumor stroma and resistance. And then we're going to talk about our BCMA next-generation iNKT CAR program. Xavier, the floor is yours.

Good afternoon, everyone. My name is Xavier Michelet. One of my responsibilities at MiNK Therapeutics is to actually elucidate the mechanism drug of action of the cell therapy products that we develop. And today, I will show you the most -- the data on the most recent innovation, which is a FAP-CAR-iNKT that targets the tumor environment and it's a really great opportunity actually to provide curative potential for solid tumors. So sorry, I lost my words. Despite the tremendous excitement generated by CAR-T therapies for leukemias and multiple myelomas, they reveal themselves poorly effective towards solid tumors. And even if those CAR-Ts are very efficient to target the tumor cells, they reveal themselves actually poorly effective to infiltrate and survive the core of the tumors. This core is extremely immunosuppressive. What does it mean? It means that it exclude any T cells or could directly target and suppose to target and kill those tumor cells. MiNK FAP-CAR is changing this part, indirectly targeting the tumor environment to allow those T cells to reinfiltrate and kill those tumor cells. And to evaluate the curative potential of the MiNK FAP-CAR, we degenerated non-small cell lung cancer mouse model, that's a mouse model. And this model is not only an example of -- sorry, it's not only a model that represents one of the most prevalent and deadly cancers but also is the perfect example, where we can show where actually the immune system and some of the PD-1 therapies are currently failing and where we do believe that the MiNK FAP-CAR can turn the tide. In this model, as you can see, the tumor cells express the markers that allow us to track the development of the tumor within the lung of the mice, as you can see on these pictures. These mouse are completely immunodeficient. So they do not have any immune system. So for that, we do infuse them with the FAP-CAR iNKT cells, but also with T cells that are specifically designed to target the tumor cells. So what about the data? When we look at the data. When the mice were infused with FAP-CAR iNKTs only, which is a red dash line, we didn't see an increase in the survival of this mice, which indicates the first mechanism of action here, which is what is like by targeting the tumor environment, the tumors, it impairs the capability of the tumor to actually engraft and develop itself as a [indiscernible]. Interestingly, when infused with T cells only and these T cells are targeting directly the tumors, we did observe an increase of the survival, but it's not good enough. Most of those mice end up dying, despite the fact once again that they are supposed to kill the tumor. There are not. However, when actually this mice, they do have a bit of these T cells and infused with FAP-CAR iNKT cells, we did observe over 90% of survival of this mice 100 days post tumor challenge, which is really impressive. But the most interesting part is that 6 days post tumor implantation -- 6 days post treatment, sorry. As you can see onto the images on the bottom right, this mice didn't show any more tumor burden. It's like they were almost completely cured of this count, as you see by the absence of the signals. Well, actually, my strategy was that T-cells the tumor burden remaining changes you can see. That suggests the second mechanism. That's a FAP-CAR iNKT cells were able to enhance the activity of these T cells to promote the curative response. And if you are wondering where are the missing mice, they are actually in the next slide. So the question remains, how does the FAP-CAR iNKT cells can enhance activity on the T-cells. And to answer that question, we're actually looking a bit more in detail in those lung tumor tissues. And those images, you can see, in blue are represented all the cells presented in there, normal cells, tumor cells, cancer cells. In orange, you have the tumor cells itself. And in yellow, are all those tumor-specific T cells that are supposed to cure the tumors. And on the left side, in the images of a lung treated with only the T cells. As you can say, in absence of the FAP-CAR iNKT, those T cells even if they are present in the lung tumor tissue, this seems to be enable to infiltrate the core of the tumor tissue present at the bottom here. However, when treated with FAP-CAR iNKTs, the image on the right, not only we found like ten-fold more T cells in her -- on tail end of this mice, we also found that those tumor-specific cells are extremely close to each tumor cells. And like as you can see on these images, it seems like those T cells are embedded within the core of tumor, so they get in. When we look at the numbers, we observe that there is three-fold more CD8 positive T cells, tumor-specific T cells that are inside the core of the tumors that compared to [indiscernible]. So I showed you today that the FAP-CAR iNKT cell can promote a curative response in this model by 2 different mechanism: first, it will impair the engraftment and the development of the tumor itself; and secondly, it will actually enhance the activity of the [ T cell ] in promoting their infiltration and their survival inside the core of the tumors, an area that is usually unreachable for them. And one very important point to remember that the FAP-CAR iNKT is the first of a kind product that showed tremendous benefit in this lung tumor content model. It is difficult to treat, but also towards a target that is widely expressed [indiscernible] encounters. Thank you very much.

Excellent. Xavier, thank you very much. The engineering capabilities that Marc spoke about earlier, were, of course, applied to this technology targeting for the first time the type of biology showing the elimination of cancer this powerfully to a FAP target, which, as Xav mentioned, is really widely expressed on a number of different solid tumor cancer. So it's hugely opportunistic, and we're quite excited about it. Further, will that technology now allow us to break barriers and improve upon what is currently available for patients with multiple myeloma, Eleni is going to tell you how we can.

