Why don't we get started? Thanks, everyone. Down a little bit in the back. Thanks, everyone. Welcome, everybody. It is fantastic to see so many people here today. I want to also welcome everybody who's joining us here online. My name is William Ho. I am the CEO and co-founder of IN8bio. We have a packed agenda today, a lot to go through. We're really excited to have the team here to go through what our company has been doing, all the work we've been doing, talking more and more about our pipeline, and why we're really excited about everything we've accomplished to date. As you know, IN8bio is a clinical stage biotech company focused on developing gamma-delta T cells for both autoimmune disease and oncology. We have a number of programs. Today, our company is focused both on our exciting T cell engager platform that was created in-house, as well as our historical cellular therapy programs in oncology. On the opportunity on the T cell engager side, there have been a tremendous number of deals even so far this year. Two, we're going to talk today about our glioblastoma and some of the unique data that we have, including some of the cutting edge technologies that we're doing in order to analyze that data. I'm going to talk a little bit about gamma-delta T cells. Quite often when we think about gamma-delta T cells, people think, "Oh, what are these cells?" The gamma-delta T cell comprises only about 1%-5% of the total white blood population. Because of that, people think, "Oh, they must not be that important." The alpha beta T cells, where most people are focused on with CD3 T cell engagers or the CAR-Ts, they encompass about 60%-70% of the total white blood population. People think, "Oh, that must be important." Quite frankly, people focus there because they're easy. With so many of them in your body, by taking a blood draw, I can get a high quantity of them. I presented once at a conference, and there was a gentleman in the crowd who actually got into a heated debate with me about what's the important cell. One of my friends, who's actually a Stanford immunologist, says, "Actually, they're wrong. The small numbers are the ones that are powerful, the ones you have to control. I think these particular cells are powerful in that they play an outsized role in coordinating the entirety of the immune response. These particular cells, I think, are uniquely positioned to allow us to utilize them to drive to deeper target depletion, both in autoimmune disease to drive an immune reset and in solid tumors such as glioblastoma to get to deeper responses, and we're going to tell you why that's important today. What is a gamma-delta T cell? The gamma-delta T cell is actually a unique portion of your immune system, your white blood cells, that bridge between the innate or the early immediate response and the adaptive or the memory immune response. For many people, I want to simplify it, because that means nothing. We use this euphemism of the war on cancer, and people think about white blood cells as our soldiers. Each of our white blood cells plays a different role. We think the gamma-delta T cell is important because they're the guy or the woman on the front line who has the radio. They coordinate where friendly forces are, where the dangerous forces are, and which ones should attack. They can call in artillery, they can call in the air force. It's not just a single soldier or single white blood cell that plays their role in trying to eradicate a tumor or to modify the immune system for autoimmune disease. It's a symphony, and the gamma-delta T cell is the cell that can communicate with the entirety of the immune system. People look at this cell and they say, "Well, how does it communicate? How does it kill things? Everyone else uses the alpha beta T cell. We came across this cartoon, as I said, a lot of people are focused on the alpha beta T cell. The alpha beta T cell is what we call HLA restricted. They can't kill anything until the rest of the immune system tells them what to do. The gamma-delta T cell plays a critical role in trying to detect stress signals in order to decide and defend our bodies against invaders, whether they be bacteria, viruses, or transformed cells that ultimately become cancer. These are powerful little cells that have unique properties that we believe overcome the liabilities across all the different modalities, whether they be alpha beta T cells, CAR T cells, NK cells. They have functions across both. They can be delivered allogeneically or meaning from a donor to a patient without driving graft versus host disease. They don't drive cytokine release syndrome. That's important in autoimmune disease, and we'll show you that data later today. Unlike the NK cells, they also have memory and persistence. Some of the earliest data, some of the first CAR Ts that were treated at the University of Pennsylvania by Dr. Carl June and Bruce Levine, 10 years later, the patients still expressed CARs with gamma-delta T cells. They were still playing a role in keeping those patients in remission. We're excited about these cells, and we're really excited about using them for both engagers and on the cell therapy side. I'm going to talk a little bit about the engagers right now. In 2021, 2022, some remarkable data came out that transformed the industry in autoimmune disease. Georg Schett from the University of Erlangen–Nuremberg published the first papers on using CD19 CAR T to deplete B cells for autoimmune disease. Previously, this was unheard of. In 2023, our landscape changed. Every single CAR T company and allo CAR T company overnight became an oncology company to an autoimmune company. Everybody. When this came out, I remember having a conversation with our attorney because we could have raised some money, and we didn't at the time, and they said, "Well, do you think it works?" I was like, "Yes, you can deplete it, but it's a science project. Commercially, I don't think it's going to work." That got me thinking about how can we use gamma-delta T cells, and how can we use the properties of gamma-delta T cells to create a therapy that not only works but is commercially viable. Why did I not think it's commercially viable? Well, part of it is this paper. All CAR Ts today, almost all of them, require lymphodepletion. That's a combination of Flu/Cy. This paper from 1973 showed that in women treated with Cy, 77% of them had permanent ovarian failure. As I said earlier, the autoimmune disease is a disease generally of women of maternal age, between the ages of 20 and 55. Earlier this year, I had a conversation with a woman who actually was recently diagnosed with autoimmune disease. She said, "I've had three kids. I'm done with kids. I still don't want ovarian failure." Right? This commercially becomes a challenge. I've asked this question in multiple settings. There's a fair number of women in this room. How many women would take a drug, who are of maternal age, that puts them at ovarian failure? I have spoken in rooms from five to rooms like this with about 40- 400. I have yet to see one single woman put up their hand. That becomes a challenge. That's why it's been so hard to enroll the patients in these CAR T studies. Also, there's a commercial challenge. As a cell therapy company originally, we have run cell therapy trials in a hospital. Even within a comprehensive cancer center, it is challenging. Inside any hospital, you have to bring together hematology, stem cell transplantation, the GMP facility all together. It is difficult to bring these parts of a hospital together to talk. Bring in rheumatology, who's in a whole different building. Increasing complexity. As many of you know, I've been in biotech for about 25 years. 17 years of those were spent on the Wall Street side. For those here and online who are on the buy side, as you know, you make plenty of mistakes, and it's those mistakes where you actually remember. The other challenge that we believe in the rheumatology and autoimmune is the commercial business. One of the mistakes I made years ago was I found a technology that sounded really sexy. Great science, treated a disease with a huge unmet need. I thought, "This is going to work. This is going to be a fantastic product." We invested in it. What I didn't know at the time, or I didn't understand, was that that product would fundamentally change the business for the physician. For rheumatologists, as it turns out, many rheumatologists actually have an infusion business associated with their practice. For those of you who are online, or those of you in this room with a laptop in front of you, go ahead, check it out. Go to your favorite AI, Gemini, ChatGPT, Grok, whichever one you want to pick, and ask the question. The majority of rheumatologists have an infusion business associated with their practice because it makes it easier for their patients to come in, see the physician, and get their infusion. Patients come in on a monthly basis for their infusion. That practice makes money by billing CPT codes for the chair, the nurse, the injection. They get reimbursed for the ASP plus 7. It fundamentally changes the business. I was wrong on that investment. It got approved. It never took off commercially because clinicians wouldn't use it. When we think about a product, it's not just the science. We have to think about the commercial viability, and how do we fit into the practice. We thought about gamma-delta T cells and their unique properties, and we thought about can we create a product that will be used that fits into the rheumatologist's practice. Today, T-cell engagers has been a hot area. Over 95% of the companies developing T-cell engagers target CD3, and that in itself drives liability. It binds the immune system broadly. CD3 is found on alpha-beta T-cells, gamma-delta T-cells, NKT cells, Tregs, and other cells, and that results in the risk of T-cell exhaustion. When your T-cells are exhausted, they no longer kill, so you lose function. It causes the risk of cytokine release syndrome. 60%-80% of patients who are treated with T cell engagers get cytokine release syndrome, with about 10% of them being Grade 3, meaning you could be in the ICU. That creates a narrow therapeutic window, which then requires dose reduction. As a result, we don't completely deplete the B-cell compartment. It never made sense to us that a CD19 CAR can get into a tissue while a T cell engager can't. If I use a high affinity bond and my T cell engager is stuck to the side of a T cell, it's essentially the same function as a CAR T. The reason we believe it doesn't work is I have to affinity detune. I have to engineer the engager so that I'm not constantly binding and overstimulating the immune system. What ends up happening, we believe, is that the engager falls off the T cell and it doesn't follow into the tissue. We've created a novel T cell engager using gamma delta T cells. As I said earlier, we've not seen any CRS in the clinic to date. We believe that our gamma delta T cell engagers can solve all three of these problems. We have a unique mechanism of action that does not drive or should not drive T cell exhaustion. We have not seen the toxicity such as CRS to date. We'll actually show you some of the data. Gamma delta T cells do not secrete IL-6. IL-6 is the validated biomarker. When someone goes into cytokine release syndrome, we treat them with tocilizumab, the anti IL-6 antibody. We do not see secretion from gamma delta T cells. Finally, the gamma-delta T cells, we have one of the first pan-γδ T cell engagers. We target the Vδ1, which are tissue resident, so they should get into tissues, and we target the Vδ2 that are both lymphoid and circulatory residents. We think we can target the totality of the B cells to drive immune reset. Our platform, our unique T cell engager, this was created in-house. Kate will talk a little bit about it today. We have a pan-γδ T cell binding domain. On the other side, we bind CD19. We also had a program that binds CD33, and then we have a unique T cell expansion domain that we have not publicly disclosed. This T cell engager landscape is huge. Even just this year, there's been a number of deals that were announced. Only weeks ago, Candid was acquired for $2 billion. They're in phase I. They target CD3 and BCMA. Earlier this year, Oro was acquired for $1.7 billion by Gilead. Again, targeting BCMA and CD3. We had Kali that did a deal with Sanofi earlier this year for $180 million up front. Again, targeting BCMA/CD19. CD19 works. Georg Schett's data proves that. I actually have had the direct conversation with Dr. Schett. After treating the patients with CD19, they've never seen another subclone. They've not seen a BCMA, a CD20, or CD22 come out. We're comfortable with the broad coverage of CD19. We're really excited about this platform, and I'm going to invite Kate to come up and tell you more about it. Absolutely. Hi, everyone. I'm Kate Rochlin. I'm President and Chief Operating Officer here at IN8bio. I'm very excited today to be talking to you about INB-619, our in-house, wholly owned pan-γδ T cell. In this case, we're talking about our 619, which is our γδ T cell engager against CD19. Will started to get at the question earlier. We know that CD19 CAR T can work, and we know that in oncology, that has been shown to work. The question is, those are costly, there's a lot of challenges in bringing those outside of the oncology setting, and the real question is, how do you do cell therapy without a cell therapy? We believe that the answer to that is T cell engagers. Specifically, we like gamma-delta T cell engagers because gamma-delta T cells are an incredibly powerful cell type. We've developed a pan-γδ T cell engager, meaning that we can activate across that entire gamma-delta T cell compartment to fully eradicate target cells. What this allows us to do is use the immune system less like a sledgehammer, like CD3, and more like a scalpel with the gamma-delta T cells. Today I'm going to show you a lot of data. We're going to walk through how we can eliminate targets without driving the CD3-mediated toxicity that you would expect from a CD3 engager. That allows us to completely deplete the B cells while opening up the potential utility of this engager beyond oncology into things like autoimmune disease, where that risk-benefit ratio really starts to matter. Finally, the safety is important here. As we think about autoimmune patients who do not have life-threatening disease, but they do have disease impacting their quality of life, how can we bring them safer treatments that don't cause side effects the way that CD3-based engagers do and don't require life-altering lymphodepletion? Will already touched on this, but very briefly, we're going to be going through a lot of data, I'm going to take a step back here and orient you to our gamma delta T cell engager. There are three different components of this engager, which is really where the magic happens. The first, up at the top, is our CD19 targeting domain. This is important because, as Will said, we are not having to activate through CD3. This CD19 domain can actually be swapped out very much like