Good evening, and thank you very much for joining us for our review of the TScan preclinical data for our TSC-100 and TSC-101. I'm David Southwell, the CEO of TScan. We're going to start with the preclinical data from TSC-100 and TSC-101, which will come from Gavin MacBeath, who's our Chief Scientific Officer. Then we'll have a review of our clinical study design by Dr. Sri, who's our VP of Medical. We'll talk about the unmet need and the standard of care from Dr. Chen. Dr. Chen is the director of hematopoietic stem-cell transplant and cell therapy at MGH, and he's also an associate professor of medicine at Harvard Medical School. He has his undergraduate degree from Yale, and he attended Harvard Medical School, and he's been working in this field for a very long time. We think he's really the ultimate key opinion leader for the program that we're going into. After that, we'll go to questions- and- answers. I've presented Dr. Chen. I'm David Southwell. I'm the CEO of TScan. I've had a number of executive positions at both pharmaceutical and biotech companies over the years. Gavin MacBeath, who's our Chief Scientific Officer, was the Harvard professor, and after that, he was the scientific founder of Mirna Therapeutics. After a number of other appointments, he joined us as our Chief Scientific Officer. Gavin and I have worked together now for about three years. Sri is a medical doctor. He's also our VP of Medical, and he is in charge of this program, so we're excited to have him on board as well. With that, why don't I hand it over to Gavin to give you a brief review of our technology. Great. Thank you. Before I dive into this program, I just want to highlight the fact that TScan Therapeutics is a T cell therapy company, and we have a number of programs in oncology, both a program focused on hematologic malignancies, which is what we'll be talking about today, as well as a solid tumor program. The program we're talking about today is focused on patients with AML, MDS, and ALL. This program is actually going into the clinic early next year. We're filing two INDs concomitant with each other this month, and then we'll be initiating clinical development shortly thereafter. As many of you are aware, patients with AML, MDS, or ALL after receiving frontline therapy, very often become eligible for allogeneic stem cell transplant therapy. The way an allogeneic stem cell transplant works is the patient is matched with a suitable donor, and the patient starts by receiving conditioning chemotherapy, which is intended to eliminate their cancer cells, but also eliminate their normal blood cells. Then following the conditioning therapy, they receive hematopoietic stem cells from a related donor so that following the transplant, those donor-derived stem cells then repopulate their entire blood system. You'll notice in this diagram that the new blood cells are colored blue to indicate that those blood cells are genetically identical to the donor rather than to the patient. Unfortunately, many patients that receive stem cell transplants often relapse, and if they relapse, they have very poor prognosis. About 90% of relapse patients will die within a year of relapsing. The program that we've developed at TScan is based on targeting what are called minor histocompatibility antigens that are expressed exclusively in blood cells. Use TSC-100 as an example. TSC-101 is very similar in nature. TSC-100 targets an antigen called HA-1. This is an antigen that's present in about 60% of people worldwide. It's based on a polymorphism. This is a peptide that's derived from a protein called ARHGAP45 that's only expressed in blood cells, and it comes in two forms. If you have the histidine, this antigen is present on the blood cells, whereas if you have the arginine form, this antigen is not present. The way this therapy works is we're focusing on patients that are positive for this antigen who have donors that are negative for the antigen. What we do is, following the regular allogeneic stem cell transplant, we take T- cells from the same HCT donor, and we engineer them with a TCR that recognizes this antigen, HA-1. Now, following the transplant, we intend to treat these patients with these engineered T- cells, and at that point, those T- cells will target any residual cancer in the patient because the cancer comes from the patient and is HA1 positive, but it won't touch any of the new blood cells because those new blood cells come from the donor and are HA-1 Negative. This program is based on a well-established clinical observation. What's been seen in the transplant field is that patients that naturally develop T- cells against HA-1 or HA-2, based on a mismatch between the patient and the donor, very often have much lower relapse rates. In fact, this is an example of a patient that developed T- cells against both HA-1 and HA-2 following donor lymphocyte infusion, and that patient had an immediate regression of their leukemia. I just wanna highlight one key feature about