Thank you, Jen. So I'm Eleni Chantzoura. I'm the Director of Discovery in MiNK Therapeutics. And in the next few minutes, I'm going to introduce you MiNK-413. And I know what you are thinking, but this is not another BCMA CAR-T cell therapy. And I will go through why. We designed this product having in mind the limitations of the current approaches. Xav mentioned tremendous excitement with CAR-T cell therapy in multiple myeloma. But the truth is that only 2 weeks ago, FDA gave accelerated approval to a BCMA bispecific that has an overall response rate of around 60% and less than 30% complete response rate. And to me, this shows that there is a lot of room for improvement. And these are some of the limitations of the current treatment that we try to address with MiNK-413. And one of the parts of improvement is obviously the CAR. Marc very nicely introduced you to our CARDIS platform and also to what a CAR is. So just a reminder a CAR is -- a CAR consists of 2 domains: the binding domain, usually an antibody, but it can be also an antibody or anything else that recognize the target of interest; and the activating domain that activate the iNKT cells in order to kill the tumor, and this acts synergistically. And this is what we have taken into consideration in our CARDIS platform. So we start with a selection process. Imagine that we have around 10 billion different sequences. We select for BCMA binding and we end up with a couple of million. But then we transform into a CAR format and expressing in mammalian cells. And from this actually 2 million, only around 20% to 25% for a CAR or binding as a CAR, so we can get rid of all this noise very fast, as you can see here in the middle of a tumor. Even more interestingly, from this 20%, most of the CARs are actually not functional, and -- so this is around 70%. And also, what I found very dangerous is that around 10% of them are functional, but they are not specific. So they can be activated by other cells as well that do not express BCMA. As Marc said, less than 1% of the initial binders as antibodies actually are functional CARs. But for me, the most important thing here is that functionality doesn't really correlate with binding. And when you have CARs there, that are the strongest binders, obviously, they are not the strongest soldiers. And we want to take our strongest soldiers in our battle with cancer. The next thing that actually has to do with our CARs platform as well is the clinical challenges. And the clinical challenges can be lymphodepletion-related toxicities, can be lack of persistence or can be the phenotype of a T cell. So I have to say at this point that our libraries are fully human. The CAR-T cell products that are now in the market are humanized, which means that they can use immunogenicity which decreases in persistence, whereas ours are free of tumor. And also, obviously, you have seen this figure before, we are using iNKT cells. And iNKT cells have different mechanisms to kill the tumor. Obviously, the express of CAR recognizes BCMA. Through the invariant TCR, that Jen mentioned at the beginning, they recognize CD1b, which is actually expressed very highly in multiple myeloma cells. And they have -- they experienced the natural killer cell activating receptors that recognize special items on the cancer cells, but also they do not express the inhibitory receptors that NK cells express. What I personally, however, find fascinating is that iNKT cells are great team players. They activate -- they recruit and activate the T cells and iNK cells of the [indiscernible] immune system, which means that they keep working even after they disappear because they have activated the immune system. It's like my favorite saying, it says, [ give him money fees and he can meet for 1 day. ] But if you teach them to face, they can have food for the rest of their lives. And this is what actually iNKT cells do. It teach the rest of the cells how to react to the tumor. Another thing that both Sapana and Xav mentioned was tumor microenvironment. iNKT cells counteract the hostile tumor microenvironment, which actually very recently has been shown to affect the persistence of the T cells and to lead to relapse after BCMA CAR-T cell treatment in the liquid tumors. Furthermore, as it was found very nicely from the clinical trials, we do believe that BCMA CAR iNKT cell therapy will need lymphodepletion, which means that we can avoid this kind of lymphodepletion-related toxicities, and iNKT cells naturally hones the bone marrow. Even after discussing the clinical challenges of the current therapies, I think the most formidable challenges have to do with the manufacturing. We have autologous cell therapies that they use cells from heavy predicted patients through a very long manufacturing process, which means that there is a high failure rate, but also then product is very unpredictable and very diverse. This process lasts 4 weeks. And unfortunately, many of these patients do not have this time. The process, even though there is like a huge evolution in the manufacturing processes and protocols, still this is not accessible to many people and also very expensive. Joy is going to go into more details in a bit, but what we have done by leveraging our experience with agenT-797 is that we have developed an in-house manufacturing process that consists of 3 steps: iNKT isolation, transduction and enrichment. And I saw this here because we can start with a very low transaction efficiency and they reach the cells over 80%, which means that we keep the genetic modification very limited, a very low [ copy ] number. So this process can give up to 5,000 doses from a single healthy donor. It is scalable, reproducible, robust. And it's going to save, right. And so to conclude, we don't believe [indiscernible] it's another BCMA CAR-T cell therapy. We have built the best CAR to express it in the best iNKT cells, which are also armored since express IL-15, and we have a manufacturing procedure that is going to give -- that it's going to make it accessible to many patients while they need the characteristics of the cells and their functionality. Thank you.

Dr. Joy Zhou has been an expert in cell therapy, a leader in the field actually with leading the cell therapy charge at Takeda, J&J and joining us just earlier this year. She fully internalized the manufacturing process at MiNK, and we are now able to manufacture cells in our own house without the capital-intensive requirements commonly associated with CAR-T manufacturing or cell therapy manufacturing overall. Joy?