a cassette. The data today I'm going to show you is on CD19. We do have data with other targets for potential in oncology and autoimmune, but today we're going to focus on CD19. We also have our pan gamma-delta T cell binding domain. This is critical because it's going to activate both the Vδ1 and the Vδ2 compartments, which really have two different functions in your body, and we're going to go through that. Then it also activates those lesser-known gamma-delta T cell compartments, 3, 4, 5. We'll show you a little of that data as well. Then finally, you may be saying to yourself, "I've heard about gamma-delta T cell engagers before, and they have had some challenges in the clinic." We believe that we have solved those, and part of the solution here is this gamma-delta T cell expansion domain. Gamma-delta T cells are scarce, and we have to solve the scarcity issue. We do that through this domain, which works cooperatively with the binding domain to the TCR and allows us to expand and activate the gamma-delta T cells simultaneously to completely eradicate the target cells. For most of us in the room, I probably don't need to explain why CD19 is a good target, but I'm going to do it anyways. CD19 is one of the broadest targets that will cover the entire scope of B cell generation. The reason we want to do this is, particularly in autoimmune disease, the goal is to get to complete immune reset, meaning we have to eliminate the immature B cells, the mature B cells, those in the circulatory system, the lymph nodes, and the spleen. We really have to get the whole gamut here. This gives us the broadest coverage. That's what we're going to be going forward talking about today. I'm going to walk you through how we identified the really unique properties of our engager, why we think that this is such a powerful tool, and then I'm going to talk about us moving that into the autoimmune setting. This was sort of our really first really wow moment with this engager, because one of the questions was, gamma-delta T cell engagers have had challenges previously in the clinic in other groups. Is that because gamma-delta T cells are scarce, or because gamma-delta T cells are not powerful enough to fully eliminate a target? With our gamma-delta T cell engager, we were able to show here that if you take Nalm-6, I know this is an oncogenic cell line, but it's a CD19-expressing cell line. If we put that into culture with just PBMCs, so peripheral blood cells, you get that growing out of control. You get 66% Nalm-6 very, very quickly. If we let that grow unchecked, it would ultimately take over the entire culture and kill everything else. If we add our engager, you can see that we actually completely eliminate those Nalm-6, going down to less than 0.1% while maintaining the immune system intact. This is our first hint that this is a very powerful engager with the ability to completely eliminate a CD19 target. The question is, what is it actually doing to the gamma-delta T cells? This is where we really started to get excited about the data, as the science nerd that I am. What we're showing you here is we're not just eliminating the target and increasing amounts of engager. You can see across the bottom there. We are actually expanding the Vδ1s in blue, the Vδ2s in green, and then other gamma-delta T cell subtypes in orange across all of these concentrations. We are actually leading to an expansion very similar to something like an in vivo CAR T would do, and activation and killing with these gamma-delta T cells. This graph is a little counterintuitive because it actually looks like at the high concentrations here, we're getting less expansion. What's actually happening there is really the most interesting part of the data. What we actually see is that the gamma-delta T cells will expand in response to our engager and in response to a target being present to kill. Once that target is eliminated, the gamma-delta T cells will start to come back down towards their physiological levels. We are getting controlled expansion and physiologic expansion of these gamma delta T cells, not runaway expansion, which would definitely be detrimental in any sort of autoimmune system. At these higher concentrations, we're eliminating that target faster. The question becomes, we keep talking about how scarce gamma delta T cells are, and they're not only scarce, but they're highly variable between patients, even healthy individuals sitting in this room. The question then becomes, can we make this into a drug? Does this actually have a property that we can take forward? What I'm showing you here is an EC50, so a cytotoxicity curve. I think what you can appreciate just by glancing at it is all those curves cluster very tightly together, meaning that the potency and the killing from all three of these different donors is very similar. When you look at the donors themselves, the gamma-delta T cell concentrations range from 0.2 all the way up to 5%. What this suggests to us is that this potency, this cytotoxicity is being driven more by the expansion and the activation of the gamma-delta T cells in response to our engager, and not just by the initial starting concentrations of the gamma-delta T cells in that individual. That suggests to us that this could be brought forward as a drug. Then another really important question is, what are we doing when we activate and expand these gamma-delta T cells? I know that anyone who's worked in gamma-delta T cells or in T-cell engagers will know that if you just en masse activate your entire immune system, they will activate, and then they will all come off a cliff. They will all die. It's really important that we are not doing that this is a controlled activation and expansion. That's what we're showing you here. This is showing you over time the expansion of the gamma-delta T cells, the Vδ1s in orange. The blues are Vδ2, and the part of the bar that's filled in is showing you the expression of Fas ligand or a ligand of activated gamma-delta T cells. What it's showing us is that at any given time, only about 50% of those cells are activated. We're getting waves of expansion and activation, and then those cells that are not yet activated are coming right behind to start activating. We're getting controlled activation and controlled expansion. I know that I'm showing you a lot of data, a picture is always worth 1,000 words, and we really like this one. One of the questions we get, which is obvious, is are you actually killing these cells, or are they transforming in some way? Are they down-regulating a receptor so that you can no longer see them? Here you can see that very clearly with Nalm-6 there on the right with our T cell engager, you can see that those cells are in fact blebbing up, dying, and you can see them condensing and then falling apart. We are actually killing and eliminating these cells, not simply transforming them. We talked a lot about the safety profile of gamma-delta T cells and why we like them. The question was then, do we still see that same potential safety profile transferred to this T cell engager? We actually looked at increasing levels of gamma-delta T cell engager across the bottom. What you can see is those things that are very highly upregulated in red, those are things like perforin, granzyme. Those are pathways in the gamma-delta T cells that are activated when they are primed and ready to kill. The things here in blue that you do not see any increase all the way across are IL-6, the validated biomarker for CRS, IL-10, the dangerous cytokines that we know drive the toxicities in CD3-based engagers, and we are not seeing them here. This gave us a really strong indication that we could bring this forward, and bring it forward and start thinking about autoimmune disease. Autoimmune disease has really been a difficult beast. The goal here is that you have to fully deplete the CD19 target cells or the B cells in order to achieve immune reset. That has been almost impossible with the current CD19s on the market. The problem is that because of the toxicities driven by the commercial CD19 T cell engagers, they have to dose reduce by usually 1/10th the dose in autoimmune, and that is insufficient to drive immune reset. The problem in autoimmune is that in oncology, we know that those patients, you have a tumor that will likely kill you, and you have a treatment that has the risk of potentially killing you, and that risk-benefit ratio may be acceptable. In autoimmune disease, many of these conditions are non-fatal. These patients have an impacted quality of life. They need better therapies, that risk-benefit still changes. How can we drive complete target cell elimination in these patients with a dysregulated immune system without overstimulating that immune system that's already attacking their body? We don't want to be driving CD3. We don't want to be driving all those cytokines because that is going to exacerbate an already bad situation in these patients. We believe that the gamma-delta T cells offer a much more precise way of eliminating those target cells, eliminating those toxic cells with a better safety profile, potentially, to help those patients. I'm going to walk you through that data in autoimmune. We looked at donors that have active lupus disease. Lupus is something that I think most people are familiar with in the T cell engager autoimmune space. We put it here because it's very familiar to everyone. The challenge in lupus is that these patients have very elevated and expanded B cell compartments, and those B cells are driving the disease. The simultaneous problem that you have here is that like oncology, gamma-delta T cells, when you have a chronic illness, whether it's cancer or autoimmune, they become exhausted. Over time, those gamma-delta T cell levels are even lower in sick individuals. You can see that here, that you have less than 1% in most cases, gamma-delta T cells, but very high expanded B cells. The question became, we can expand healthy gamma-delta T cells. We can kill healthy B cells in that PBMC culture, but would we still be able to affect dysregulated or sick gamma-delta T cells and B cells to drive eradication? We decided not to make it easy for ourselves because as I said, there are CD19 engagers out there. We need to know that what we're doing is comparable to what is in the clinic. I'm going to talk about two comparables that we looked at today. Both of these have been effective tools in oncology. They've had challenges in the autoimmune setting, again, because we have to dose reduce to 1/10th. First is blinatumomab. That's a CD19 T-cell engager. It has 2025 sales of $1.6 billion in 2025. Our engager structure is in the middle there, and then on the right-hand side, you can see the mosunetuzumab, and this is a CD20 T-cell engager. It had sales of about $120 million. We're going to compare in culture to both of these commercially available engagers and our engager to look at B cell depletion and the impact on gamma-delta T cells. Importantly here, we also put the size, and the size matters, as we say, in T cell engagers. At 75 kilodaltons, what this allows us to do is it allows us to avoid first pass clearance in the body, but it also allows us to get into the tissues where we need to drive this engager, drive gamma-delta T cell activation to actually achieve immune reset or full B cell depletion. That's why we're talking about that here, and that's why it's so critical in the design of this engager that it can do that. Here on the left-hand side, what you can see is in the green, that's our INB-619. In blue, it's the mosunetuzumab, and in orange, it's blinatumomab. What you can see is by day four and day six, our gamma-delta T cell engager can drive complete B cell depletion comparable to these two commercial engagers. We thought this was powerful, and this is in lupus donor samples. What I'm showing you on the other side there on the right is even more powerful. A lot of people said, "Well, you must be driving alpha-beta T cells." There's no way that this could just be mediated by gamma-delta T cells. We actually show you each individual cell compartment, and you can see that in blinatumomab and mosunetuzumab, you're getting broad expansion and activation of the CD4 and CD8. These are the alpha beta T cell compartments. That is what we know drives some of the toxicity in those engagers, even though it's also driving the efficacy in that case. In our gamma-delta T cell engager at the bottom, you see we are only driving gamma-delta T cells. You see no expansion in green of the CD4 or the CD8, suggesting that we are mediating this elimination of the B cells only through the gamma-delta T cells, and we believe that that's very powerful. I would be a bad scientist if I just showed you one concentration and told you to believe me. We actually did a dilution series here. I'm showing you, we started at a very high concentration for our engager, and you'll see why on the next slide when I start to talk about cytokines. We started at five nanomolar. We looked at the physiological concentrations for blinatumomab and mosunetuzumab. We actually took those out of FDA filings, we are using them at the concentrations that they should be used at to drive B cell depletion in vitro. We actually did five-one dilution series all the way down, and you can see at all three sets of concentrations, our engager is able to drive B cell depletion comparable, and in some cases better than the clinically applicable CD19 or CD20 engager here. Not only does this work, but the fact that it works over this broad range gives us a therapeutic window to play with. It means that as we start to go into animals and humans, we can use this in this wide range to figure out where it is optimal. If it only worked at one concentration, we would be highly restrictive in how we could take this forward, but this shows us that it's very potent at a wide range of concentrations. The real question is: What's going on in the cytokines here? If we're driving cytokines while we're eliminating these B cells, then everything I told you about this potentially being a safer modality doesn't matter. That's exactly what we looked at here, and we specifically looked at day four because that's the day where you see the maximum killing from all three engagers. We thought that was the best day to look because if you're going to see them, that's the day they're going to be there. What we actually see is in green, we see much lower IL-17, IL-6, which is a biomarker, again for CRS, and IL-10. Importantly, we also see much lower levels of TNF-alpha, which is known to actually drive the IL-6 CRS cytokine response through myeloid cells. The reason that we likely see very little to no IL-6 production here is because of very limited impact on the TNF-alpha. We really are seeing what we expect to see here, and we're very excited about this profile and its potential to bring it forward in autoimmune patients. We really designed this to overcome the challenges. I know I've talked about this quite a bit, but we're able to drive both Vδ1s and Vδ2s. We are able to actually use this to expand