HA-1 and HA-2. These are not cancer-associated antigens, like, for example, WT1, as you see on the left. Instead, these are much more similar to CD19 in that they are lineage-specific antigens. These are proteins that are expressed in all blood cells of hematopoietic lineage, and as such, have very uniform distribution. You can see on the left that the HA-1 levels and HA-2 levels across various patients with AML are very uniform, unlike a cancer-associated antigen like WT1 that has very, you know, great dynamic range. You'll notice on the right that these antigens are only expressed in hematopoietic cells and not expressed in any normal cells. In these diagrams, you see some expression in lung and small intestine, but this is actually due to contaminating blood cells in the samples that we use for these studies. These are in fact very hematopoietically restricted antigens. To develop a TCR therapy to treat patients, we relied on our own technology platform to discover TCRs that recognize HA-1 and HA-2. I'm highlighting the three key parts of the TScan platform, but it was ReceptorScan that we used in this case to discover new TCRs for HA-1 and HA-2. Just by way of summary, we were able to identify naturally occurring TCRs for HA-1 and HA-2 with very high avidity. You can see the EC50s of these TCRs are, you know, very potent. Then to develop a cellular product, we need to deliver the gene for that TCR into the T- cells of these HA-2 donors. But our delivery vector is an enhanced delivery vector. We actually use a transposon transposase engineering system to engineer the T- cells of these donors. In this system, we've made three key features to the delivery vector. First, the delivery vector delivers the TCR gene itself, and we've made a few small mutations in the constant region of the TCR to really promote high expression of the TCR on the surface of the T cells. Secondly, this is an enhanced T cell product because we co-deliver the gene for CD8 along with the TCR. What this does is it enables us to engineer not just cytotoxic T cells to recognize HA-1 or HA-2, but also helper T cells to recognize HA-1 or HA-2. The final cellular product is actually a mixture of both cytotoxic and helper T cells, both of which have been engineered to recognize their targets. Finally, we include a purification tag in the engineering process so that we can really purify the engineered T cells to remove any non-engineered T cells from the product. This is really important in an allogeneic product because we don't want non-engineered T cells to induce GVHD as part of the process. I'll just share two quick slides on some preclinical data with the TSC-100 and TSC-101. What these data show is that the product that we developed, shown in orange, is a very potent cellular product. It induces cytotoxicity in HA-1-positive cancer cell lines. It does so actually with higher activity than a competitor TCR that was developed to recognize HA-1. In the middle, you see that the T cells efficiently produce cytokines, and at the right, they proliferate effectively when they encounter target. On this slide, I'm showing you some data from TSC-101, which is the product that targets HA-2, and you see very robust activity of this engineered T cell product. Finally, this is the product TSC-100 on top and TSC-101 on the bottom, and their activity relative to primary AML and primary ALL samples from patients that are either HA-1 positive or HA-2 positive. What I'm showing in this figure is that this product is effective for patients that are either homozygous or heterozygous for HA-1 or HA-2. On the top, the dark blue indicates patients that are homozygous for HA-1. The light blue is heterozygous for HA-1. You see no difference in activity in the AML and ALL samples. Similarly, on the bottom, the dark purple is homozygous for HA-2. The pink is heterozygous for HA-2, and again, you see robust activity in the heterozygous samples as well. Then finally, just one piece of data around the toxicity profile of this product. On the left, as part of the toxicology package in the INDs, we tested the engineered T cells to see if they recognize any non-blood cells, so non-hematological cells. We tested it against a variety of normal cells, and we see absolutely no activity against normal cells indicative of no problematic off-target effects. On the right, the one safety concern that we have with an allogeneic product is potential graft-versus-host disease induced by non-engineered T cells in the product. You can see on the right mixed lymphocyte reactions in which the white bars are a non-transduced T cell product. The blue bars are TSC-100, and you can see when they're co-cultured with allogeneic antigen-presenting cells on the left, there's no reactivity observed with the TSC-100 product, whereas the non-transduced T cells show potent alloreactivity. With that as background, we're, as I said, filing INDs on these two products and we'll be putting them into the clinic in a multi-drug