Thank you very much for the introduction. My name is [indiscernible] VP at MinK therapeutics. I have been medium cell and biologic product development as well as GMP production for over 20 years. As you already heard from today's our [indiscernible] speakers and also our outstanding internal researchers, how amazing the sense about our iNKT cells can potentially offer curative treatment to the patients with cancer and/or [Audio Gap] diseases. Now I wanted to [Audio Gap] about how in CMC overcome the CMC cell therapy, large- scale manufacturing challenges to allow us to transform these amazing signs into actual accessible and affordable off-the-shelf product to benefit our patients. As we all know, for the cell therapy, the biggest challenge is to produce multiple badges from 1 donor to reach many patients as well as donor dependency. For all the autologous drugs products available on the market, like the patient to their own set -- that's not only to lead to high cost of production, in most cases, it will cost more than $0.5 million per treatment, but also limits the product to the patients. Now at MiNK, we develop our iNKT cells into allogeneic off-the-shelf products, which should be easily accessible and available to the patient via our large-scale manufacturing. You may ask, how would you be able to achieve that scale is get manufacturing from 1 dose per patient to more than 5,000 dose in package. Our unique and proprietary manufacturing process combines our unique reagent large-scale cutting-edge technology for cell expansion, cell purification and fill finish with minimal dependence on the donor. The donor -- this is automatic large-scale manufacturing process with limited donor dependency allow us to manufacture [Audio Gap] doses provided and also multiple batches per donor. That would drive down our cost of goods significantly less than 5% of our current available cell therapy product. Besides our fully internalized manufacturing capacity well positions in a strong position to ensure stable, timely and robust product supply product supply. Now with our accumulated knowledge and [Audio Gap] manufacturing experience, we are confident that we are able to deliver more than 600 doses per year to meet our commercial -- or to meet our potential commercial demand. To conclude, our MiNK right now is ready to transform our novel iNKT cells into an accessible sorry, rather accessible and affordable product to benefit millions of patients in the very near future. Thank you very much for your attention.

I'm just going to add a couple of zeros to your doses per year, 600,000 doses per year from our internal manufacturing. Very well done. As a result of the effort that Joe has launched at MiNK, we've been able to supply cells to be at the sites when the patients need them, and that's no more important than patients who are really in the ICU suffering at the edge of life. And I have to honor Dr. Terese Hammond, who's with us tonight, who at the beginning of the pandemic before we even understood what this virus that we were facing was, she was on the front lines and treating patients with their own hands in that in a set thing where even autopsies were being eliminated. Dr. Hammond was actually going in invasively getting samples and sending them to the NIH so that we could better study and understand the virus threat that we were facing. We had the great fortune of working with Terese as a leader on our Phase I clinical trial, where she courageously took these cells and administered them to patients and she's going to share the outcome of our trial results now. Dr. Hammond.

Thank you, Jen, for your kind words. I hope I can live up to this during the presentation. I'm very honored to be here. And it's through the I think the vision of Jen, the amazing scientists from MiNK and my dear friend, Steve O'Day from Agenus that I'm able to tell you a very unique story today. And hopefully, this will be the first chapter of a book that evolves and becomes a very, very long story for these unique cells. Maybe it's because we're both first responders that I feel so devoted to these cells or maybe I'm just a little [Audio Gap]. And I was able to -- the honor of being able to treat 5 critically ill patients with COVID-19 respiratory failure with these unique iNKT cells. And to be honest, I just want to sort of set the stage for you to frame this in a different way because I know that really, you've been hearing about solid organ and about cancer today and through SITC. But I just -- I aim to sort of convince you the critical illness, respiratory failure invasive infection that cause sepsis, COVID-19, killed many, many more people at a much -- with much more lethality than most cancers now. Because, frankly, oncologists have been leading the way. It's hard for me to admit that as a pulmonary critical care doctor, but oncologists have really forged the path for cell therapy and for making advancements and how they treated their patients that now I think it's time for us in other fields of medicine to sort of embrace. The ability to use cell therapies and critical illness, I think is just sort of coming to the forefront. Again, these cells are so special. They are able to go to areas of damaged tissue whether it's the lung, the kidney, the liver, they're able to really have a situational awareness in those tissues to activate the right components of the immune system. And at least in our patients, they were able to -- in these very early trials show really astonishing survival benefits. And this includes in the very sickest patients. I personally gave these cells to 5 of my patients [Audio Gap] so sick that they would have died without the most advanced therapy we have, which is a lung bypass machine, something called extracorporeal membrane oxygenation or ECMO. Essentially, when the lawsuit that they can't even extract oxygen or give oxygen or extract CO2. [Audio Gap] blood and then returning it back to the patient. And we were able for this [Audio Gap] on this lung bypass machine all in the third cohort. So they received $1 billion of these special cells. And I think as you've heard to give a billion cells in a community setting, so we got these cells Mr. Frosty and our pharmacy, we were able to use a plasma therm to thaw them, and we were able to infuse them in patients that were in my ICU on tremendous mechanical support successfully. We were able to do it with essentially no side effects. We had 1 significant event that we reported, but it was probably related more to COVID than anything else. Without any cytokine release syndrome, we were able to give these cells to these patients. And we were able to improve survival. Now at the beginning of the pandemic, I think I speak for a lot of clinical people, a lot of physicians that were at bedside. We had very little that we could offer patients with severe COVID or respiratory failure there. In the first 2 cohorts of the study that I'm talking about and talked about this morning, elderly patients who were placed on mechanical ventilators for COVID, at least in my institution, 90% of them died. And I think that, that sort of bore out across the board. As COVID advanced, as COVID continued as the pandemic evolved, we started to use steroids and other therapies, monoclonals. With Dr. O'Day, we were able to actually be part of trials for monoclonal antibodies. And that improved survival, but it also presented another problem because as these patients were on steroids [Audio Gap] survived the first 2 weeks or 3 weeks of their COVID, they often succumbed to systemic fungal infection or health care associated or acquired pneumonia? So not only were these cells were able to get both activating cytokine release syndrome. But we were also able to do it in a way that these cells significantly reduced the forms of infection in these patients that were treated. And we were able to demonstrate at least in these 20 patients that we increased the anti-inflammatory response. We also decreased the amount of pro-inflammatory cytokines that were seen pre and post treatment in these patients. And overall, a cohort of people that had an average -- 60% more survival -- or mortality rate, a 40% survival. We were able to demonstrate 70% survival rate, [Audio Gap] 25%. Finally, in this study, we were also able to show that there's just a transient autoantibody production when the cells were given to these patients. By day 14, those auto antibodies were even the ones that were circulating there, were going away. So there's a potential to redose these cells and people that remain critically ill. So in the few minutes that we've had together, I hope that you've sensed my passion for using these very unique cells in other modalities in other ways, beyond cancer and critical illness. I think there are multiple aspirational visions of how these cells could be used in critical illness beyond just acute lung failure beyond COVID-19. COVID-19 has certainly given us all an opportunity to collaborate. And I think that again, because of Jen's vision, we've all been able to come together and do something very unique here in -- at the bed side that I hope becomes a much greater -- much bigger and much greater story as it plays out. But I guess I just sort of want to end with the concept that we have a much bigger opportunity with cell therapy in critical illness. And I'm optimistic, I'm excited and I'm enthusiastic to continue to offer these kind of novel therapies to patients that I care for in the intensive care unit who have very little chance of surviving with the traditional therapies that we use now. So this is really, while early, has certainly given us great enthusiasm and promise that we'll be able to better treat these patients at some time in the future. Thank you very much.