and activate the gamma-delta T cells. I want to spend a minute on why driving Vδ1s and Vδ2s are both important. This goes back to what Will was saying earlier. These cells evolve together and they have different functions. The Vδ1s are a little bit more persistent. They also reside more in the tissues. They hone to tissues and they function there. The Vδ2s circulate in your lymphatic system, in your circulatory system, and when they sense a threat, they'll become migratory and move into that tissue to eliminate it. We think that it's really important to have both of these working in concert so that we can eliminate the B cells in the circulation as well as in the tissues to achieve immune reset. The reason I want to show you this is because of the next slide, which is my favorite slide in this entire deck, because I think it illustrates how powerful your immune system is and why we have some of the redundancies that nature built in. When we look at lupus patients or any autoimmune patients, every patient is dysregulated in a different way, and each patient may be dysregulated in a different way during the course of their disease. These are two different lupus donors that we looked at, and we looked at many. Both of these donors on day zero, they are indistinguishable from one another. They have low levels of gamma-delta T cells. Hard to tell what's going on there other than the cells are just very scarce. As we treat them with the T-cell engager, you see in donor 1 you get massive expansion of the Vδ2 compartment. In donor two, you get massive expansion of the Vδ1 compartment. In both we got complete elimination of the B cells. This would only be achievable if you had a pan-γδ T-cell engager. If you were treating with some of the historical engagers that targeted only the Vδ1s or only the Vδ2s, you would have only been able to impact one of these autoimmune patients and not both. This really illustrates to us why we think working across the gamma-delta T cell compartments is so powerful. Today I've talked to you about this program. We're very excited and continuing to bring it forward, working in animal models now, which we expect to have some data released later this year. Looking at multiple models, we have shown today that we expand gamma-delta T cells, that we are one of the first pan-γδ T cell engagers, both targeting those Vδ1s in the tissue and the Vδ2s in the circulatory system, as well as those other minor compartments. We don't secrete IL-6, believing that we show a safer profile that could be beneficial in autoimmune disease. Finally, we really believe that for autoimmune patients, this modality, using a biologic with the power of a cell therapy, allows us to avoid the high costs of manufacturing in these patients. It allows us to avoid the complexities of lymphodepletion and address a very broad market in autoimmune disease that is still lacking effective treatments for these patients. Thank you very much. With that, I am going to introduce. That wraps up our T cell engager portion. We will be releasing more data, as we said, and very excited to share that with you at upcoming medical meetings later this year. I will take a moment here to introduce Dr. David Reardon as we switch gears now, and we're going to talk about our clinical programs in glioblastoma. We're going to be talking about our phase I and phase II data. Dr. Reardon is here, the head of neuro-oncology at Dana-Farber, to share his clinical experience and his practice of glioblastoma and really set the stage for why this challenging disease remains so challenging and what he has seen from the clinical perspective and where he believes we may be able to move the needle or what we need to think about in terms of moving the needle for these patients. Thank you very much for being here today, Dr. Reardon. Of course. Thank you so much. Well, that was very exciting. I think a tough act to follow, actually. Yep. That'll do. Okay. I'm going to switch gears and now talk about therapeutic application for treating cancer patients. I focus in my practice and our team on glioblastoma. The major unmet need, I think, at this point in medical oncology, it's fair to say. These are disclosures. Putting things in perspective and why I'm excited to be here and talk about what I feel is an out-of-the-box innovative treatment strategy that we desperately need to have an impact in a very challenging cancer. Just set the stage and introduce you to the challenge and the difficult problem we deal with patients who have brain cancer. Of the 20 million patients afflicted with cancer on an annual basis, brain cancer is relatively low on the chart. It's only number 19 out of all of the cancers, so not anywhere near as frequent as many others. On the other hand, the mortality associated with this is disproportionately elevated. It's the number 12 cause of cancer-related death in adults, and it's actually the number one cause of cancer-related death in children. Of brain cancers, glioblastoma is the most challenging, the most difficult. This affects about 13,000 patients in the United States each year and a comparable number in Europe as well. Like most cancers, it's a little more common in men than women. It can happen at any age, but it increases in frequency as we get older. The average patient in my clinic is in the sixth to seventh decade of life. For reasons we don't understand, unlike all the other aggressive cancers, glioblastoma does not metastasize, or exceptionally rarely. Even in end-stage patients, it's almost unheard of. In 25+ years, I've had one or two patients. It starts and stays in the brain, and instead of spreading outward, it spreads inward, and it's incredibly invasive and infiltrative from that original source of the tumor moving outward and then destroying in its path. The MRI scan in the upper corner, I don't know if I can point or not, but the white area on the MRI scan in the upper left corner is the tumor. The darkened area in the center is where brain used to be, and it's empty now. It's dead tissue, empty cystic space. That white area around the perimeter is where the tumor cells are expanding and growing and dividing, and that's the picture on the right panel here of the incredibly dense cellular nature of the tumor in that leading edge as it's moving outward and extending into the adjacent brain and essentially destroying what's in its path. This remains an incurable and, unfortunately, essentially a universally fatal cancer. Today in clinics around the world, including in my clinic yesterday when I saw newly diagnosed patients, I am offering them a standard of care that was defined in 2005, 21 years ago. That standard of care includes maximum safe surgery that can be done, radiation therapy, and cytotoxic chemotherapy with temozolomide. With that standard of care from the date of diagnosis, the average time to progression when the tumor activates is about seven months. Ultimately, unfortunately, the time median survival for patients is a little over a year, just under 15 months on average. With that standard of care based on that chemotherapy, we do have a classification of patients who are more likely to have a modest benefit with that treatment, particularly the chemotherapy, and it depends on the methylation status of the methylguanine methyltransferase, or MGMT promoter, associated with the tumor. This gene essentially neutralizes the chemotherapy that we have. It basically reverses its ability to be toxic to the tumor cells. 55% of patients have an increased expression of that gene, which means the chemotherapy is even less effective and able to be helpful to them. In about a third of patients, the gene is not activated or at a lower level, and the chemo offers some modest benefit for them, but it's still far from curative. We do know, unfortunately, because of the historical experience, patients who have the unmethylated MGMT with the lower likelihood of benefit from the chemotherapy are older patients, are patients who have poor performance status or comorbidities, and patients where the tumor is too deep for a meaningful resection, where there's bigger tumor burden to start off with, have a poorer outcome. Just to highlight the frequency of the disease, this graphic shows that although it can happen at any age, and unfortunately, I've taken care of infants and young children with glioblastoma, it does increase in frequency as we get older. You can see the incidence peaking in men in blue and women in red in the sixth-seven th decade of life. The chart on the right-hand side indicates that the older you are when you're diagnosed, the poorer your outcome is going to be, and you can see it drops off fairly precipitously. It's still well under 50%, even in the best of situations, but it drops off pretty precipitously as we get older. I get a question of why does this happen? Why does this happen to me? What caused this to happen? Despite what's in the tabloids associating brain cancer with cellphone use, in terms of environmental factors, that's not true. The only environmental factor that's been clearly associated with the development of brain cancer is prior therapeutic radiation to the head or scalp. There is a small, low risk many years down the road of brain cancer happening in that context. Other than that, we do not have any good insight into what causes these from an environmental exposure perspective. The other part of this is, well, what about my immediate family members? Are my children going to get this? Are my brothers and sisters going to get this because this happened to me? Fortunately, there does not seem to be, for the vast majority of patients, an inherited or genetic predisposition in only about less than 5%, a small percentage of patients. How do patients typically present? They typically present fairly quickly and acutely with progressive neurologic deficits, usually over a matter of a few days to a few weeks. Depending on where the tumor is localized, it will translate into associated neurologic deficits. The part of the brain that controls the hand may lead to hand weakness. The part of the brain that regulates our ability to articulate and speak may lead to speech difficulties, et cetera. It just depends on where it's involved. Oftentimes, cognitive function, memory, keeping track of things, multitasking, personality, and behavior can be affected depend on the anatomy that's involved. Because it's growing inside the confines of the skull, where there's only so much room for compensating for that buildup, there can be headache and pain from that, and some patients can have seizures. Our workup when patients present with these types of symptoms over a short interval of time is a state-of-the-art MRI scan where we can see and identify with very good anatomical detail now with state-of-the-art MRI scans, the size, the extent of the tumor, and where it seems to be infiltrating into the adjacent brain. We need to get a sample of that, either by biopsy or resection, in order to definitively confirm the diagnosis. The MRI picture is very suggestive, but it's not a perfect 100% confirmation. All patients have to go to surgery. If it's resectable, we try to resect it. If it's not, at least get a biopsy to confirm the diagnosis. This is what I'm offering my patients in clinic today. The standard of care that I mentioned was defined in 2005. It was a landmark study at the time. Prior to that, all we had was radiation therapy. We could have surgery, and then patients got a palliative course of radiation therapy. When the chemotherapy part of the treatment came along, and that was given with radiation over six weeks, and then monthly, five days in a row for six months, that addition of chemotherapy when compared in a randomized trial to patients who got radiation therapy alone, had a modest shift of the improvement. You can see the overall survival benefit of two and a half months. That was the average benefit. That was sufficient because of a lack of any other option or treatment to gain FDA approval for the chemotherapy, and this is still what we offer patients today. Why we're not doing other treatments is not for lack of trying. This is a collection of 11 phase III studies that have been run around the world, looking at innovative chemotherapy strategies, targeted therapies, even immunotherapies, trying to raise the bar and improve outcome for patients with glioblastoma. Unfortunately, all of these trials were negative and did not improve survival. The important question, and I think what's exciting about what we're hearing about today, is why are these treatments consistently failing and not working? What are the hurdles? What are the roadblocks that we need to overcome? In my experience, 25 years in working with a variety of different pipeline agents and treatments, the number one, number two, number three cause of why these treatments fail is they don't get to the target effectively. Delivery is the main issue, by far and away. Unlike other cancers, brain cancer is protected by the blood-brain barrier. Mother Nature designed our brain to have an extra level of protection against anything that could be potentially harmful, and that's the blood-brain barrier. The flip side of that is that the blood-brain barrier also excludes most of the cancer treatments because they are potentially harmful. They won't get in and effectively get to the target. In contrast to my colleagues who treat lung cancer and breast cancer and colon cancer and others where they give the drug, they know it's got an exposure to the tumor, we cannot make that assumption in brain cancer. We need to know that it truly is able to get in. Unfortunately, as I said, the majority of drugs don't get into the tumor effectively. Many of these failures have been because we never really confirmed in the first place that the drug is able to get to the target effectively. The other reasons for failure, similar to other complex challenging cancers, significant redundancy, heterogeneity, and a remarkable ability to adapt and become resistant. Some of it's intrinsic and already present, but often is very quickly acquired during the course of treatment. This is just a graphic to highlight this very important protective structure of the blood-brain barrier. 