clinical trial. I will turn it over to Dr. Chattopadhyay to talk about the clinical development plans for this program. As we turn it over to Sri, I should mention that if you have any questions, please do enter them in the chat and we'll address them later on. Thanks, David. Thanks, Gavin. If you go to the next slide, I'd like to show you that we are on track of our liquid tumor program to embark on a multi-arm phase I trial, in which we'll be developing both products, TSC-100 and TSC-101 simultaneously. How this trial will progress is that all patients who are considered eligible for reduced intensity conditioning-based haploidentical donor transplantation will be enrolled in the study. They will be assigned to either the treatment arms or the control arm, depending on their HLA types and their minor antigen types. If they are HLA-A*02:01 positive and HA-1 positive, and the donor is mismatched either on the HLA type or the minor antigen type, then they get assigned to the TSC-100 monotherapy arm. If they are HA-1 negative, they are almost certainly going to be HA-2 positive, because that's present in over 97% of the population. If they have a suitably mismatched donor, they would be assigned to a TSC-101 monotherapy. Patients who have different HLA type, not A*02:01, would be assigned to the standard of care control arm, where they would receive transplantation alone. Now, the advantages of this design is that the inclusion of a control arm enables comparisons of both safety outcomes such as graft-versus-host disease rates, as well as early efficacy readouts such as donor chimerism rates between the treatment arms and the control arms. The same control arm is used as a comparator, so this makes for a more efficient design. Because we are developing two products simultaneously, it maximizes chances of patients receiving active therapy. That would be 40% of the patient population, and that should lead to faster recruitment. This kind of a design has the potential to transition seamlessly into a registrational trial, which would be a multi-arm, multi-phase study, pending regulatory discussions. In the next slide, we address one concern that's related to this HLA-based treatment assignment or randomization, which is that patients with different HLA types may have different outcomes. To address this concern, we collaborated with the CIBMTR, the Center for International Blood and Marrow Transplant Research, which is the largest registry of bone marrow transplant patients in the U.S. We compared outcomes of patients who are undergoing reduced intensity conditioning-based haploidentical donor transplantation with HLA-A*02:01 or different HLA types. That's shown here in this table. When we looked at six different outcomes, disease-free survival, relapse rates, overall survival, non-relapse mortality, acute and chronic GVHD rates, there was really no difference between these two categories of patients. These data support this HLA-based randomization or biologic assignment. In the next slide, we talk about, you know, the endpoints of our clinical trial and early readouts that we would expect from this phase I trial. The primary endpoints for this study would be, as expected for a phase I trial, the adverse event profile compared to the standard of care. We would also define dose-limiting toxicities, and we would evaluate the patients who are able to receive multiple doses of the investigational products. The secondary endpoints would include relapse rates at six months, one year, and two years, disease-free survival, and overall survival. Exploratory endpoints would include kinetics and percentage of donor chimerism by day 100, minimal residual disease rates, persistence of the engineered T cell product at day 100, and I'll explain these exploratory endpoints in the next slide. At the bottom is a table that shows us the expected relapse rates. This is based on CIBMTR analysis. You can see here that the relapse rates at about six months are about 22%-23%. At one year, they're about 33%. At two years, it's about 40% or so. The next slide, we'll be particularly interested in early surrogate markers of efficacy in our initial dose cohorts. These would be four different markers that we'd be looking for. The first measurement is donor chimerism kinetics. Donor chimerism kinetics have been poorly defined for patients undergoing a haploidentical transplantation, but there was an abstract published at the American Society of Hematology meeting that showed that control patients achieve about greater than 98% whole blood chimerism at a median of about day 35. There was a wide range, with some patients achieving it as early as day 15 post-transplantation or as late as day 170. This is something that we would be comparing between the control arms and the treatment arms. What we would expect is that TSC-100 or TSC-101 patients achieve faster and greater levels of particularly CD3 cell chimerism. CD3 reflects T cell chimerism. This happens to be delayed, and a