Thank you very much, Dr. Hammond. We share your passion for this. And the data that we've generated through these trials have actually generated the interest of DARPA to start to advance this science even further, it's so novel. DARPA, as we believe that these cells may actually be more -- be beneficial beyond what we're seeing with respect to anti-inflammatory, pro-inflammatory cytokine release stimulation also immune disregulation as a whole. So we're in discussions with DARPA now and going into the contracting process to support the advancement of these cells and treating the types of illnesses that Dr. Hammond share with you. I'm going to ask Dr. Marco [indiscernible] to just share a couple of words about some of the translational findings. Marco has been working with some of the world's experts in identifying ways in which we can understand the persistence bioavailability of these cells. Where are they going when we dose them. We've shown some data preclinically, but now we're going to continue to expand that clinically. We are showing some preliminary data at this time and more data will be coming out towards the end of this year that will help us understand where the sales are tracking to you? And what are they doing when they get at their will further explain some of the key features and benefits that we're observing in the clinic. Marco?

Thank you, Jen. So my name is Marco [indiscernible], I'm Director of Translational Research at MiNK Therapeutics [Audio Gap] for the best part of the last 10 years, I've been working towards bringing iNKT cells into therapeutic applications. So I'm very excited to work with MiNK, who are the leading company in bringing [Audio Gap] into therapy and pretty duct things in the plan to modifying T cells. So as some of the team previously [Audio Gap] they have mentioned agenT-797 is MiNK Therapeutics, unmodified. And as you've heard today, iNKT cells [Audio Gap] so they have a pretty broad specificity pretty reaction. The activity span the pro and anti-inflammatory spectrum. So we are -- we believe that iNKT cells have applications in multiple fields given the variety of reactivities. And we have been using, as you've heard, iNKT cells and clinical trials in diverse settings, including [Audio Gap] and COVID as well as settings and cancer, including multiple myeloma and solid tumors. And I think our idea that iNKT cells are able to act in these different settings is kind of validated by the results we've seen to date, the encouraging initial results from our cancer trials, showing induction of stable disease and also the robust data from our COVID trial. So how do we think that anchor T cells are working in these different settings. So obviously, in solid tumors, for example, in the solid tumor settings, in progressive tumors in particular tumors are refractory to current treatments. They tend to be highly immunosuppressive and the tumor microenvironment is immunosuppressive. Now as you've heard, iNKT cells are able to counteract the immunosuppressive effects within tumors, but target myeloid cells, suppressive myeloid cells and also recruiting immune effector cells, downstream immune effector cells, in particular, NK cells and cytotoxic T cells. So we would hope to see in the solid tumor setting that there are signatures, biosignatures of actually pro-inflammatory activity induced by the iNKT cells. In the odd setting the COVID-desginated odd setting hyperactivated immune system, which basically leads to hyperactivated immune cells, which induce injury of the lung. So in the core COVID, we would hope that's the -- by reducing the inflammatory environment and inducing an anti-inflammatory immune response. So it seems that our [Audio Gap] actually indicated that these differential effects are occurring in each respective trial. So here you can see data from interferon gamma levels in serum from our solid tumor trial. As you can see, and has been mentioned by David Einstein, that there is a spike in different gamma on the second day of treatment. In our patients, this does seem to be dose level related. It is most with the patients treated with the higher does. Now as mentioned in an gamma is the key proinflammatory cited guidance preceded by iNKT cells indicating that agenT-797, in this case, is activating antiinflammatory mechanism in solid tumor. Now we see this only in our solid tumor study. We haven't seen this in a our study despite an [Audio Gap], and we haven't seen it in now multiple myeloma study. So this does seem to be an effect of agent-797 in the context of solid tumors. And you should remember, that in solid tumors, the actual activity is going to be highly localized where the tumor is. The fact that we can detect it in digital areas and serum is encouraging and would tell us that actually, there's a lot more to see in the tumor. So we do have tumor material, localized tumor material. And currently, the analysis of that is ongoing. And hopefully, we will have our initial readouts on the actual tumor material and biomarkers by the end of the year. In the COVID adds setting, is entirely different. In those cases as mentioned, we see no indications that there is an enhancement of TH1 infringement Th1 proinflammatory activity. And as previously mentioned there is action in the COVID odd setting. But instead, what we observe is a durable and quite impressive increase in the key anti-inflammatory cytokine into looking 1 receptor antagonist, so IL-1Ra. The mechanism of how this works. It's not a cytokine by T cells have this exactly works is not fully elucidated, but there are many candidates who secrete [Audio Gap]. But the fact that we see this increase in the setting of covered and hard, again, would indicate that iNKT cells are driving an anti-inflammatory response in this setting. [Audio Gap] response, which would downregulate the hyperactivated immune system and the therefore mitigate lung disease. Another thing [Audio Gap]. So it is now that IT cells are refractory -- or more refractory to the effects of immunosuppressive T cells iNKT cells, for example. But we would see from here that actually the iNKT cells can modify with inpatient patients treated with immunosuppressive steroids that the iNKT can nevertheless modified the cytokine profile in these patients. So they are active in these spaces where other cell therapies may not be active. And if you basically compare these different -- very different settings and the activity of the iNKT cells in these different settings, you will see that the INKT cells are able to respond differentially and that they are responding in a contact-specific manner, which again is quite a unique capability of iNKT cells. They don't seem to behave like a traditional monotherapy. They seem to be a lot more adaptable in their responses.