400 mi of capillaries in our brain of the bloodstream that are all protected by this extra layer of protection so that it deliberately excludes many different types of molecules, but particularly those that could be harmful. Unfortunately, that includes most cancer therapeutics. The analogy I use in thinking about glioblastoma is an iceberg. What we can see on the MRI scan is the mass, the macroscopic mass of the tumor. We see it because it highlights with contrast. When we inject intravenous contrast for an MRI scan, it highlights the macroscopic part of the tumor, where that density of the cells is most concentrated and present. That only is the tip of the iceberg. The infiltrating leading edge and extension of the microscopic part of the tumor, the below the surface part of the iceberg is where we really critically need to get the drugs and the treatments if they're going to have an impact in this disease, because that's what's moving outward, that's what's going to cause patients to have worsened symptoms, and that's what's ultimately going to kill them. That's where we typically have failed because the blood-brain barrier is disrupted where we can see the contrast uptake. That's by definition. That's why we can see the contrast. That's because of the damage to the blood vessels or alteration of the blood vessels the tumor causes. Where it's infiltrating into the adjacent brain microscopically, the blood-brain barrier is intact there, and that's where the treatments we critically have to show need to get to if treatments are going to be effective. The other factors that are important in predicting failure has come back to other aspects of complex cancers like heterogeneity. This is a very exciting time in medical oncology. We've got the ASCO meeting coming up in another week or so. We're hearing a lot more and more about exciting targeted therapies, biologic therapies, where we can do a deep dive in each patient's tumor and try to identify what may be the best drug for that patient based on the profile that's unique to their tumor and trying to personalize oncology. We know these targets involve complex cell signaling pathways that are giving the tumor cells a growth advantage because of the dysregulation that happens within the tumor. The different components of the downstream aspects of the pathways allow us to select targets and drugs that can block these specific components of the pathways and try to get the right drug for the right patient. Unfortunately, there are very few cancers where that is a straight-line path. Chronic myelogenous leukemia, when Gleevec came along, everybody got excited because we had a targeted therapy that could block the BCR-ABL fusion transcript and effectively treat patients with this genetically driven type of leukemia. Unfortunately for many cancers, particularly solid tumor cancers in glioblastoma, it's far from a straight shot. It's more like L.A. with the complex freeways here, with lots of different detours and capabilities where you simply block one on-ramp, the tumor has many capabilities of working around it and circumventing that. That's why, in glioblastoma in particular, many of the molecular targeted therapies that we've worked with, unfortunately, even those that get in, haven't been able to be successful because of the heterogeneity within tumors. This is, I think, a fascinating study that highlights that where a small number of tumors had multiple biopsies, up to six biopsies, of a single individual patient's tumor. Sampling different regions within the same tumor. Within those different regions of the same tumor, we saw very different and disparate gene activation signaling pathways in the upper panel. In the lower panel, different molecular drivers associated with genetic abnormalities giving the tumor cells a growth advantage. Even in a given individual patient's tumor, it's almost like we're fighting multiple cancers in one patient because of this heterogeneity. When we give treatments, we can knock down a percentage of the cancer cells, but ultimately, the component that is not sensitive or acquires resistance, because of that heterogeneity, that's what's able to repopulate and come back. Those are the little red dots ultimately that may have been not present initially and then come back, and then are ultimately actually selected for by the treatments we give that eliminate the sensitive part of the tumor and encourage the non-sensitive part of the tumor to come back. We need treatments that can widely attack multiple targets, aren't limited to a single treatment, and potentially can impact and have an impact in the brain. Immunotherapy. Everybody was really excited. I'm still very excited about it in our field, despite how things have gone. It has transformed how we treat many cancers without question. From the original observations by a sarcoma surgeon here in New York, William Coley, back in the 1890s, that his patients who had infections after he did their amputation for their sarcoma, they lived longer. He said, "Well, I'm going to start inducing infections in my patients after I do their amputation to try to help them live longer." Of course, all his peers laughed at him at that point, and he didn't know what was responsible for it, but it was the immune system associated with activation against the infection that we now know those Coley's toxins that he administered to his patients was driving that. The foundation, if you will, for our current immunotherapy treatments. The field of immunotherapy languished for over 125 years actually, before in the last 10 years, we've had incredible breakthroughs with cellular therapies, vaccines, and checkpoint inhibitors that now are transforming how we treat many cancers, including replacing chemotherapy and radiation for some cancers. There's over 100 U.S. FDA-approved cancer indications for immunotherapy drugs. This is a very impossible-to-read slide, but it highlights different drugs and the number of indications that they're approved for now, all immunotherapy treatments, and what are currently used as standard of care. Glioblastoma is not on that slide, even though you can't read it, and I'm sorry if you could read it. It's unfortunately not there. This is one of the cancers that has proven difficult to treat and refractory to our available therapies, in particular immune checkpoint therapies. Again, not for lack of trying. These are the seven phase III trials looking at various immunotherapy approaches for glioblastoma that unfortunately have not been successful. Vaccines, primarily, and checkpoint blockade. It's not because the tumor's in the brain. That's one thing people initially reacted with. "Well, the brain has immune privilege. The immune system isn't in there as much as it can be elsewhere in the body. We know when cancers that metastasize to the brain, and we treat them with immunotherapy, if the cancer in the body is sensitive to immunotherapy, that metastatic cancer to the brain will be comparably responsive to the immunotherapy treatment. It's not simply the fact that the cancer's in the brain, because metastatic disease, if it responds in the body, responds to treatment as well. It's unique to glioblastoma in particular. Glioblastoma is remarkable in many different ways at being refractory and able to protect itself from many different angles of attack and treatment, and it's unfortunately true for immunotherapy. I think of glioblastoma as a perfect storm of pulling many different factors together, again, with lots of redundancy and overlapping protective capability to evade the immune system, to limit the effectiveness of the immune system, and prevent it from being effective. The tumor secretes many different molecules that are immunosuppressive. It attracts in macrophages from the bone marrow that are normally in our body to help clean up inflammatory reactions. The cancer hijacks them and makes them protective against the tumor cells, and these are the dominance of all of the yellow dots on this multiplex immunofluorescence photograph. The blue dots are the tumor cells. The yellow dots are these macrophages that have come into the tumor and been hijacked to be very protective. Even the normal structures in the brain, the glia, the astrocytes, the things that are normally present there to help the neuronal cells be able to organize and function effectively, those are subverted by the tumor to actually be protective against the tumor and make it harder for therapies to work. This is a major challenge of why immunotherapy, I think in one slide summarizes why immunotherapy has been difficult in this disease. We definitely need out-of-the-box treatments, thinking about how we can overcome some of these limitations of the remarkably suppressive microenvironment of the tumor and get the effector cells into the tumor to be able to make a difference. Just to wrap up here, how do we raise the bar? We need innovative out-of-the-box therapies. I'm very excited about what we're talking here today. It fits that bill and I think offers significant hope. We have to, for any drug we're considering for this disease early in development, way before we get to phase III studies, invest in small studies, but studies that can give us an indication, is the drug truly getting into that infiltrating leading edge, and is it having a meaningful effect, what it needs to do when it gets there? Those are critical questions that we need to answer before a drug moves further into development. Then, like most complex cancers, we're not going to be able to rely on a single treatment. It's unrealistic to expect we'll hit a home run with one treatment. We're going to need to think about putting things together with potentially complementary mechanisms of action that could add together in order to get us to a meaningful long-term outcome. By hitting from different angles of attack, we also can make it harder for the tumor to acquire resistance. Very importantly, I think this microenvironment question of this tumor, focusing on that in addition to the tumor cells, but the tumor cells don't live in isolation. They're in this very complex, protective environment that we need to better understand and overcome. Thank you very much. Thank you. Thank you, Dr. Reardon. With that, it's a great lead-in to our drug-resistant immunotherapy platform. It actually reminds me, Daniel, who's in here, we actually saw each other a couple of weeks ago. I remember Daniel was saying, "Data looks fantastic, really exciting, but nobody believes it." I said, "Why does nobody believe it? It's the data." For some of you in this room, I've been in the industry for over 25 years. We've known each other for 20 years. Some of us have worked together in the past. I think everybody knows that for all those years, I've been considered someone who is serious about the biology, about understanding the details and how we execute. It actually reminds me of another situation 20 years ago that people thought was impossible and a recent image that I saw that was posted on social media on both LinkedIn and X, and that's multiple myeloma. People said it's impossible. This image actually shows the progression of how we've made an impact. 40 years ago, it was a death sentence, but throughout the progression of time, we have incrementally made changes where today this is a long-term survivable cancer. We believe IN8bio and with the technology and the approaches that we're taking, we're at that cusp. We're in the 2005 making in those incremental changes, right? It was the approval of Velcade and then Revlimid and then pomalidomide and those daratumumab. I still remember, I think it was 2010 at ASH when we saw the first M protein reductions. Today, that combination, it's those changes, those combinations that are making an impact for patients. That's what we're trying to accomplish here at IN8bio. Little has changed, as Dr. Reardon just said, in over 21 years. 2005 is when the Stupp protocol was published in The New England Journal of Medicine. The median overall survival remains about 14.6 months. The most recent change is the Tumor Treating Fields from Novocure that on Wall Street most people didn't believe. It's putting the data at around 20.5 months, 20 months. Only about 10% of patients utilize it because they don't want to wear the hat. We believe we can make a difference. There are about 14,000 patients newly diagnosed every single year with GBM in each of the United States and Europe. People often come to me and say, "It's a small market." At the weighted average cost of the cellular therapies from last year, the projected over half a million per CAR T, it is not a small market. It is still a multi-billion dollar opportunity, one that needs the resources and the investments to help make a benefit for these patients. We believe our Gamma-Delta T cells can accomplish this. Last December, we raised new capital. It's been, as people know, a long winter for biotech that we came out of last year. After we raised new capital, the first question I got from everybody was, "How did you do it?" The second question that I got from everybody was, "Why GBM?" Right? People just assume, are you some kind of masochist? Do you want to go into something that's difficult? The reality is no, that's not actually the truth. We are fundamentally focused on biology and trying to figure out how do we actually come up with a successful therapy. As Dr. Reardon said, "Delivery." 96% of GBM patients actually get a surgical resection or a biopsy, and that allowed us to put a catheter in order to deliver cells directly into the tumor bed. When I was an analyst, I, again, learned the hard way. If your soldiers are not on the battlefield that you think they are on, you're going to lose. We accomplished or overcame the first variable. We know our cells are there, and Kate will show you some of that data today because we put them there. The second issue, heterogeneity. How do you target the heterogeneity? We looked at some of those complex pathways. There's too many pathways for one single drug to overcome. We thought that the gamma-delta T cell is the perfect weapon. With its T cell receptor, its innate abilities, it can target the heterogeneity of the tumor, and better yet, we can take advantage of it through the NKG2D ligands, and we'll show you that data today. There's complexity in every treatment. It also happened to be that Temodar or the standard of care in glioblastoma is lymphodepleting, so we can use that as a lymphodepleting agent. That came into a role because originally we were thinking, how do you ultimately get to an off-the-shelf therapy? Some of the reasons why the allogeneic cell therapies have failed is not that their cells do not kill. It's simply that they're rejected. When we first thought about where do we go, what organ systems do we go, we thought about what are the organ systems that are immune privileged. Historically, there were only three, the brain, the eye, and the testes. If you're going to go somewhere where you don't get allorejection, the brain made actually quite a lot of sense, right? Local delivery to a brain where you're not rejected. Quite often, people ask me the question, how do you know that the gamma-delta T cells can kill, even with our T-cell engager? On one of our competitors, Adicet, they've shown data. We know the gamma-delta T cells can kill. On B cells in autoimmune disease, they show B cells going to zero. What they can't control is allorejection. That is not a component of the gamma-delta T cell. Their cells, the B cells, come back somewhere around day 21 and day 28. That's because the NK cells rejected the graft and the B cells are starting to grow back. We know gamma-delta T cells can kill, and we can harness that. We want to harness it to take care of any residual glioblastoma because this is the disease that you're looking at. There is a big, massive, ugly tumor. You can see the dark purple, and everybody thinks, "How do I eliminate that?" One of the