delayed CD3 cell chimerism has been shown recently to predict for relapses. This is what we expect to be watching early on in this phase I trial. T cell persistence is the next marker. Sustained persistence of our T cells have been shown to correlate with anti-leukemic activity in the past. What we would hope is with our dosing regimen that TSC-100 and TSC-101 treated patients achieve greater than 3% engineered T cell persistence at day 100. The third measurement is T cell activation markers. The expected results are that T cell activation at sites of tumors have been shown to predict clinical responses. We would look for TSC-101 cells in bone marrow or blood specimens and look to see if they exhibit activation markers. The fourth measurement is minimal residual disease rates, which is also called MRD. MRD is detected post-transplant by flow cytometry in about 10%-15% of AML patients. If they are detected post-transplantation, these patients have uniformly bad outcomes. What we would look for is that TSC-100 or TSC-101 patients do not have detectable MRD compared with patients in the control group. In the next slide we talk about the proposed dose regimen, and this is pending regulatory approval. We're just in the process of submitting our INDs. I would like to point out that this dose regimen is different from the dose regimen that we proposed in the poster. This has been changed since the poster submission in response to some preliminary feedback from the FDA. What used to be dose level minus one in the poster is now dose level one. The way that this treatment would be administered is that patients would receive conditioning chemotherapy from days -6 to -1. This is typical for patients who are undergoing reduced-intensity conditioning. They would receive their stem cells on day zero. They would receive a graft-versus-host disease prophylaxis called post-transplant cyclophosphamide on days three and four, and their counts are expected to recover by about day 21. Once their counts recover, they would receive in the initial dose level a single dose of the TSC-10X product. Once the preliminary safety profile has been established for the single dose, we would then proceed to dose level two, where we would give the same dose about 40 days after the initial dose. This would allow for monitoring for any acute and sub-acute toxicities between the two doses. The second dose would only be administered if there's no excessive toxicity noted with the first dose and if the TSC-10X persistence is less than 3%, after review by the safety review committee. The third dose level, we would escalate the second dose and not the initial dose, because the initial dose would be given around day 21, where the patients are still fragile. The advantages of this kind of a dose regimen is that it's modeled off of donor lymphocyte infusion regimens, which is familiar to bone marrow transplant clinicians. A single-dose cohort establishes initial safety of the products. The repeat doses adapt to idiosyncratic toxicities, which could be unique to patient-donor pairs. For example, graft-versus-host disease can be unique to a patient-donor pair. The second dose would not be given if the first dose does cause graft-versus-host disease. The repeat doses increase the likelihood of TCR T cell persistence, this has been shown in multiple studies, and thereby minimizing the chances of relapse. Escalating the repeat dose is safer since the first dose is given soon after HCT, when patients are still fragile and they're too weak to withstand any potential toxicities. In the future, we may amend this protocol, if needed, to administer three doses if we find insufficient T cell persistence, even at day 100, despite giving two doses and despite escalating the second dose. That's our proposed dose regimen. With that, I'd like to turn it over to Dr. Chen, who can discuss current clinical practice of hematopoietic cell transplantation, unmet needs, and potential impact on the field. Thanks, Sri. My name is Yi-Bin Chen. I run the transplant program at Mass General, as you said, and it's my pleasure to be here today. I'm very excited about this type of platform and product and look forward to seeing where this research takes us. My task here is just to talk about the current sort of unmet needs and the current practice for AML, MDS, and ALL. This is a general diagram that shows that most of these patients, when they're diagnosed, most of them at least who require treatment, will receive at least an initial regimen of induction chemotherapy. These patients will then achieve some sort of response with a minority of unfortunate patients who are refractory who ultimately cannot be saved. The majority of patients who achieve a response, we do see, in consultation for hematopoietic cell or bone marrow transplantation, there is a small minority that are considered favorable risk for AML and ALL mostly, who can be cured with chemotherapy approaches. The vast majority of patients who are adults, do