Marco, thank you very much. So I think what really resonated with me on the translational data that we're observing is that the iNKTs themselves are actually addressing biology that we're trying to address with other therapeutic modalities and they're doing it on their own. Our final speaker before we go to your questions is Dr. Lidya Lynch, and I'm so thrilled that she's our closer for tonight because I think of her in some ways as my therapist, my cell therapist because I often go to her, and I say, "Oh my God, you the world [Audio Gap] iNKT cells or T cells, what is the best cell type to use. I'm completely consumed by iNKT cells, do you agree. So I've asked her, I'm hoping she's going to answer it in a way that I'd like her to an I've asked to give you a picture of what she sees, what she knows about these cells and where she thinks the possibilities are for the application of these cells beyond some of the observations that you've seen tonight, Lidya?

Thank you so much, Jen, and to MiNK. I'm really delighted to be here. It's a setting that I'm not used to speaking in because I've come in with the view of the basic biology of AT cells. And -- as Jen mentioned, I don't just study in iNKT cells. There's a group of an innate cells. There's gammadelta cells and made cells as well. And they're grouped together because they're set apart from all the other T cells, which recognize MHC and peptide these do not. But they -- and I have really quite unbiased because I like them all. And the features of these -- so I'm going to talk to you today about why I feel these are particularly exciting in cancer but also in other future directions because we're not with these innate T cells were not limited to cancer. So we've heard today, this is just a summary. Some of the reasons why [Audio Gap], we have been less successful therapies directed on yet [Audio Gap] cells, for example, have difficulty traffic and infiltrating into the solid tumor. Once they're in there, it's quite a hostile environment that can be hypoxic. It could be nutrient-deprived but also [Audio Gap] product is really very important. And if you require autologous T cells, a patient with cancer is often older and also has cancer. And [Audio Gap] game. So there is an unbiased competition in the lab, which I'm convinced innate T cells are the belt would win. And so iNKT cells as we've heard, they can kill, they can kill in vitro, they can kill in vivo. They do a very good job. We also -- they also help other cells to kill. They're transactivators. This is why I think they're so potent. We know the antigen, and we can expand them. And this is a really key feature because it's actually unprecedented the expansion that you can get with iNKT cells. Mate cells, on the other hand, can also kill tumors in vitro -- but if you look at a lot of different solid tumors and look at single cell sequencing, make cells have the potential to turn bad in the tumor. They can produce IL-17, which is associated with metastasis and so maybe you don't want them there. whereas iNKT cells don't. They may require antigen, but 1 feature of Mate cells is that they're very limited in their expansion. -- model T cells can also kill. They don't produce IL-17 in humans, they do in mice, but not really much in human tumors. However, they can also turn into wound healers in the tumor, which you might not want -- they don't require our antigen, which initially might think is a good thing, but it means that we can't expand them. We are very limited in the expansion. And so for this reason, in the tenant in [Audio Gap] MiNK we believe I think to can naturally address the problems recurring to the active cell therapy. -- they can recognize CD1d an antigen via lipid and also [Audio Gap] they can also recognize stressed tumor cells specifically. They are naturally home to tissues, same work site in an Marc's slab and also image bank we condition, which is what the -- we've been studying this for a long time, and we've been waiting for this to finally be realized that they are probably the best living medicine that we have. And I think today, we've seen that actually MiNK have demonstrated how iNKT cells are the -- agree with our own bias competition. They are an excellent choice for immunotherapy and they've actually proven that the inherent features that I've just mentioned that we've been talking about for 10 years, and we long suspected would be beneficial for adoptive cell therapy actually are. So -- sorry, the question is for -- thinking to the future of iNKT cells, how might we make them better. And so here, we've heard like 3 or 4 different ways that they've already -- that MiNK has already tried to make them better. Xavier's presentation on [Audio Gap] T-cell is the most exciting work that I've probably seen about 5 years. That's the nature for publication already. I think it's amazing. And then also the other [Audio Gap] and all the other modifications -- but 1 thing that we're interested in because my lab study immuno metabolism, the things that you'll be -- you don't enhance them even further is metabolic reprogram and to help them deal with the harsh tumor environment. And so here's just some reasons why we know -- actually, you probably all know this, in the tumor, it's hypoxic, the tumor is very metabolically active component of lactate. All of these things can impair the T cells once they finally get into the tumor. And so we have -- we kind of know these iNKT cells inside out by now. And so here's just an example. We've felt a multiomic approach to see what pathways they use, what transcriptional programs, what metabolic programs they use. Here's just a little example of iNKT cells at steady state, iNKT cells 4 hours after [Audio Gap] activation, which is when they're producing a lot of cytokines and after 72 hours, which is when they're proliferating. And we're able to see what metabolic pathways and what cytokines they need for each of the features that they do. And then just as a proof of principle, what we're calling [ calls ] marvelous medicine, we have tweaked the food that we feed them to help them to overcome the harsh environment of the tumor. And this -- here, this picture just shows that we've been able to improve the metabolic fitness of the innate T cells. We have been able to make -- have more mitochondria, which is important for the longevity of the tumor, and these are just plots of seahorse, which measures their energetic activation. So here, Gen 1 is the starting material of metabolic enhancements [Audio Gap] fitnesses in vivo and humanized mouse models. And so here, when we can metabolically enhance them, we can see clear infiltration, increased infiltration and survival in the tumor, and they keep their metabolic fitness and as a result, the tumor has decreased. And these are already [Audio Gap]. This is the beyond cancerous immune system. And we've heard today a lot about cancer and also infection, but it's not the only side of iNKT cells. They have also been implicated in graft versus host disease, in weight -- -- body weight, energy expenditure and metabolism helping to restore a metabolic disorder and obesity. And that's probably because they are like smart cells. This is just an example of how we may -- because we have a lot of information of the different cells -- or the different things that they produce. And what they need to produce them we could take, for example, the ones that make [Audio Gap] infection. But also there's a small population that make [Audio Gap]. And these may [Audio Gap] situation versus [Audio Gap] or when you actively transfer them back in, the metabolic disorder was restored and also the most last week, not through any sickness behavior, but through increase of energy expenditure. So Finally, I hope this kind of is a little snapshot shown that iNKT cells are versatile. They transactivator cells. They've been known to be the conductors of the immune cell orchestra. MiNK have shown that they can be expanded beyond anything we had hoped, and they can also be manipulated for distinct functions in different diseases. Thank you.