interesting slides from Dr. Reardon that we actually hadn't seen before, it's not this purple mass that kills you, right? The purple mass can actually be resected, cut out with a scalpel. It's this little tiny corner that ends up growing back, and that's the challenge. How do we ultimately take care of that? This mass and this environment, the reality is we have to shift the environment. Often, we're used to seeing people wanting to see RECIST criteria responses. The tumor mass at first diagnosis and as the disease is progressing looks like the left-hand side. That's not going to be a successful immunotherapy. As Dr. Reardon said, glioblastoma is globally immunosuppressive. We need to shift the balance from the left towards the right-hand side because that's where we have a chance. Again, in the brain, it's historically considered immunoprivileged. That means there are no immune cells. If I have no soldiers there, I have nothing to fight with. This is some data of checkpoint inhibition across different diseases. The different colors represent different subsets of immune cells. Those that hit the threshold above the dotted line are generally indications that respond to checkpoint inhibition. As you can see in GBM, there are almost no immune cells in that tumor microenvironment. In some of these things, the only difference are the gamma-delta T cells. We can physically change this ratio by putting cells in the brain. Last year at ASCO, Dr. Burt Nabors, our clinical principal investigator, had an oral presentation at ASCO. Dr. Reardon actually got up and asked the tough question. We actually got together the next day, and he was asking this question about tumor burden. You're going after surgery. How do you know you're doing anything? It just so happened that I actually had a couple of slides, because what we're doing actually goes against conventional dogma. As he showed, when Coley first presented his data, people said, "What are you talking about? It doesn't work," right? There's this old joke of how does science progress? One funeral at a time. Someone comes up with something, gets a Nobel Prize, and everybody believes that until it's disproven sometime in the future. The checkpoint inhibitors, we thought we wanted a huge tumor in order to have enough antigen and enough signal to trigger the immune response. This data is actually in ovarian cancer patients who are undergoing surgical resection. It's actually looking at the gamma-delta T cells and the cytokine production relative to residual tumor burden. Those patients who had a full resection, meaning we could not visibly see any of the tumor, you can see the cytokines are higher. I had a tumor that was large or over 2 cm, which quite frankly, if you saw the image that Dr. Reardon showed earlier, that was much larger than 2 cm. There is so much immunosuppressive cytokines being secreted by the tumor that it shuts down the immune response. This went against the conventional dogma. Also, as the tumor persists, it actually actively avoids the immune response. We change the signals. It sheds signals. It actually downregulates its sensitivity to avoid being detected by the immune system. We need to shift this balance back the other way. We need to make a cold tumor hot, and chemotherapy can actually help us accomplish that. A lot of people ask me, "Oh, did you want to be an entrepreneur? Did you want to be a CEO?" Quite frankly, I never did. I thought I was going to be a Wall Street or a portfolio manager. Then I came across Dr. Lamb. For those who know the story, he got stuck in New York City in what was ironically Winter Storm Juno. Up in Boston, it was in 2015, you had 10-foot snow drifts. I got a phone call from a gentleman I had met from UAB who said, "Hey, that guy I told you about, he's in New York City. The city shut down. His flight got canceled. Would you like to meet him?" I took him out for lunch. We talked about gamma-delta T cells that I'd never heard about and his approach and why. It took months of phone calls and emails. One day I said, "Holy crap. I think this works." It's been 10 years. We're really excited about the data we're going to share today. It was a differentiated approach. The reality is it went against dogma. The approach is actually quite simplistic and elegant. Our drug-resistant immunotherapy utilizes chemotherapies that are alkylating agents, meaning they drive DNA double-stranded breaks. DNA double-stranded breaks are one of the most powerful immune activators in our bodies. If we didn't respond to them, we'd all be walking around with tumors. When I have a DNA double-stranded break, our body does three things. One, it triggers repair. If it can be fixed, it's fixed. It triggers apoptosis or cell suicide. If it's eliminated that way, it's fine. As it turns out that the cells will actually upregulate the NKG2D ligands, the immune markers, to say, "Hey, I've got a cell that's damaged. It can't be fixed. It's not committing suicide. Hey, come eat this thing and get rid of it." That's what we did. We took advantage of that process to eliminate residual tumor cells. It is a powerful immune signal. In fact, I was talking to Jeremy, our chairman, last week, one of the challenges with glioblastoma is it's insidious. One of the things that he said was, chemotherapy needs cell division. They need cells that are dividing. He said, "If you're moving, you're not dividing." Also, if you're in senescence or you're quiet, you're not dividing. The chemotherapy can't identify those cells. It can't eliminate those cells, but they're still stressed. What we found is we can use the chemotherapy to upregulate a marker on the surface of the residual tumor cells by hundreds of percent. The challenge was that chemotherapy killed the white blood cells themselves. All they did was they hijacked the tumor's own resistance mechanism. It turns out, it's this protein, MGMT, and we genetically engineered it into our gamma-delta T cells so that they can survive combined dosing. By combining dosing and working with the standard of care, we have a highly heterogeneous tumor. The bulk of it is cut out with the surgeon's knife. We undergo the standard of care Stupp protocol, and that drives us towards minimal residual disease. Conventional therapy, you would keep treating until the patient relapses and then switch therapies. Our approach was to use this combination, genetically engineer the gamma-delta T cell so that it will survive combined dosing, dose them together, so we upregulate these markers, here marked by the red triangles on the surface of the tumor cells. The gamma-delta T cells remain functional. We can identify residual cells and eliminate them. It was probably maybe about four or five years ago. I was walking the poster sessions at ASCO that I actually came across a very interesting poster at UCLA. Because most people, they may understand it, but they can't visualize it. I'll say, ignore the mathematical calculations in this image. very simply, the time to progression and overall survival is a function of only two numbers, the time until the tumor regrows and the depth of your response. If I can prolong the time until the tumor starts to regrow or I get deeper, it's just math, right? The patient progresses when the tumor grows at a constant rate. GBMs double roughly every 50 days when it crosses that baseline, and then you start growing. If we can impact just these two numbers some way or form, we can prolong the progression-free survival and the overall survival. Our approach was a little bit different. Look, we know for years people are used to looking at RECIST criteria responses. Even a partial response, people are excited about. It's a 30% shrinkage. If the tumor is doubling every 50 days, it's just math. It's not a lot of doubling cycles before I'm back to where I started and the tumor's growing again. Especially in a cell therapy, there's no addicted pathway where the tumor can remain static. I either killed the cell or it's growing. Standard of care, the debulking obviously shrinks it and buys the patient time. Our hypothesis was that if we gave just a single dose and reduced the number of residual cells, if the standard of care can eliminate 95% of the cells, my goal isn't to have it to grow back and shrink it by 50% again. It's how do I eliminate what's left of the 5%? If I have one dose and I can cut that in half at 2.5, it's 50 days just to double. If I can continue to dose, with every dose, if I can prolong the time until the tumor is back to where it started, if I can get to deeper and deeper remissions, maybe I can outpace the tumor's growth and prolong both progression-free survival and overall survival. With that, I'm going to pass it back to Kate and talk about our clinical data. Thanks, Kate. Thank you. Here I am coming at you with more data. I'm really excited to be presenting the data from our glioblastoma program. I will, of course, steal my own thunder by saying that this data will be updated at ASCO on June 1st, so in about a week. Please do come see our poster. We are poster number 442, and we'll be very happy to talk to you there. The data that we're going to be sharing today from the clinical data cut is actually from our SNO presentation earlier this year. It was cut late in 2025. I am going to be sharing some very exciting new correlative data as well, though, today. As Will said, how do we actually treat these patients? This INB-200, which is our phase I, and INB-400, which is the phase II, is in newly diagnosed GBM patients using an autologous cell therapy that is resistant to chemotherapy. We do newly diagnosed because the goal is we want to attack this tumor with everything that we have early on to try to drive that tumor down and, as Will suggested, either hold it there or potentially outrun it. This is what that trial looks like. In Dose Level 1, the patients got a single dose. Dose Level 2, they got up to three. Dose Level 3, they got up to six. All of the patients in the phase II that we're going to talk about today got up to six. This is how the treatment is sequenced. The patients go in for their typical surgical resection. After that, we do an apheresis, where we actually manufacture all of their doses for the treatment. They then do their standard chemotherapy and radiation, and then we actually give them the cell therapy during their maintenance temozolomide on the first day of every maintenance cycle. Either one, three, or six. We're looking at safety, MTD, but we're also looking at time to progression, overall response, PFS, OS, and then biological response. This is what this looks like, and this looks complicated, but I want to break it down just a little bit because, as Dr. Reardon said, we don't want to do monotherapy after monotherapy. What we want to do is try to drive synergies because that is the most powerful way that we can eradicate these really insidious tumor cells early on. On the top here, above that blue line, that's the Stupp standard of care regimen. That's the surgical resection, standard chemo rads, and then the maintenance cycle. Below that blue line, that's what we have added, and those are the gamma-delta T cell doses that the patients get. The patients will come in. We actually do an IV dose of temozolomide, and that's to really sharpen that PK and drive that cellular stress that Will talked about on the residual GBM cells. We concurrently, right at the same time, we infuse those gamma-delta T cells directly into the brain with the idea being that that temozolomide will paint them like a target for our gamma-delta T cells to be able to seek them out, recognize them, and kill them. We want to get rid of any of those residual cells because we know in glioblastoma that patients don't die from metastases, as Dr. Reardon said. The majority of patients will actually relapse within 2 cm of their initial resection site. We know that there are residual cells there that we cannot see, and that is what is killing these patients, and that is what we are trying to eliminate here. We have this trial that ran at four centers. The phase I was at UAB with Dr. Burt Nabors. In the phase II, we expanded to Moffitt, The Ohio State University, and Cleveland Clinic. I want to point out first that we're going to talk about our 17 treated patients today. We saw no major toxicities. We saw no ICANS, no CRS, even though we were dosing directly into the brain. Again, demonstrating that safety profile of those gamma-delta T cells that we talked about earlier when we talked about T cell engagers. Then we also saw no safety or efficacy concerns in these patients. I'm going to walk you through the cumulative data as of our end of 2025 data cut. The first thing I want to do is orient you to these groups of patients we'll be talking about. There are several groups. We talked about there's single doses and repeat doses. For the purpose of the data analysis, we combined all of the three and six-dose patients together because the whole idea behind this therapy is that we use repeat dosing to keep beating back those potential residual GBM cells. That's in the bottom here in green. Those are all the repeat dose patients. In the course of enrolling this trial, we ended up having a number of patients that were initially enrolled, but for one reason or another, did not receive treatment on the trial or did not receive our cells. They only received the Stupp standard of care. We're going to refer to those up top as our control standard of care patients. Those patients didn't receive our cells for any number of reasons. Primarily, they chose to decline getting an experimental cell therapy infused into the brain. In some cases, there were issues with apheresis. In some cases, they no longer wanted to participate in a trial, or they were not manufactured properly or efficiently. Really, those are the reasons, but we're going to look at those as our control group. What I want to point out here is we had 10 of those, about the same with methylation status, so 60% unmethylated versus 50%. That's important because methylated patients are generally expected to do a little bit better. We have 80% total resections in our control and only 43% in our repeat dose patients. That matters because patients that get a total resection, even though we know it is not curative, generally do a little bit better. In the control patients, much higher percentage of total resections. Median age, about the same, 64-67, about the same percentage, 60% male versus 50% male. These groups are somewhat comparable, and I'm orienting us here so that when we look at the data, we can see what the demographics behind that are. We also, I want to note, have similar KPS or performance scores between these two groups. On the KPS score between both were comparable at 80. Here's the totality of the data, and we were very excited about this because we see a strong effect on both PFS and OS, or progression-free survival and overall survival in these patients. The first row I want to walk you through here, this is the historical data from The New England Journal of Medicine paper that actually established the Stupp regimen, the