require a bone marrow transplant for a curative approach. I'll talk about transplant basics in the next slide, but once we get through transplant, approximately 60% of these patients do have a durable remission and are considered "cured." The other 40%, if they don't, unfortunately, have complications of transplant, do experience disease relapse. Relapse remains, the leading cause of long-term failure, for these patients, unfortunately. A lot of our research has started to focus on how we can reduce the rates of relapse. This type of technology is exactly that. It's a post-transplant intervention to potentially increase our odds to better achieve a durable remission and ultimately cure more patients. Next slide, please. Just an overview of transplant. As we said, not everybody who has these diseases who are adults require transplant, but the majority of who are young and fit and increasingly older, who we wanna consider a curable approach do. When we see patients, we do assess clinical characteristics like age, presence of comorbidities, their performance status to ultimately determine transplant eligibility. The ability to find a donor these days is much less of an obstacle than before. When I started training, sort of the availability of donor or what type of donor was a big factor, in if we made a choice to proceed with transplant. These days, with the improvement of platforms, to use mismatched donors such as haploidentical donors, has, advanced so much that, matched siblings, matched unrelated donors, haploidentical donors, as well as mismatched unrelated donors are all viewed fairly comparably, to proceed with transplantation. Lack of a donor is really not a realistic option for the majority of patients, that we see. The conditioning regimen refers to the week of chemotherapy, with or without radiation that is given to the patient before transplant. For a patient with a malignancy, that serves two purposes. It does debulk or drive the malignancy to an even deeper response, but more importantly, it immunosuppresses the host to allow them to accept the donor cells and engender what we call donor engraftment. The intensity of the conditioning varies, and it depends on how fit the patient is and their organ function. For a young, healthy patient in their 20s, we will give high intensity chemotherapy or radiation because we know it does benefit patients in terms of treating the cancer even more and preventing relapse. Whereas for an older patient, we have to scale down the chemotherapy or the intensity of chemotherapy to avoid toxicity. As we do that, we do incur higher rates of disease relapse, and that's been proven in prospective randomized trials. The overall prognosis for patients you'd see in the previous slide, but it really is based on the biology of the underlying disease. In general, those statistics are listed there below. That three-year survival rate for all adults is right around 50%, for those diseases. Next slide, please. There are unmet needs in transplant medicine. We've certainly made a lot of advances over the last couple of decades, but we're certainly not resting on our laurels. As I said, disease relapse remains the leading cause these days, for long-term failure for our patients. We've made tremendous progress in reduction in early mortality from infections, organ injury, through better supportive care and graft-versus-host disease prevention, and that has led to more long-term survivors, who ultimately have the chance to relapse. We are taking different patients to transplant than before. They're older. They have biologically worse disease as defined by certain mutational profiles. That has led to an increasing burden of disease relapse in our long-term survivors. As sort of was mentioned before, patients who do relapse after transplant have a fairly dismal prognosis. While we can achieve a remission in a minority of patients and maybe even a long-term remission, the vast majority of patients who relapse do ultimately die of their disease. Historically, the treatments for disease relapse have not been great. Obviously giving cytotoxic conventional chemotherapy to a patient who's had a transplant and then relapsed really does not result in long-term success and ultimately causes a lot of toxicity that we unfortunately have experienced. The general framework is to try and get the patient into remission and ultimately consolidate with perhaps donor lymphocyte infusion or even a second transplant. Obviously, we'd like to avoid that type of therapy if possible. The ways we've developed to try and reduce relapse, the most popular way is to give some sort of post-transplant intervention. I myself and others have participated in maintenance therapies, and this has only become a reality with the advent of targeted therapies that do not have off-target toxicity that we feel safe to give in a post-transplant setting. Now, unfortunately for probably at least two-thirds of ALL and about 80% of AML, we don't have targeted