Thank you. Thank you very much to our speakers, our panelists our presenters. I want to open up the floor for questions. [Operator Instructions].

Kalpit Patel from B. Riley. Maybe a couple of questions, starting with Dr. David Einstein, I understand that these data in solid tumors are still a little early. But are you seeing any evidence of deepening of responses over time in those select patients with stable disease.

[Audio Gap] so we haven't seen, I think, enough time point to make.

Okay. And then there was a chart in the presentation showing modulation of interferon gamma. There are certain spikes in certain patients [Audio Gap] did that correlate with stable disease? Or do we not have that data?

That is a good question. Marco might be able to talk about that. I remember that we have the information about different dose levels, but I don't know.

Increased dose not that spike of both term [Audio Gap].

So it's a fairly small end. Okay. Fair enough. And then Dr. Exley that there's [Audio Gap] -- I guess, how should we think about dose escalating going forward in these patients?

That's a great question. We're already up to $1 billion. Which is certainly a lot more than you'd have normally. And they're about -- typically in patients, they're about 0.01% of your T cells. So pretty rare cells compared to 5 or more percent NK cells, mate cells and gamma delta cells that Lydia was talking about. So there's hundreds of fold difference in them compared to these other very active cells that we can increase the amount of substantially. So because we can get large quantities of them, we can have that huge therapeutic window. It really is quite unusual. So you can think of it as like antigen-specific T cells, which are pretty rare as well, sort of like that's the sort of therapeutic window you want to get.

Okay. And then one, maybe just a preclinical question for the FAP-CAR-NKT. Are there certain biomarkers that you would recommend -- valuating as this program maybe enters the clinic next year for that asset? Yes. I guess that's something that we are trying to evaluate [Audio Gap] specifically, that would be a major point, their activation, their level of infiltration. All of that will be very important to read.

Thanks, Kalpit I'll just add to that, that I think particularly in the context of top expressing tumors such as non-small cell lung cancer. We would look to go for a biomarker agnostic approach and then interrogate response both clinically as well as immunologically [Audio Gap].

This is [indiscernible] B. Riley. 1 follow-up here. So just curious, before and after the infusion of the 797, what cell population have changed in the tumor [Audio Gap] environment?

Before the administration, the characterization of the product, the formulation.

No. So within the tumor micro after the infusion of this cell therapy.

Okay. So those data are forthcoming. We've developed some very specific assays to interrogate that. Preclinically, we have made some observations and perhaps we could have Sappana speak to some of the modifications that we see intratumorally in the solid tumor preclinical model [Audio Gap] that we published last year, [Audio Gap] phenotypically administration of the cells, we can see cells can home to the tumor, persist. Any additional data that you can share now that's publicly available on [Audio Gap].

It has been a bit difficult to look at [Audio Gap].

Yes, like. So I think a lot of our preclinical studies are done in the general graph model, which like doesn't have like the other human components. And that's why we develop this in vitro assays to investigate that and we have like future direction going forward to look at it by agenT-797.

I mean, what Marco showed as you see this interferon gamma spike in the solid tumor trial. So if we do this in our xenograft model, you see that 797 is a product that is balanced in terms of Th1 H2 cytokines it produces -- the cells we retrieve from the xenograft tumors are TH1, they're all TH1. So the cells do seem to do what we think happens in the solid tumor patients, which causes this interferon gamma spike is that they are really getting pro-inflammatory when they're in the tumor. So this -- it's actually borne out by the [Audio Gap].

It's Jack [ Cowin ] here from Baird. I guess maybe to start on the preclinical side, about to hear any thoughts about the selection of IL-15. Did you evaluate other interleukins as well while looking at IL-15?