one that Dr. Reardon talked about that set up the standard of care 20 years ago. Median progression-free survival of 6.9 months, median overall at 14.6. Our control patients did a little bit worse. Median PFS at 6.6 and median OS at only 13.2 months. Our repeat dose patients there at the bottom, they had a median progression-free survival of 13 months, almost double the expected in the standard of care, and getting very close to the OS that we saw in our control group. Progression-free almost as long as the control group was alive. We saw a median overall survival at 17.2 months, and this is still climbing. This number is still increasing. Even that we think is a remarkable achievement. Here it's particularly important because one of the things that we've seen in some cell therapies in GBM is when you have a cell therapy that targets one, two, three different specific targets, the tumor will find a way to escape those targets. It'll down-regulate those, it'll up-regulate others. Sometimes you will see an extension in progression-free survival. When those patients relapse, they relapse with very aggressive tumors, and unfortunately, the OS does not change. The patients essentially die on time, even though the PFS is longer. Here, we are seeing an impact on both PFS and OS, and I think part of that is attributable to the remarkable way that gamma-delta T cells recognize multiple different targets to tackle that tumor heterogeneity potentially. The metric I'm showing you here on the other side is the number of patients that were progression free longer than they were expected to be alive. We calculated the OS for each individual patient based on their tumor demographics, their age, and their gender. Here you can see only one in the control group went longer than expected, but almost 60%, eight out of 14, were progression free longer than their predicted overall survival would have been. We think that's a meaningful marker for these patients because we're trying to give them time when they're first diagnosed, when they feel better, when they're able to have meaningful time before they progress. For those of you who are saying that seems like a bit of an odd metric, I'll give you the metric that everyone is used to looking at here. Nope, or I will not. There we go. Real cliffhanger. This is actually showing you the Kaplan-Meier curves here, and it's showing you that both with the progression-free survival and the overall survival, even with these somewhat small numbers of 10 control and 17 treated, we are seeing a statistically significant separation of the curves. I think that is very meaningful. Here you can see that the median OS is still not reached. Those patients that are still going have been censored here. We'll be giving updates on all of this at ASCO in about a week. The question here is, we're seeing impact on PFS, we're seeing impact on OS, but what is actually happening immunologically in these patients that we're treating with our gamma-delta T cells? What can we start to understand about the biology that's happening in both the patient and the tumor to make sense of what we are seeing in these numbers? We've gone pretty deep and looked at what is actually happening. The first thing we actually looked at is what is happening with the number of gamma-delta T cells peripherally in these patients. As we said, we're dosing these cells directly into the brain. When we look peripherally in the circulating gamma-delta T cells, this is what we see. In the orange, you're seeing the patients that got just one dose. What you would expect when patients get repeated lympho-depleting chemotherapy for one year, you see those cells start up here and they go right down off a cliff. With the Dose Levels 2 and particularly three in green, where you look at that bracket, you can see that those gamma-delta T cell levels with the multiple doses are actually sustained in that low normal level. Why is that so meaningful? This is particularly meaningful because many, many years ago, Larry's first observation in gamma-delta T cells was that naturally recurring high levels of gamma-delta T cells correlated with improved survival. It's been shown now not just where Larry looked in leukemia, but across multiple solid and liquid tumors. What that means is we are now being able to take something that was observed clinically and induce it therapeutically. We are able to sustain those gamma-delta T cell levels. What's happening with the rest of the immune compartment in the body? When we actually look at that, you can see again in orange, the single dose, all of these immune cell compartments, they start high, they start going off a cliff over time. You can see in the three and the six dose patients here, especially in that green, you see those immune cells stay at those higher levels, and this is looking at both alpha beta, CD8, CD4, CD3, and gamma-delta. Why is that so important? This is really important in glioblastoma because these patients get constant lympho-depleting chemotherapy. Oftentimes, if that becomes too much for the immune system, those patients become too lymphopenic. They do have to go on treatment breaks and allow their immune system to recover. That causes delays in treatment. Those delays in treatment we know are very negatively impacting patients' outcomes. If we can help sustain the peripheral immune system, this has a lot of potential benefit, not only to help the patient where we're putting the cells at the site of action, but also to help these patients maintain their current courses of chemotherapy and basically go through that entire maintenance cycle effectively. The question is, okay, we see higher levels of gamma-delta T cells, so I'm telling you that's great. Previous work has suggested that that's important. Does that actually matter when we can look at that in relation to our patients' overall survival? The answer is that it does. We actually looked at the level of peripheral gamma-delta T cells along the bottom, and we looked at that compared to patient overall survival. You can see that there is a very strong correlation here with a Spearman of 0.7 showing that the higher your levels of gamma-delta T cells, the more strongly you correlate with improved survival outcomes. This is meaningful. We wanted to go and say, well, how are those levels coming about? Is it you just need to get one dose, and if you happen to have a really strong immune system, then that's enough? Is it really the multiple doses that are driving these levels? When we broke it down by dose, you can see in orange in the single dose, you do have lower levels of gamma-delta T cells. It is those higher repeat doses, three and six doses, that are actually driving these high gamma-delta T cell levels that are then correlating with those improved outcomes and essentially going all the way back to Larry's observation 30 years ago that these are important cells. I've told you a lot about what's going on in the periphery, but then the final frontier in GBM, what is actually going on at that tumor microenvironment? What is going on in the brain of these patients, and how can we start to understand how our therapy is impacting the tumor, progression, and the microenvironment, all in that space that is really difficult to image? We can do broad imaging to see the tumor, how do we get down at a granular level to understand what is happening? I'm going to talk today about some of the single-cell analysis that we've been doing at IN8bio because we feel that this is really the next frontier, final frontier of understanding some of those mechanistic interactions in GBM. If you are a biologist, this histopathology slide will look very familiar to you. If you are not a biologist, this will look like a very confusing slide where you don't know what to look at, and that's okay. What we are trying to show here is this is how we look at tumors typically. We get a biopsy. You can take sections of that biopsy, then you can stain for a handful of markers to try to understand what's going on. The resolution isn't always great, and you're limited in how many things you can look at the same time. Here we're showing you a patient that underwent treatment and a patient that did not. The first one there is a patient that did not undergo treatment. At diagnosis, you can see that there's essentially no immune cells infiltrating that tumor. You don't see these sort of little brown dots that you do on the other side. After treatment, when these patients are re-resectioned, that patient eventually relapsed, you still don't see immune cell infiltration. Part of that is because your brain, as we spoke about, is an immune privileged site. We don't want a lot of inflammation happening there. We don't want a lot of cytokine secretion and immune activation going on. That helps you most of the time, but in the context of a brain tumor, it hurts you because your immune cells can't get where they need to be to fight that tumor effectively. On the other side here, I'm showing you a patient that was treated with our DeltEx DRI or our genetically modified gamma delta T cells. At diagnosis at the top, you can see the gamma delta T cells. There are really none present. On the bottom, when this patient unfortunately did relapse around 10 months, you can see a massive amount of gamma delta T cell infiltration. Interestingly, when this patient was resectioned, they took out what the relapsed tumor was there, it was mostly dead necrotic tissue and some tumor tissue, suggesting that these gamma-delta T cells are still active at this site, potentially got outrun by this aggressive tumor. The question is, how do we get deeper than this? How do we understand more about the complex interactions that are driving these? What we did is we actually used AI tumor mapping to go deeper. We were able to take these sections from these patients, use machine learning and AI to look at up to 50 different markers at the same time, and use microfluidics with Elucidate Bio. What we were able to do is actually look at the proteomics and the actual protein expression on the tumor cells, the surrounding healthy tissue, and the tumor microenvironment where these two bodies are interacting. Then we were able to look at the transcriptomics to even get deeper in the single cell to look at what is driving that protein expression on the cell surface from a mechanistic standpoint. We were actually able to get all the way down into the transcriptome to understand what's happening at diagnosis, treatment, relapse, and tumor remodeling. This is data that we are actively working on at IN8bio. I'm just going to give you a little bit of a flavor for it today because I know that there's a lot here. We're very excited to continue presenting data on this as we move forward. Our initial study design, we wanted to look at unmethylated patients who were both treated with our DeltEx DRI or our gamma-delta T cells, and patients that were not treated, so one of our control patients. We looked at diagnosis, and then we looked at relapse. The reason that we're doing that is to try to understand a lot of these patients go a very long time with our treatment and do not relapse or do not recur. They're not always the ones we expect. Sometimes the patients that have the best prognostic indicators don't do as well, and some that have very poor prognostic indicators were going years without relapsing. What can we understand about the tumor at diagnosis and through treatment that could help us explain or stratify or understand these differences? We also looked at a methylated patient here as well. I'm only going to show you a little bit of data, but this is so exciting to us because the first thing that jumped out is when we looked at these patients at relapse, what we saw is we had turned a cold tumor hot. GBM is classified as a cold tumor. There's very little immune cell infiltration. We were able to drive immune cell infiltration. We were able to reduce cell proliferation. Importantly, and you can see those blue bars sticking out there on one side, we were able to clear granulocytes and neutrophils and other debris and cell types from that tumor microenvironment in our DeltEx or our gamma-delta T cell treated tumors. That is important because clearing out that tumor microenvironment that is so resistant to therapy, that creates that protective boundary around that tumor, if we clear that out, those gamma-delta T cells can infiltrate and get in there and attack any of those residual tumor cells. We're taking away some of that protective barrier. Here, I quantified some of that, and I think these numbers are really striking. I personally think this is some of the first time we've ever seen data that gets this deep into understanding what is happening at a cellular level in a tumor, in a GBM. We are able to get an 18x increase in CD8 T cells in that tumor. We are able to decrease the tumor burden by 24%. Importantly, we get an 82% reduction in cell proliferation. This is Ki-67 as a marker of cell division. We get a 90% reduction in the granulocytes. That is that suppressive, really packed, dense tumor microenvironment where immune cells cannot get in. That's how much we're able to reduce it. Finally, unfortunately, what we see in these patients at relapse is that we see an increase in the M2 macrophages slightly and Tregs, which are both immune suppressive cell types that the tumor is starting to activate in order to try to escape the therapy that's there. What this tells us is we can get deep. We can get to single cell in understanding these GBMs. This helps inform our trial design, how we can dose augment, dose and intensify early on, or potentially continue dosing beyond six doses to keep driving these tumors down. This importantly gives us the tools to now build on this with additional tumor samples that we have to try to understand the mechanisms behind tumor response, resistance, and escape. Today, we've talked a lot about our GBM program. I think that there's no question that these patients need and want better. We believe that our gamma delta T cells are showing a difference at both PFS and OS, and that we can mechanistically show both peripherally and also in the brain how these cells are functioning and driving these outcomes that we see. We believe that the gamma delta T cells are really correlating strongly with the survival outcomes. Importantly, that we are able to turn this very cold tumor hot. I thank you very much for your attention today. Please come join us at ASCO to get more updates on this, and thank you to the whole team that works on this internally at IN8bio. I'm going to pass it over to Patrick McCall for our corporate updates. Thank you. All right. Well, thanks everybody. I know it's been a long morning, so I'll try and keep this short and sweet. I think we're pretty excited about what's coming up. We have a pretty strong second half of 2026. We have approximately $21.1 million of cash on hand as of March 31st, which gives us the ability to get into the second quarter of 2027, but more importantly, some of these major milestones up ahead. Going back to the December 