All right. Welcome to the B. Riley Virtual Oncology Conference. I'm Andy Fletcher, a Research Associate on the biotech team here at B. Riley. Our next presentation comes from IN8bio, and I'm pleased to be joined today by IN8bio CEO, William Ho, and CFO, Patrick McCall. If you have any questions for us, please email them to me at afletcher@brileyfin.com. Will, Patrick, thank you for joining us today. I will let you have the floor. Great. Thanks, Andy, and thank you everyone for joining today online and through YouTube, at this conference. We appreciate the team at B. Riley inviting us and giving the opportunity to speak. To kick it off today, as we started a new year, the team at IN8bio wanted to come up with a new mission statement, and we came up with something simple, Cancer Zero. That's our goal. Our team believes that Cancer Zero can one day be a reality, and our goal is to challenge the status quo and design programs with our gamma-delta T-cells that can one day really come to the benefit of patients, hopefully by eradicating their cancer. On the right-hand side here, or on your left-hand side here, this little green tri-trinket is actually a gift that was given to our scientific founder, Dr. Larry Lam, 30 years ago. 30 years ago, it was given to him by a little six year-old girl who was being treated for her leukemia. Unfortunately, she didn't make it and ultimately passed from her disease. It was that experience that led Dr. Lam in 1992 into the stairwell of a hospital in tears and made him start his journey into what might make the difference for cancer patients. It was through that he actually found the gamma-delta T cell and its association with better survival outcomes. On this slide, the data set in the middle, that Kaplan-Meier curve, is actually Dr. Lam's. In the mid-1990s, he actually found that patients being treated for their leukemia patients as their immune systems reconstituted, those patients that had higher levels of gamma-delta T cells actually did significantly better. Through the years, numerous other publications on the left-hand side from Stanford in 2019, on the right-hand side, a separate study out of Europe in 2017, replicated that data and demonstrated that gamma-delta T cells are associated with better survival outcomes in cancer patients. These are powerful killers. Here in this slide, we're showing gamma-delta T cells in white, and what you can see is they're swarming, aggregating, and killing a brain tumor cell, which is expressing green fluorescent protein and showing up as green. Ultimately, the gamma-delta T cells are able to completely eradicate and eliminate all of the tumor cells in this microscopy. We're focused on developing gamma-delta T cells as a cancer therapy. Our thesis to be successful in cancer therapy sits on three legs. 1. We believe we have to demonstrate durability for cancer patients. Unfortunately, it doesn't matter if the tumor shrinks, if the cancer patient ultimately relapses within weeks and ultimately dies from their disease. 2. We believe we have to have tolerability. With the advent of cellular therapy, the early experiments with alpha-beta T-cells were powerful, but adverse events such as cytokine release syndrome, tumor lysis syndrome, and neurotoxicities have all resulted in patient deaths. We believe that we need to have a more tolerable therapy, and we believe gamma-delta T cells can play a role. Finally, to target the entirety of the tumor, especially against a solid tumor, we have to be able to target the heterogeneity of the tumor. The natural endogenous receptors of the gamma-delta T cell can do that. My apologies for the phone. We've advanced a deep pipeline. Today, we have three clinical programs. INB-200 is our first solid tumor glioblastoma. We announced data two weeks ago, very encouraging patients remaining in long-term complete remissions. INB-100 is in leukemia patients, the first donor-derived gamma-delta T cell program into the clinic, and here again, we're demonstrating long-term complete remissions and the potential safety of donor-derived cells. Late last year, we cleared our 3rd IND. This was our first corporate-sponsored IND for INB-400, an autologous program entering into phase II in frontline glioblastoma. We have a deep pipeline behind it. I'm looking forward to telling you more about it today. Underlying our approach is actually a concept that is very different. Over the last 10 years, investors and others have been trained to look solely for responses. Here I have a number of curves describing the progression of potential patients, a tumor. If we didn't treat a tumor or the tumor is resistant to conventional standard care, the patient would have very rapid progressive disease and would follow along this red curve. With conventional standard of care therapy, such as chemotherapy, surgery, and radiation, we follow this blue curve where we see a response. Unfortunately, we know that