So I mean, 15 is a pretty logical point for us to start with because it's a very good cytokine for tweaking IL-15 performance specifically in cancer also. And we also know it's a critical cytokine for NK cell activity and also for T cell activity. So as a first choice for armoring, it was obvious. And also, we're not the only ones using this particular bit of armor in their cell therapy. So given what we know that NK cells and also what it does for NK cells and T cells that we know we need to attract more of in the tumor, this was a very logical first choice. We do have, of course, other cytokines and other was moved to the whole product. But for some of the CARS, you have to be a little careful because they're pretty toxi -- you can feel pursue this.

Great. And then on the clinical side, I had a question for Dr. Hammond. I was wondering of the 3 patients that responded on ECMO, you mentioned that they were, I guess, surviving out to 90 days. Did any of those patients come off of ECMO and I'd love to hear how that, I guess, aspect of the experience compared to what you'd expect without the cells?

Yes, absolutely. So there are actually 4 patients. I treated 5 patients altogether, 4 of them were on ECMO. One patient, 1 of our first patients to be treated actually had came off [Audio Gap] at a double lung transplant and kidney transplant about 5 weeks ago. The average length of time for the 4 patients that we had on ECMO was 133 days, which was pretty stoic on [Audio Gap] COVID. And so when we look at our other cohorts, our average survival time on ECMO was about 42 or 43 days. So we certainly saw that these patients were living longer. They were having less [Audio Gap] infections. 2 patients actually succumbed wanted, I think or 92 days and 1 at about 160 some days. But the reason that they died was because we was drew care, they weren't long transplant candidates, and they were unable to come off as well.

Okay. And then with the long duration response in mind, how do you think about multiple doses of cells as well, both in oncology and in the ARDS?

Yes, definitely. And I think that that's a great question, and that sort of goes to the idea we're giving 1 billion of these cells, do we need more cells? Or do we need another dose? We certainly saw that around 30 days because we were able to follow these patients out for a very long time, around 30 days, we started to see an increase in nosiconial-type infections in patients -- these patients in the first few weeks of the time that they were dosed with iNKT cells and then 5, 6, 7 weeks out, we started we did a lot of bronchoscopies and we started to see that suddenly these patients had CMV positive results from their bronchoscopies. So my gestalt my gut says that we should be redosing these patients. And the science says that it doesn't look like they're generating autoantibodies to the INKT cells -- so I think it's feasible that we could redose. But of course, I would give that back to the scientist to really speak in detail about it.

Great [Audio Gap] oncology side as well?

[Audio Gap] because we have a bank of them. thanks to join colleagues. We're able to potentially give them different ones. We should have less likely to have the risk of accelerated rejection. So I think it's very feasible, very practical and very desirable.

And Yes, from a clinical perspective, I think that certainly 1 very valuable piece of information from this trial will be the on-treatment biopsies, both for persistence of the product as well, and it addresses a prior question as well. I think from the tolerability perspective, there's every reason to think that it could be redosed. I think the real question is, do you need to? Obviously, from the patient's perspective, the fewer doses, the better. But I think that remains to be seen. What's needed for maximal effect.

Matt Phipps from William Blair. Dr. Hammond [Audio Gap], but they did report some donor-specific antibodies. So just maybe could you clarify that?

Yes. So there were some so when they were matched, MHC Class 1 was matched. We certainly saw that the more matches at the donor matches -- more matches to the donor. There are fewer auto antibodies generated in these small amounts of autoantibodies. There didn't seem to be any effect when you match the MHC Class I from a scientific perspective. But by day for we actually saw that those [Audio Gap] over the facts from dosing these cells and at least the small auto antibody that we saw decayed over a very short period of time. Would that be fair to say, Marc. He's got -- he's my collar friend.

And I guess just wondering if you have a utilities -- or do you think it's a difference given the inflammatory state of the ARDS patients.

But we also noise would letter treatment, they contain and some base -- please we have a much stronger time period in the cat brand to follow. So we basically [Audio Gap]. So we can analyze them. [Audio Gap].

Marc, I don't know maybe a question for you, but do you think that there's a need for [Audio Gap] their pulsing or addition there? [Audio Gap].

Great question. So it's something that allows us to control and tune and enhance the activity of the iNKT cells uniquely gains on switch in addition to having a depleting antibodies of switch, for example, built in with a engineering. So it's another level that we want to explore, haven't exported hugely because we haven't yet had the need, and we're building up in a very logical fashion, I think. But -- absolutely right. That's certainly another thing. And there's 1 of the nice things about some of these lipid ligands. There are lipid ligands which can produce a more Th1 biosimlar Th2 bjos, you can choose the flavor of the response you actually want. So they have this unique ability, and we really can't do that with other even in innate cells.

And last question for the company. I mean for Jen, you guys talked previously a little bit about biospecific approaches or some kind of a redirecting antibodies. I wonder if that's still something under the hood or if you're leaning more towards the CAR approach at this point.

So the CAR approaches have some obvious benefit and the preclinical data, I think, speak for themselves, the iNKT engagers and the ability to develop are absolutely something that we'll be advancing and we'll be talking more about share what we're thinking yes.