agents to give. This only serves a minority of our patients. While we do eagerly await the results of those trials, there's a whole population that is not met by the use of targeted therapies post-transplant. Thus, a cellular therapy such as this is super attractive to be able to give to prevent relapse. Another unmet need is access. You know, I think even though I myself and the community have published data on the ability to transplant patients 70 or even older, and at this point, our transplant program does not have an upper age limit for allogeneic transplant, as it's much more about biological age than chronological age. We still suffer from historical views on who should be referred for transplant, and I think referring physicians are colored by the poor results of the past in these older patients. I think if we're able to improve upon a platform, and show results are better, we ultimately result in many more referrals and also more patients able to undergo transplant. Finding a donor, as I said before, is not a huge obstacle now, but getting the product itself, especially if you're using a donor through the unrelated registries, remains a big issue. The median time to get the product from when you start for an unrelated donor is at least two months, if not three months. This was so emphasized over the last two years during the pandemic, where obtaining products, especially fresh products, through the registry was extremely complicated and uncertain. Many of us moved towards using haploidentical transplants more because of the convenience, the cost, and at least being able to work with the donor, him or herself. Next slide, please. What would be the potential impact of this product? I mean, I think really exciting to be able to deliver a cellular therapy in the post-transplant space. We do a transplant ultimately because the therapeutic mechanism is that immunological graft versus malignancy effect. That's how we realize transplants work, which is the donor cells are able to attack the underlying malignancy, just like they would fight any infection. This is probably the purest and first example of immunotherapy that we use. We've talked in the community of somehow cultivating that graft versus malignancy effect or the ability to deliver some cellular therapy for at least a decade, but have never been able to realize that. You know, we got some starts with NK cell-based therapies, but for manufacturing and other concerns, those trials have not moved forward. This type of therapy is really attractive for those reasons because we're ultimately trying to build upon the effect of why we did the transplant in the first place. If we're able to succeed, as we talked about before, we can envision getting more people to transplant. We can think about dialing down the conditioning regimen because if we have something to give that is disease modifying, then we do not have to give as intense a conditioning regimen, and thus we can reduce the toxicity and perhaps even the non-relapse mortality of transplant regimens to begin with. To be able to reduce that, you can ultimately offer that therapy to a more frail, more sick population. If we're able to prove that haploidentical donors with this package has better outcomes for curing patients in the longer run, I think we're better able to get patients a transplant faster. We do lose a few patients every year in waiting for donors as they relapse, and we could hopefully be able to improve upon that. Beyond that, I mean, if you have a successful product, and this is making a couple of jumps because obviously this trial has to get finished first. If this product is successful, you can envision a few applications that are relevant to the field. If you're able to, you know, reduce conditioning from that perspective, you can perhaps even use the product as part of your conditioning regimen, and thus you're able to reduce toxicity even more. Perhaps you can give it as a treatment for refractory disease and get patients into a debulk or a remission state to then be able to offer more patients transplant. We think about non-malignant disease. You know, as you think about the future of things like gene therapy, for hemoglobinopathies or sickle cell, we're always searching for a conditioning regimen that can, debulk host hematopoiesis to engender engraftment. Currently, all of the applications use cytotoxic chemotherapy, which ultimately do have toxicity and possibly even leukemogenesis, as I'm sure you've all heard of. Using a targeted agent such as this would be super attractive to be able to accomplish those types of things. Those are just a few of my comments on how this might fit into the field and fit some unmet needs. Obviously, I'm happy to take any questions. Thank you. Thank you, Dr. Chen. Again, if you have questions, just pop them in the chat, and we'll address them until we're out of time. The first question we got comes from one of our analysts. Have you discussed your manufacturing program with