ultimately, while we can shrink the tumor, all of these patients eventually relapse, and unfortunately, most of them will pass away from the progression of their disease. At the nadir, at the trough, all of the cells that remain are unfortunately resistant to conventional care, and they grow back very rapidly. With the advent of checkpoint inhibitors and immunotherapies in around 2010, 2011, it was actually the early programs such as Yervoy almost died because there was a question, how could these therapies be prolonging life when we can't see tumor shrinkage? In fact, the early data showed that Yervoy only shrunk tumors by about 10%. In fact, now today we know we may actually get progression or pseudo progression, but the progression of the disease follows this yellow line where we have durable remissions. Our goal is to do better. Can we use what's in our armamentarium with the standard of care to shrink the tumor to its maximum ability? Then can we dig deeper? Can we use novel immunotherapies to target those cells that are resistant or the cancer stem cell populations, and elicit an immune response to change the direction of the curve? Ultimately, if we can do that, we can achieve durable responses, and perhaps one day we may be able to achieve Cancer Zero. To develop our cell therapy, we're focused on the gamma-delta T cells. Today, we have one of the most comprehensive platforms out there. We can develop Vδ1s, we can develop Vδ2s, and we can create both sub clones from induced pluripotent stem cells, giving us the potential to one day go towards off-the-shelf cell therapies. Once we pick a cell, though, we still have to determine ways of targeting the tumor. There have been very successful CAR-T targeting CD19, CD20, and BCMA, but the bigger challenge has been solid tumors. Solid tumors are heterogeneous. We have to find the unique target that's on the tumor cell, all of the tumor cell, and none of the healthy tissues. Unlike in CD19 and BCMA, where we can ablate the entire B-cell compartment, we can't do that with many of the other leukemias, such as T-cell leukemias or many of the solid tumors. Unfortunately, the patient still needs their organs, and it's very difficult to generate the therapeutic window. As we look, this is what's known as an H&E stain. This is staining where the healthy tissue is pink and the tumors are staining purple. On the left-hand side, these are blood cancers. ALL, where we've seen significant success with the CD19 CAR-T. On the top, this is within the blood. As you can see, the tumors are widely available. If you think about the video I just showed you, it's easy for the T cells to swarm or the immune cells to swarm and to aggregate and to kill those blood cells that are floating around in the plasma. In the bone marrow, there's still space. You can see, densely packed tumors, but there's still space, and immune cells come from the bone marrow, so it's an environment that's conducive to effective therapies. On the right, this is a solid tumor, a glioblastoma. Unfortunately, you can see the large mass of the cells. In 1 gm of a solid tumor, there may be as many as 1 billion tumor cells. We have to find a way to target this and to target the heterogeneity. In fact, it's not just the mass. If you look carefully, I could surgically resect all of the mass and have an edge. If you look carefully along the left-hand side of that, in that pink healthy tissue, there are plenty of individual tumor cells that may remain. That's the challenge. How do we target those? Our chemotherapy-resistant cell therapy or CRCT approach is unique and differentiated. When a patient presents with a tumor, they have a big, bulky, heterogeneous mass. Most of that can be resected through surgical resection and treated through conventional care such as chemotherapy and radiation. Unfortunately, as we drive the levels of the tumor down, what's left is residual disease that is resistant to cancer therapies. If we kept on treating, we would get tumor progression, a big, bulky, resistant to patient tumor mass. Unfortunately, the patient would most likely die. Our approach, as I said earlier, is can we do better? Can we dig deeper and target those other compartments? We found a way to use the gamma-delta T cell in combination with chemo. With certain chemos that are known as alkylating agents, they function by triggering the DNA damage response or the DDR pathways. What we found is the DNA damage response can be incredibly powerful in generating an immune response. In fact, people thought in 2016 that chemotherapy was going to disappear, that we would move towards CAR-Ts and targeted therapies when companies like Bristol and Merck found that immunotherapy combos with chemotherapy are incredibly powerful. We can generate immunogenic response. We can generate an immune signal. What we found is we can actually force an upregulation of the NKG2D ligands. Those are the innate stress ligands that