So we're still building that platform because it's an obvious question in the conceptual side of things, they both redirect iNKT cells to the tumor, 1 with an antibody, you want to be a CAR. The CAR, of course, does more because it adds signaling and it adds armor. But we think if you think about the native product of 797, there's a huge potential to optimize the sort of numbers in the diseases where you want to go, and that's probably easier with an antibody. So that's the reason -- one of the reasons why we're still developing the platform, it gives us flexibility to work with the native cells in indications that are probably easier to address with an antibody than with a modified -- gene-modified cell. Of course, down the line we think you can even further enhance the activity of a modified cell because the clinical path to get there is quite lengthy. But we think that both of these options and the way we are using them and with antibody-based drugs allows us [Audio Gap] opportunity or separately develop these products. Also from a manufacturing perspective, they have quite different costs associated with them as well. So we're pursuing them both. The CARS obviously are now first and foremost, but we are definitely working on the biospecific platform.

And I just wanted to add 1 of observation. So ARDS is a spec inflammatory process, but 10 or 15% of people who develop ARS will eventually go on to fibrosis and end-stage lung disease. And so the question is, can these cells also modify that disease process as well? And I think that that's really intriguing from a pulmonary perspective.

I think some of the features of these cells that we're continuing to lose to date is, but they may be protected with the lung epithelial to do, which opens up a number of development

Yes, there's a question from Justin Zelin from BTIG. I was wondering if the panelists could talk about the pet synergies from inks, T cells to be combined with additional agents and any plans to do so in the future?

Maybe I'll just make 1 introduction, which is very important. I mentioned it earlier. Agenus was borne out of -- MiNK was borne out of Agenus, [Audio Gap] that are advancing in the clinic. And a number of them have been advancing in the hands of our esteemed partners, the most recently announced was, of course [Audio Gap] molecule just delivering remarkable benefit across a host of tumors that have never responded to immune therapies previously and an R&D day to follow. Agenus makes share something very important, certainly a vision to advance programs very efficiently and to leverage and advance our business and expand our innovations to patients as quickly as practical and that includes through partnerships. Agenus and MiNK also share an alignment and nonexclusive access to our pipelines with relations, but also to deliver those combinations, which is I think, first of its kind in the industry, actually, to be able to do this. So we have the opportunity to identify what would be the best biology and the products to address the biologic targets? What are the problems we're trying to solve and how do we solve those problems using our platforms, our agents and our combinations. We have very sophisticated in vitro tools that you'll hear more about to help us understand those mechanisms and how to approach biology with different therapeutic approaches. And we also have a host of clinical stage assets that are now bearing out remarkable data that we believe will be complementary. David Einstein presented a slide that we had shared at [ CR ] a couple of years ago, and it shows that using this Fc-engineered botencilimab murine model, version, combining it with PD-1, we saw an elimination of metastatic lesions to the lung in a melanoma model of about 30% to 40%. When you add the cells to that combination evaluating in the clinic and now that we've demonstrated these cells can be administered tolerably, they could be administered in combination with commercially available anti-PD-1 KEYTRUDA and Opdivo. We have the opportunity to now accelerate our development plans in tumor types that are otherwise unresponsive to what's available. So yes, I'll turn it over to David Einstein to share his thinking on where he believes we may want to take this.

Yes. So I think there's a lot of exciting places this could go, you could imagine. And certainly, a traditional kind of post checkpoint inhibitor setting for trials. You could imagine upfront, right? So certain in the kidney can world, we're very used to using dual checkpoint inhibitors as first-line therapy for metastatic clear cell kidney cancer but with not coming off of treatment entirely in the long term. I also think that there is room in kind of early recurrent settings for some of these approaches provide the toxicity as low. But I think we would start in some of those advanced settings.

Hunter Rogers from William Blair. I was wondering if with the engineered CAR iNKT products, if you see any changes to the tissue homing properties compared to the natural [Audio Gap].

Yes. So short answer is yes. So in into to go to tissue and is going to the tumors. Is that try to buy it, but it's also going, for example, in a in the bone marrow. Interestingly, when we have an engine in iNKTS, the proportion of sales going into the tumors compared to the bone marrow, for example, is huge. So much more of them are going directly into the tumors. So engineering them or redirecting them with [Audio Gap] activity.

I'm Emily Bodnar from H.C. Wainwright. Thanks again for hosting the event. I think this is a question for Dr. Einstein. Could you just talk a bit about your interpretation of the initial combination data in solid tumors? I know it's only 3 patients, but how does that kind of compare to what you saw in the monotherapy arm? And could you just discuss how many months of disease stabilization you think would be considered positive for patients heavily pretreated.

Yes, great questions. I think that certainly, we're all eagerly awaiting more long-term data. I think that you certainly saw some maybe enrichment for some degree of tumor response in the combination arms, albeit with 3 patients. But 2 of 3 of those had some degree of tumor shrinkage. So that may be promising, but I think it's still very early. As to what would constitute a clinically meaningful stabilization of disease, we note from some other disease spaces that 6-month PFS is a pretty good surrogate for IO therapies in terms of overall survival. And so I certainly think that kind of long-term data would be very suggestive. I think we also have to recognize that stable disease is not just 1 entity, right? So there's anything between like the versus like plus 30, minus 20, that's a big range, right? So I think we'd want to look a little bit more granularly at those stable disease. Does the stable disease deepen over time? Or is it plus 10% that isn't really stable. So I think we'll have to get down to the weeds a little bit on that. And of course, any of the responding lesions, we want to see whether that's confirmed with follow imaging.

We have 1 more question.

This is a serious comment, but I've been fantasizing for quite some time about having infusions of iNKT cells native, not modified by the way, for prophylaxis and rejuvenation purposes. Now Lydia, your presentation convinced me more than ever that my fantasy should be born to be reality. Any reason not to do that. [Audio Gap]

I'm going to go ahead and close the meeting. I want to know truly the anchoring which the list for your time and participation and our scientists and for all of you for your support. Thanks for joining us today.