25 financing that Will talked about, that was led by Coastland Capital. We have a second close in that of $20.1 million, which is directly associated with the animal data on our TCE program, which will be coming in the second half of this year. Later at ASCO, in the next week, I can't believe it's already June, we'll be presenting additional long-term follow-up on the GBM program and at a major medical meeting later in the year while we're completing these discussions with the FDA on what is the potential path forward for GBM and is there any accelerated pathways for it. As we're doing this, we'll be completing the INB-100 expansion cohort. We're providing that long-term follow-up later, late in the end of this year so that data can mature. I will mention that with both of these programs that are either completed in the clinic or nearing completion, the cost left with that is very, very de minimis. There's not much left. Perhaps I think the most exciting part, as we've all been really focused on, is that T cell engager and the animal data that's coming up. We're going to be providing that data early in the second half of this year, with that gives that ability to get the second close, which will get us through the IND for the first program in INB-619, the T cell engager, and gets us through all of 2027. Thinking about that, we have a very strong cash position, zero debt. The ability to get that second close, which will get us through all of 2027, I think is pretty important to us with all the milestones we have. When I think about this, we've done this on a fraction of what others have raised. You look at other companies out there that have raised hundreds of millions of dollars just in an attempt to get into the clinic. We've gotten two drugs into the clinic, multiple programs in preclinical development, all in a fraction of that cost. To me, that is one of the most remarkable things, and we've done that through being very disciplined, efficient, and effective with the capital we have. That is what I think makes this the most compelling opportunity in IN8bio. With that, I'm going to hand that over to Will for closing remarks. Thanks, Pat. Just to go back a little bit. The financing in December, I know some of our investors are listening on the webcast. It was led by Coastline Capital. I really want to thank them for all of their support. They purchased their shares through pre-funded warrants. In addition, the 13 filings are all out. We had great support from existing and new investors. We had participation from Alyeska, Franklin Templeton, 683, Stonepine, and other healthcare specialists. Thank you all for your continued support and trust in the team. I also want to thank some of the members of our board. We have our chairman, Jeremy Graff, here with us in the front, as well as a very, very robust and strong scientific advisory board. Every single day in our business, our team is looking for ways to innovate and to make a difference for patients. We follow the biology. We are efficient with capital. Today, I think we are at the cusp of a new frontier. If you look at social media and what's going on out there, quite obviously everyone's talking about AI. AI, AI, and how we use that. I think with all these technologies, what do we do with it? Are we all just going to be sitting at home playing games? I think the next frontier is actually health and longevity. We are using these technologies, and continuing to advance our programs. I think Kate showed you some data. We're at the cutting edge of technology in doing some of this single cell analysis. It wasn't possible when we started some of these trials. What we're seeing, the effects that we're having on progression-free and overall survival isn't just a line in the sand for time, but we're seeing those distinct changes in the tumor microenvironment in the cells themselves. That's giving us confidence. We're advancing two programs in high unmet needs. Our T cell engager, we're really excited. We followed the biology. We have a unique platform, a unique program that we think can overcome the challenges that we've seen across the landscape of T cell engager development today. GBM, an unmet need where patients have not seen a difference in over 21 years. It's quite possible some of the people in this room today were not even born at that period. Right? We are seeking to make a difference. Just because something is difficult doesn't mean we shouldn't pursue it. We, on our team at IN8bio, continue to progress our programs. We're focusing on the high unmet needs. We have continued to execute over the last couple of years. One of our first investors is sitting here. We have continued to demonstrate and execute on our milestones and bring new data. We're excited about this year. We're going to present new data as early as next week. We'll have more data throughout this year, and I want to thank everybody for attending today. I want to thank you for your interest in our company, and I want to thank you for joining us on our journey. Thank you. With that, we just hit 11, perfect timing. Why don't we have the team come up, including Dr. Reardon? We're going to run a Q&A session. Josh in the back has a microphone. If you have any questions, please raise your hand and he'll come to you with a Yeah. Thanks, Will and team, for hosting this event. It's very helpful. Maybe a few questions, if I may. First question is for the management team. You're expecting to meet with the FDA in the second half of this year. Maybe just help us understand what you're hoping to get accomplished. I think we're trying to understand from the FDA what the potential regulatory path forward is. I think it's not surprising to anybody that there's been a lot of fluctuation in the FDA. The prior administration had made comments about potential pathways forward and what they're focusing on. That's all changed. Just like everybody in the audience, both in person and online, we're trying to understand where the FDA is as well. It has been a difficult path in GBM. Obviously, there have historically been limited investment in the space, and we're trying to understand what the path is and is there a path forward. Is there something that can be run that's a reasonable size, that is feasible? We've been doing a lot of statistical analysis. We've been doing a lot of analysis of different trial designs, Bayesian designs, understanding the powering, the assumptions, and trying to understand what a potential path forward may look like. Okay. A question for Dr. Reardon. I guess from what Will briefly said, it seems that you might have been a skeptic previously about the GBM data. Now that you've seen the data in detail, maybe just help us understand what you thought of the data, what additional data that might be needed to perhaps generate either broader interest, if there isn't already any, and how do you see this particular therapy put in practice? I think the data are quite compelling, very candidly. Anytime we have a treatment where progression-free survival exceeds overall survival, the predicted and expected overall survival, that's remarkable. From my perspective in this field, we're used to very modest increments. As I showed you for temozolomide, the improvement in survival that led to FDA approval was 2.5 months, and even less in the unmethylated patients. Quite nominal there, 0.9 months. Here, seeing a therapy where we're seeing an improvement in progression-free survival that actually exceeds the predicted survival, I think is very meaningful in this context. I think the biggest thing is we need to get this out and expand the studies and validate these results in larger groups of patients. I think the exploratory analyses trying to better understand potential biomarkers or predictors of patients who will benefit more or those who may likely benefit less will be very important. As I tried to explain, this glioblastoma is not one disease. It's very different and varies from patient to patient, so understanding what may be helpful or predictive of patients who are more likely to benefit from this type of an approach. I think the data are quite compelling compared to what we've seen with other cell therapy approaches that are really focused on single targets or, and now with the second or third generation CAR T-cell therapies, two or maybe three targets at the most. It really is, unfortunately, likely to just set the tumor up for the ability to escape and downregulate or advance the subpopulations that don't express the target. We need something that's going to have a broader attack and be able to actually take advantage of the heterogeneity within the tumor rather than be limited by it. I think the biology here that is driving all of this is very compelling. I think the preliminary results are very exciting. The safety profile is quite compelling as well. I think we just need to move forward and enlarge the studies. The FDA is always going to want to have a benchmark of an appropriate randomized control cohort of patients to meaningfully demonstrate the improvement in outcome. I think actually the path forward for accelerated approval here is pretty straightforward and could be readily realized. That would then be contingent on subsequent study to validate and for full approval. I think the FDA is very sympathetic for diseases like GBM, where we're struggling so much trying to come up with better therapies and is supportive to try to encourage the development of promising new treatments to raise the bar here. I think it's going to be important to think carefully about the registration plan, but an accelerated approval path I think would be very exciting and potentially achievable, and I hope in the shorter term. One last question, if I may. In your pan TCE, what was the in vitro study? Was there a difference in terms of the ratio of Vδ1 versus Vδ2, or does it matter at all? Just curious about the potential PK and PD profile. I think that right now we've shown that we expand both the Vδ1 and the Vδ2. I think specifically in the autoimmune background, where you see dysregulated patients, you see more stark differences sometimes in which compartment is expanding more, though that can happen in healthy individuals as well. Some of that can be a function of the T cell engager, but it can also be a function of your background immunity. If you just had an infection, if you just had something going on, you may also have one compartment that's slightly more responsive than the other. The goal really of the pan-γδ T cell engager is to activate both, because really they evolve together and they work most powerfully together. Prior approaches to T cell engagers focused on just either the V delta ones or the V delta twos, and I think that may have been part of the challenge because it is difficult to predict which patients will respond or how well they will respond, and that can change over time as well. I think TBD as we bring it into the clinic, but I think from what we've seen in vitro, it's very exciting and we see strong responses from both compartments. Yale Jen from Laidlaw & Company. Thanks for the R&D day. It's very comprehensive. I appreciate that. We got two questions here. The first one is in terms of INB-619, that the animal study will be a critical one for the next round of financing as well as moving things forward. What's the expectation you may have for, let's say, successful animal study, and how would that help to move to human study in probably next year? I follow up. Yeah. I can give a somewhat high-level answer to that. We're in a number of different animal models right now. I think the standard when you're looking at anything relating to CD19 is looking at B cell depletion. I think you want to make sure that that translates efficiently from where we've seen it in vitro to where we see it in a whole animal model. Clearly looking at CD19, there's a number of different models available across oncology and autoimmune to be able to look at B cell depletion. The key criteria for us is we have to be able to look at B cell depletion and gamma-delta T cells. The majority of these models were originally designed or conceptualized to just look at alpha beta T cells, which are a much more larger subpopulation. We're being very careful in how we design and execute these models to be able to look at our engager. I know that's very high level to answer your question. I think that, again, you can start to get deeper, look at things like cytokine response and proliferation. The very first target would be B cell depletion. Great. Thanks. In terms of the FDA meetings later this year about the 200/400, what might be the total clinical package you may have? I assume it include the one you are going to present later at ASCO, but would there be additional things before you talking to the agency? I'm on mic. I think we'll be presenting an update on the data that Kate talked about at ASCO, updated median overall survival data. I think going to the agency, it's not just about the data that we have in hand, but it's talking about what a protocol might look like, what the statistical analysis plan would look like, if we have any CMC questions or whatnot. The guidance is to go to the FDA as a potential Type B or Type C meeting and get guidance on what would be acceptable on a registrational trial. Okay. As Dr. Reardon suggested, we actually didn't prompt it, if there's any pathway for accelerated approval. I think there's a lot of data we can bring to them, a lot of the correlate data we've looked at. Again, all of this needs to be confirmed in larger studies, but we do think it's very exciting because as GBM has not seen movement in standard of care in over 20 years, we think that all the data that we can bring to bear, not only on patient outcomes, but understanding why we're seeing those outcomes will ultimately be an important part of discussion with FDA. Great, maybe just one question for Dr. Reardon. I know you're talking about your standard of care for GBM. Just curious, I know the Avastin never improved the survival, do you use that periodically? Thanks. Bevacizumab or Avastin is approved in the U.S. for glioblastoma patients. It's based on a progression-free survival benefit, not an OS benefit. It does help patients. We do routinely use it for patients. We tend to use it when we have to. That's typically when patients are starting to get symptomatic or developing worsening symptoms related to the growth and progression of the tumor. Avastin can have an important benefit in decreasing a lot of the swelling and edema associated with that infiltrating leading edge of the tumor that's causing patients to develop significant decline. The only counter-therapy to that process that can help patients symptomatically is steroids. Steroids, particularly the ones that affect the brain, dexamethasone in particular, have a myriad of significant side effects that ultimately become very problematic for patients. Most of my patients hate being on steroids as much as they hate their underlying tumor. Bevacizumab, because it decreases the permeability of the blood vessels in the tumor, leads