tell your body that there is DNA damage, and those cells should be eliminated. The problem is that many of the chemotherapies that can drive that signal also kill white blood cells in a process called lymphodepletion. If I have a signal but my white blood cells are all dead, it doesn't matter. That's what we fixed. We found a way to genetically engineer our gamma-delta T cells by hijacking the tumor's own resistance mechanisms and genetically engineering them into our cells so that they can survive combined dosing. That allows us to upregulate an immune signal on those cells that remain. Because our cells can survive, we can then target those other compartments. This is the data demonstrating that. On the left-hand side, these are chemotherapy-resistant glioma cells. These cells do not die from chemotherapy. What you can see here is an upregulation of the innate stress ligands, in some cases by as much as an average of 600%. On the right-hand side, these are glioma stem cells. They express transcription factors like KLF, Oct-4, and Sox2. So these are often quiescent cells. Again, by dosing with chemotherapy, we can upregulate an immune s-marker on these cells. This is important. At the recent Society for Neuro-Oncology in November, I attended a scientific session. Luis Pereira at Memorial Sloan Kettering had indicated if you don't target the cancer stem cells and those cells that are resistant, it doesn't matter. Those cells will be given the opportunity to grow back, and the patient will ultimately progress and die of their disease. Our goal is to do better. Our INB-200 program is in solid tumors. Our first indication is newly diagnosed glioblastoma. It's a 3 + 3 design. Patients get an escalated dose from 1- 3- 6 doses. They will dose escalate from 10- 30- 60 million total gamma-delta T cells. This is in the front-line setting where patients are diagnosed, they're surgically resected. At that point, we apheresis them or manufacture a product that is cryopreserved. They undergo six weeks of daily radiation and chemotherapy. We don't treat them at that period because the radiation often causes edema that requires the use of corticosteroids. In the maintenance phase, the patients receive cycles of chemotherapies five days every 28 days for up to six months. Within the first few hours of receiving the chemotherapy, we infuse the gamma-delta T cells directly into the tumor bed by going through a catheter that we inserted into the patient's skull. We pursued glioblastoma specifically because we can deliver cells directly through that catheter. It reduces the variables in the hypothesis test of the clinical trial. We don't worry about T-cell trafficking, and we know they're in the tumor because we put them there. As we move towards the holy grail of allogeneic cell therapies against solid tumors, the advantage is that historically, the brain is considered immuno-privileged. We're not worried, too worried about a process known as host versus graft, where the patient's immune system will wipe out the infusion that you gave. In addition, the complexity of bringing transplant protocols such as lymphodepletion into the solid tumor setting is tremendous. Another advantage of going to glioblastoma is the standard of care since 2005, temozolomide, is, in fact, itself lymphodepleting. We don't have to deal with the complexity of lymphodepletion, and these patients are lymphodepleted through the standard of care for a period of 12 months. The standard of care, as I mentioned, hasn't changed since 2005. The median overall survival, unfortunately, is very short at 14-15 months. The progression-free survival is at seven months. In those patients who are unmethylated, which means they don't respond to chemotherapy, it's even shorter at only five months. For the older patient, this paper on the right-hand side came out also in The New England Journal of Medicine. 12 years later, it's even shorter. Overall survival is five months shorter, and progression is only about five months. To date, we've treated eight patients. We have not seen any significant treatment-related adverse events. We have not seen any dose-limiting toxicities. Importantly, we haven't seen the typical cell therapy toxicity of cytokine release syndrome or the neurotoxicity or ICANS. Most of these events are actually related to the underlying chemotherapy. We've had two patients die of progression of disease. Unfortunately, we've had three unrelated deaths, including cardiac arrest, sepsis from a ruptured pancreatic cyst, and a pulmonary embolism in a patient. Thus far, we're encouraged by the safety profile, and we do not see increased toxicities as we increase the number of cycles and the dose. Here, our durability of response is listed in this swimmer's plot. The patients who received a single dose are listed in blue. The individual doses are demarcated here by the orange circles. Where we expected them to progress are actually