the FDA? What kinds of validation assets, assays would be required for final product approval? Asking this given the issues encountered by Iovance, although those aren't engineered cells. Perhaps, Gavin, you're the right person to answer that. Sure. I'd be happy to answer that. So we actually have a fairly unique opportunity with this program. Since we have two products that are, you know, very, very similar products, we've actually had the opportunity to have two pre-IND meetings with the FDA, one around TSC-100 and the other around TSC-101. We were able to get all the questions that we had around the CMC part of this package answered very, very nicely by the FDA. In terms of, you know, release assays for the product, we don't actually face the same challenges that Iovance faces, right? Because with Iovance, their product is not a defined product. It's different from patient to patient. They don't know what the targets of the T cells are, and so it's very difficult to build a potency assay if you don't know what the target is. In our case, we don't face those challenges because obviously the target of TSC-100 is HA-1, TSC-101 is HA-2. We have cell lines that are HA-1 positive, A*02:01 positive, other cell lines that are HA-2 positive, A*02:01 positive. Those are used in our potency assays as part of the release criteria for the drug. In fact, we have a whole series of assays that are part of the release criteria that assess potency, they assess sterility, they assess cell viability, purity, and these are, you know, essentially the and vector copy number. These are the key release assays. These have all been vetted with the FDA in these pre-IND meetings. Thank you, Gavin MacBeath. Maybe the next one is for Dr. Chen. How do you think about reduced intensity conditioning versus myeloablative conditioning? Would the ability to clean up residual leukemia after the transplant change your view on when to use reduced intensity conditioning? Yeah. I mean, this is a active question in the field. Before we had any post-transplant interventions, our judgments were fairly primitive. It was based on sort of how old the patient was and organ function. We basically only had two types of regimens, either myeloablative or non-myeloablative. The field has gotten more complex. It's obviously a spectrum, and we now have every center now has different regimens that range from very non-myeloablative to intermediate and reduced-intensity to full myeloablative, and it's really a spectrum and not a binary choice. What we do know is that in randomized trials, you know, conventional myeloablative regimens do cause more toxicity, but they do result in much lower rates of relapse compared to their reduced-intensity or non-myeloablative counterparts. How we operate these days is, you know, if we look at a patient and we assess them, their age, their fitness, their comorbidities, and we pick a regimen that we think is, shall we say, as much as intense as we can give them without causing undue harm. Those are not exact calculations by any stretch, but it's sort of more of a clinical judgment. None of this, you know, we need to get better. We need to be able to factor in what's the disease response pre-transplant in terms of, the most powerful judgment of that is measurements of MRD. There's already data saying that if you're MRD negative versus MRD positive, based on whichever assay you wanna choose, probably dose intensity of your conditioning regimen maybe matters more or does not matter at all. You know, there's clearly retrospective analysis showing that. We have to be able to work that into our judgment. If we have post-transplant interventions such as an effective maintenance or preemptive type of therapy, it's only intuitive that the same would apply, that the intensity of your conditioning regimen would not be as important. You know, long answer to your question is that I think in the next couple of years, we're gonna get much more sophisticated, hopefully, in being able to make judgments on this. We already do it, you know, in our group discussions. I can tell you that if someone, let's say, has a FLT3-mutated leukemia, and they're on the borderline of myeloablative or reduced-intensity, I will readily give them reduced-intensity transplant because I know I'll be able to give them a FLT3 inhibitor upfront as maintenance. That type of practice I think will only get more common, and if we have an effective therapy like this, then I think we'll have the general ability to do trials to show that we can scale down the once very toxic myeloablative regimens that we still continue to use. Great. Thanks. The next question. My sense is that transplant regimens slash procedures vary considerably from center to center. Will you standardize the background transplant regimens and procedures in the clinical trial? I guess that's either going to Sri or Gavin, whichever of you would like to answer it. Yeah. Sri, why don't you go ahead? Okay. Yeah. Yes, this is true that