to decreased swelling. It's not anti-inflammatory like the steroids, but it allows us to accomplish the same endpoint, the swelling can decrease, patient symptoms can improve, their quality of life can improve. We use it when patients are developing those symptoms and having those issues. There are rare but serious side effects of hemorrhage and stroke and blood clots and intestinal perforation. Another reason we don't use it liberally or use it when we need to use it. It can help and improve quality of life. As you mentioned, unfortunately not improving survival. Can I do a follow-up? Bevacizumab or Avastin is the anti-VEGF, right? Anti-VEGF dries, essentially shrinks the blood vessels. One of the risks in GBM in the MRIs is looking at fluid flow. The risk is you're getting a false PFS because you're shrinking or drying up the vasculature. We looked at that. Across all the patients that were treated, only two actually received any Avastin. We also looked at dexamethasone use. In the treated periods, the reason why we actually went into the maintenance phase for treatment and not during the induction phase of daily radiation and chemotherapy was so we could actually taper off the dexamethasone. Putting a patient on an immunotherapy in the face of 16 mg a day of dexamethasone doesn't do anything. It shuts everything down. Those who've known me for many years know that I am critically focused on all the details, and I am a cynic as an ex-Wall Streeter, right? I look at ways in which we're going to fail. I looked at whether or not patients were on Avastin. Is that why we're seeing the difference of PFS? I looked, did we enroll a whole bunch of KPS scores of 100, and that's why they're doing better? In fact, we weren't, right? The median KPS was 80 coming in. We had a vast majority of 80s, some 70s, I think 90 or so, and there was not a big change. We looked at every which way in which we may be biasing our numbers. I even looked at the analysis of the total patients and said, "What happens if we take 30% off?" We'll take 33 patients off of the 10 on the control arm, four patients off the top, and we still get greater than 30% change in PFS. Thank you, everybody. Well, Will and Kate, great update today. Curious on the T cell engager program, as you think about treating patients, if there's the possibility looking ahead of redosing or repeated dosing for that particular treatment. Second question is, as the program continues to mature, conceptually is the thought of multiple warheads or payloads that you might be able to include in that therapy and so hence, I guess, that brings you into a bi- or tri-specific type of therapy. Thank you. Do you want to go on the- I can at least tackle the first question in terms of redosing. I think that's a really important question. If you do need to redose, that's part of where the cell therapy is in autoimmune or the CD19 cell therapies become even more complex because you are continually lymphodepleting those patients in order to redose. The benefit of the T cell engager is that you would not need to. I think what we've actually seen is in our cell therapy patients, we dose and we actually see elevated and persisted gamma-delta T cell levels out over a year, and we show that positively correlating with survival outcomes. We know that those elevated levels of gamma-delta T cells in patients have been shown to be safe across multiple settings. I think that the idea of redosing with a gamma-delta T cell engager where you're not hammering that immune system where you're targeting, I think would be something that we could absolutely consider and could be beneficial. Just to follow up, I think we have to look at the animal data and see what the PK/PD is. Arguably, with any kind of engager, it does allow you to redose. Again, people often ask the question, as I said earlier, does the gamma-delta T cell actually deplete B cells? Adicet's data definitively shows you can deplete B cells. Their challenge, I think, is the question if you look at their data, they deplete them from 21 days, 21-28, they come back. We think it may be because of allorejection that the cells come back. The question is, compare that to Georg Schett's data. Georg Schett's original data, they showed that the alpha-beta T cell, because it has an autologous, it can knock out the B cells. The B cells don't come back until day 85 or day 100. The question is, does the difference of B cell depletion from day 28 to day 85 matter? Nobody knows until the clinical data comes out. With this particular approach with the T cell engager, arguably, yes, you can redose to knock down those T cells. In addition, I'd say our molecule actually is a trispecific, so we have other moieties on it that helps drive our expansion domain. There is one other company that just came out and raised financing, Cytospire. They're not in CD19. They're not in B cell depletion. They are leading with the EGFR gamma-delta. Turns out two teams, both with experience. I think our advantage is we have over 35 years of experience with the biology of gamma-delta T cells, and our team has put two programs into the clinic, and so we have specific clinical expertise. Their poster that came out at AACR showed with at least EGFR, not only does it knock down, but they can redose and there's actual definitive biologic effects. I think T cell engagers with a gamma-delta T cell can work. Amazing presentation, guys, and thank you for taking our questions. Just a quick one for Dr. Rochlin. On the slide that compares blinatumomab and mosunetuzumab, there was a more deeper response early on at day two from the other two assets compared to 619. Your overall B cell depletion was the same at day four. Does that early response matter in an autoimmune oncology setting or? It's a great question. Really that slight delay in response that we see is because of the system that we're working in. We actually expand the gamma-delta T cells, that little two-day lag that you're seeing is where those gamma-delta T cells are kicking off, and they're starting to expand and activate. While we do see a slight delay, you see that it catches up very quickly. In a way that sort of ensures us that the biological mechanism that we think is happening, where it really is the expansion and the activation that's driving that efficient depletion, that is that little bit of delay that you're seeing. I think from a therapeutic standpoint, I don't necessarily think that would be an issue. It is quite a short lag. We have looked across multiple donors, both autoimmune and healthy, to see if we see differences in that, and it seems to be somewhat consistent. Even in an autoimmune background, and that one was autoimmune, we don't see a really long lag. We don't see autoimmune taking a week to activate, whereas healthy took a day. It seems to be very consistent in that sort of quick kickoff. You're correct in your interpretation of the data. Thank you. Any further questions? Thank you. I just want to say, I think you guys did a really good job at explaining the science without dumbing it down too much. My question is, on your pipeline on the website, you have both autologous and allogeneic GBM INB-400. What's going to be the difference in that actual product? Is it just further engineered to be? I can speak to that. Yeah. When we first went to the FDA, and this is in the way back machine, we went to them and said, "Gamma delta T cells are known to be able to go from donor to recipient without any type of issues. They don't have to be HLA matched." We went to the FDA, and we said, "This is our great idea. We're going to do the first people that have ever done genetically modified gamma delta T cells. We're going to do it allogeneic, and we're going to infuse it directly into the brain." They said, "That sounds great, but no way." We knew the biology should work that way, but so we had to take it a step back, and actually, this program we talked about today was the very first genetically modified gamma delta T cell that was put into a human, was INB-200. Adicet came a little bit after that. We started with autologous, to your point, and the goal would be when you're talking autologous and GBM, these patients do tend to be a little bit older. They have a tumor that it can be immunosuppressive. They are not always doing really well. We can manufacture from those patients. If we were able to manufacture from a donor, that could be a more efficient process. The question you ask, though, is, are the products the same? Of course, they're not, because when you have an allogeneic product, the release criteria are going to be slightly different. It's not actually more engineered, but the final composition of the product is a little bit different, and that's per FDA guidance on what they consider an allo versus an autologous product. We actually can manufacture both already in our lab, and so our leukemia program is allogeneic. We're very comfortable with those criteria from FDA. Starting with auto was more that we were going genetically modified into the brain and wanted to de-risk that before bringing allo forward. The data we showed today was all auto, so that would be the thing that would go forward more quickly. I think thinking about allo in the long term, though, still makes sense. Thank you. I wanted to do a follow-up on that as well, because the term off the shelf gets thrown around a lot for various products. If you look at this one in particular, assuming that allogeneic moves forward and universal donor moves forward, you have a box of cryopreserved vials from a universal donor that any neurosurgeon in the country could pick up the phone and say, "I'm getting ready to do this resection in three days. Can we do INB-100 or INB-200? Can we ship these cells and use them?" The concept is not hard to understand, where a bank of these cells can be frozen and available, that can be ordered by any hospital pharmacy. I will mention strategically, as a company, as a board, we will interact with our investors. Look, the environment has shifted dramatically over the last five years, right? When Larry and I first started the company, I came across it because I was an investor looking at how do you get to allogeneic and iPS-derived cell therapies, especially against solid tumors. There was a hype cycle, things got really exciting, and then all the allo cell therapy companies crashed. Today, every single one of those companies has become an autoimmune company and unfortunately dropped their oncology programs. I think there's still biology that doesn't make sense. I think if you go back to Georg Schett's original New England Journal paper, not everybody realizes this, but there's some language in there that doesn't make sense. What he said in there is that the reason that CD19 CAR T works is that the CAR T can get into tissues that the engagers, and early on he used Rituxan. We have blinatumomab and others. They can't. That doesn't make sense. If the CAR T can get into a tissue that an engager can't, in oncology, everybody should be pursuing CAR T, because that means you can get to deeper remissions with the CAR T. They don't. In oncology, where we can dose higher, where we can use higher affinity interactions between the CD3 or whatever binding domain, we know that Rituxan works in B-cell diseases, right? We know that blinatumomab is highly efficient. It has a poor PK because of its small size, but it's highly efficient at depleting B cells. There's this crosstalk in those papers that people don't seem to realize. It's probably because of the biology, not necessarily CAR T. Things will ebb and wane. CAR T and cell therapy's been out of favor for a little while. Hopefully, one day it comes back, but we will do everything looking at the biology, looking at the markets, looking at investors and the capital markets and what's feasible. Thank you. To the point of risk, are you guys able to share what method you're using to genetically engineer the cells? It is publicly disclosed that we use a lentiviral vector-based modification in these cells. Thank you. Yes. To Rich, actually, I thought about this. I never made this comment. This is actually fascinating. Right now, one of the hottest things in biotech is in vivo CAR T. Everyone wants an in vivo CAR T. If you look at the recent AstraZeneca data, they had five patients. Of the five patients, every single one of them got CRS. One of the patients, three of them were Grade 3. Unfortunately, 1 died. I was having a conversation because investors come to people. They say, "We want in vivo CAR T." They think, "Oh, I'm going to take this risk." Thank you for this question. I'm going to bring up an anecdote, a conversation that I had with my wife a couple of weeks ago. She has a PhD. She does licensing at one of the major hospitals, and she early on spent six years on Wall Street. She said, "Everybody's coming to me for in vivo CAR T." Everyone is coming saying, "Do you have in vivo CAR T?" Everybody's interested. You've seen some of the deals, $2 billion for a preclinical asset and whatnot. There was a brief period of time for about eight months that she actually went to a well-funded gene-editing company out in San Diego. She said, "Everybody's coming to me asking if I have in vivo CAR T technology." She said, "I was at a gene-editing company." These gene-editing companies are looking at monogenic single protein deficiencies and trying to inject locally in order for muscle or some other tissue to produce this single protein. It's like everybody wants a multi-protein structure that I'm going to infuse into someone that's supposed to get into one cell type, an alpha-beta T cell, delivered systemically. It's like nobody will touch gene therapy because the AAV and the LNPs kill people, and you have liver toxin, everything else. Yet everybody wants in vivo CAR T that I'm going to deliver systemically that's supposed to get into a single cell. Some of these companies are targeting CD7 because CD7's expressed onto the surface of a lymphocyte. It's already also expressed on the surface of an HSC. If I put a stimulatory domain or a promoter onto an HSC, that's called a leukemia. Everything has risks, but we think our approach with both the cell therapy and the T cell engager, the way our structure is actually formed on the T cell engager, if we can demonstrate that it works, we think it's transformational. It does everything it's supposed to without the tox. It drives expansion, and it functions like an in vivo CAR T without all the fancy gene engineering. I like to use this. Steve Jobs had said at one point when he was alive, "In order to get things simple, your thinking has to be so on target, because simple is hard." All kinds of people do all kinds of things with engineering and think there's no risk, but there's always risk, and we've taken approaches that are simple but elegant and addresses the biology. Any other questions? Well, thank you everybody for joining today. I want to thank everybody in the company and Dr. Reardon for joining us. I think it was a wonderful R&D day, and thank you all for your interest and your continued support.