noted by the vertical orange lines. The median progression-free survival across all patients is seven months. All patients that received a single dose went beyond that. In fact, as we show here, all patients went beyond their expected progression-free survival based on their age and their MGMT status or the response of the chemotherapy. What we're encouraged by is that as we've increased from 1- 3 doses, we're actually seeing longer progression. None of these patients have actually progressed. Unfortunately, patient 014 did die of a pulmonary embolism. They had an MRI just a few short weeks before their death and actually showed no signs of progression. The two additional patients treated with three doses, we announced it three weeks ago that they remain progression free and stable, one out 18 months and one out 15 months. We're encouraged. Patient 009. Actually, they're both clinically asymptomatic off of treatment, and patient 009 we're aware actually went back to work. Improving the patient's quality of life and the durability of response is what we're trying to do. We've initiated dosing in the third cohort where patients will receive up to 6 doses. As of December 31st, patient 015 has received 5 doses. Unfortunately, that patient did show signs of progression, but not locally in their brain. Over 95% of patients with glioblastoma relapse within centimeters of the original resection cavity and ultimately progress and die of their disease. Unfortunately, this patient progressed due to leptomeningeal disease. They had a progression down in their spinal cord, down towards their the sacrum or towards the end of the spinal cord. We will continue to track these patients and actually provide an update in the middle of this year. What's also interesting, because we often get the question: How do you know you're doing anything? In patient 001, I note there's a little A and a little B. A is where that patient was first diagnosed, and we actually have tissue samples. B is where they ultimately relapsed, and what's interesting is we actually find evidence of immune activity. Glioblastoma is historically considered immuno-privileged or cold. Here, these are H&E stains. The tumor stains a dark purple. In A, you can see there are not a lot of gamma delta T cells. We're staining for gamma delta T cells. On the right, we did a digital subtraction. Below in B, we're seeing apoptotic tissue on... or necrotic tissue on the upper right. Below, we're actually seeing infiltration of gamma delta T cells. We've actually stained. We see infiltration of alpha beta T cells, B cells, NK cells, and the gamma delta T cells, and so we're excited. Moving on, INB-200 is our second program in leukemia patients undergoing a haploidentical transplantation. Here, we are trying to test the safety of donor-derived cells. It's a 3 + 3 design. Patients will receive escalating doses from 1 x 10^6 to 1 x 10^7 cells per kilogram. This is the first time a donor-derived cells have been given in a patient completely myeloablated for transplant. It's being run at the University of Kansas. The goal was, as patients' immune systems are ablated for transplantation, there's a period of about 90- 100 days in which they're vulnerable to both viral infection from reactivation of Epstein-Barr virus or cytomegalovirus, and as well, engraftment of residual leukemic cells. Unfortunately, as the haplo transplant protocol or what's known as the Hopkins protocol with post-transplant SLA was originally developed, Leo Luznik and Ephraim Fuchs from Johns Hopkins University, found that the relapse rate is actually high. It's 51% at one year. Here, we're showing the Kaplan-Meier curves. You can see the relapse rate at one year on the top, and the mortality rate is inversely correlated. If the patients relapse, they unfortunately die, as you can see in the survival curve below. The patients we've enrolled thus far as of December 9th are here. I'd like to point out the cytogenetics. We did not cherry-pick these patients. These are high-risk patients. Some of them have relapsed, but they include genetic and cytogenetic abnormalities, including trisomy 8, DEL7, FLT3, IDH, and other mutations. Some of them require, such as patient 009, required multiple rounds of induction therapy just to get their tumor down so that they can be transplanted. We're encouraged. We announced additional data earlier in December that all of our patients treated thus far remain in complete response. In fact, the first patients are now out over two and a half years. We have two patients over two years, the third patient treated remains over 18 months in complete remission. We're excited about the progress that we've made, and we will provide updates this spring, likely at the EBMT conference. I'm proud of the team. In December, we announced the clearance of our first corporate-sponsored IND, INB-400. This is meant to push our INB-200 program towards phase II clinical trials. This will be enrolled at 12 centers around the country, and the center includes major glioblastoma and transplant centers such as Duke, City of Hope, UC San Diego Health, Cleveland Clinic, Moffitt, among others. We're initiating those sites now and look forward towards enrolling the first patients by the 3rd quarter of this year. As we move forward, as per new guidance, finalized in November of last year, the allogeneic product will be a separate drug product and require a separate IND. That IND will entail the phase 1B, bringing a donor-derived product into the relapsed glioblastoma setting. If that appears safe, we will move to both arms B and C and test the difference between donor-derived and autologous patient-derived cells in the front-line setting, but also running an expansion cohort in arm B in the relapse setting that could potentially be registrational. We're encouraged. Last year was a difficult year across all biotech. We executed and delivered everything we said we would with clinical data at numerous medical meetings, the announcement of an iPSC-derived gamma-delta T-cell program in the spring, and the clearance of our own corporate-sponsored IND late last year. This year will be a busy year with numerous anticipated milestones throughout the year. We've built a tremendous team with deep experience in gamma-delta T cells, in finance and business, as well as in clinical development with Dr. Trishna Goswami, our Chief Medical Officer, having joined us from Gilead in Immunomedics. We're excited about the power of gamma-delta T cells. We're excited about everything that we've accomplished since our formation in 2016. We have a lot more to do. We have a unique platform developing gamma-delta T cells with unique know-how in how to expand and to genetically engineer gamma-delta T cells at scale. This has proved to be a robust platform with reproducible manufacturing. Very recently, we cleared the CMC processes through the FDA. Our team has tremendous and strong expertise across the breadth of development and the operations of a biotech company. We have ambitious goals. We have ambitious timelines. We're excited about the progress that we made, and we welcome you to join us in our journey as we seek to accomplish our mission of Cancer Zero. Thank you. I'll open it up and see if there's any questions. Andy, I think you had a few. Yeah. May be time for one quick question, Will. Related to INB-100, how many patients worth of data do you feel that we need to really get a good sense of the impact that you're having on complete remission in the post-transplant setting? Look, we actually believe that the data that we have is actually quite promising already. I think if you wanted a controlled study, very similar study run years ago by Dean Lee when he was at MD Anderson, with a similar protocol in the post-transplant setting, with NK cells and gamma delta instead of gamma delta T cells, showed a separation of the survival curves across only 20 patients. In this particular study, in fact, we believe there's already a signal there. It's not statistically significant yet, but if you go back to the one of the research articles that you guys had actually published a few months ago, look at the cytogenetics of these particular patients. In that research article, you actually found an article looking at patients with high-risk cytogenetics. In particular, in that paper, they indicated, as an example, those patients with DEL7. The relapse rate for DEL7 mutations is actually 75% at two years. When we talk to KOLs, many of them will say that most of the patients with similar cytogenetics in our own patients thus far, by two years would have expected to relapse. Almost all of them. Essentially 95% of them. We're encouraged. With just a handful of patients, we see that we have morphological CRs out two and a half years. All the first-treated patients have gone by 18 months. The reality is, early on, some of our advisors had said, "Look, you have two patients beyond one year. If you have a third patient hit year, you have something." That third patient is now at 18 months. We believe that if we come later this year at various medical meetings and announce that all of these patients are in CR, that that will continue to be encouraging about the potential. Look, at this point, I have two trials, two indications, two different patient populations, two different clinicians, two different hospitals. Both of them are demonstrating robust data with durable, complete responses. We're excited about it. We don't believe that it's an accident. It supports our preclinical data in solid tumors demonstrating a complete eradication of the tumor. We're already excited about what we're doing. Great. With that, I think we are out of time. Thank you, Will and Patrick, for joining us today, and we look forward to updates from IN8bio throughout the year. Thank you to the audience for tuning in. Thank you.