there is variability across different centers in the U.S. What we are trying to do is to homogenize the practices but still allow some flexibility for the investigators. The first decision we had to make is whether to allow both reduced intensity and myeloablative conditioning, and we decided to stick only to reduced intensity conditioning because the treatment-related mortality is much lower with reduced intensity conditioning compared with myeloablative conditioning. That would make it more standardized to do reduced intensity conditioning across multiple centers. Now, within reduced intensity conditioning, there are three or four different types of regimens that are used across the U.S. We have included three or four of those as possible regimens in our protocol, and we believe them to be roughly equivalent. Those should not add to the variability of the outcomes. The second was the choice of donors. Because of the need to mismatch donors and patients, we chose to stick to only haploidentical donor patients rather than include all kinds of different donor types. That would make it easier to recruit patients because, you know, nearly all patients would have a haploidentical family member. It would also make it much easier to find the right mismatch, you know, in order to treat these patients with TSC-100 or TSC-101. These were the two decisions we had to make, the types of conditioning regimens and the type of donor types. We sort of fixed those in order to make the trial, you know, a little bit more homogeneous across the U.S. The third decision we made was, you know, the graft-versus-host disease prophylaxis, and that fortunately is pretty standardized across all centers, you know, for haploidentical donor transplantations. That includes a combination of post-transplant cyclophosphamide, mycophenolate, and tacrolimus. That's something that is used universally, and so that is something we didn't really have to address. We've come up with an approach that's acceptable to multiple centers across the U.S. and yet enables, you know, a fair degree of patient homogeneity so that we can look at differences in outcomes between patients in the treatment groups and patients in the control group. Thanks, Sri. Actually, I think the next question is for you as well. If you show an improvement in CD3 chimerism in the phase I study, what is a meaningful improvement, and how do you think this improvement translates to more common outcomes like MRD? Yeah. That's a great question. The problem. I don't have a great answer to that. The problem is that donor chimerism rates and kinetics have not been well-defined for this, the population that we are interested in. That is, patients who are getting reduced intensity conditioning-based haploidentical donor transplantation. Now, patients who are getting haploidentical donor transplantation tend to have higher degrees of donor chimerism compared with patients who are getting matched unrelated donor transplantation because of what's called post-transplant cyclophosphamide, which can eliminate any, residual, patient-derived cells. At the same time, we do expect that even, you know, with some more subtle results, we'll be able to shift these donor chimerism rates and kinetics, to faster donor chimerism and higher donor chimerism than the control group. This is something that we would define on the trial as we learn. We are planning to do far more intense evaluations for donor chimerism rates compared with studies in the past. We'll be able to assess these patients in parallel, patients in the control group and patients in the treatment group. We haven't established cut points yet for CD3 chimerism rates. For whole blood chimerism rates, that has been defined. We need it to be greater than 98%. For CD3 chimerism, we would want it to be greater than 95% at the minimum. This is something that is poorly defined in the historical literature, and so we'll have to prospectively define as we move forward. As of now, we expect greater than 95% to be favorable. This is also based on a recent study that was just announced at this ASH in 2021, talking about the UK FIGARO trial, where greater than 95% CD3 T cell chimerism was predictive of good outcomes, even in patients who had MRD positivity post stem cell transplantation. That's the number we're using for now. Great. Sri, the next one probably goes to you again. Do you have a data cutoff rate based on CIBMTR relapse analysis? Data cutoff? I'm sorry, can you repeat that question? Do you have a data cutoff rate based on CIBMTR relapse analysis? Data cutoff date. I don't fully understand the question. Is that in- The answer is I don't know. We have a lot of questions, so why don't we move to the next one. Yeah. For Dr. Chen, how does the Baltimore protocol change the practice of transplant and impact post-transplant therapies? Well, the Baltimore protocol, I think you're referring to the post-transplant cyclophosphamide platform. It's been one of the biggest advances in transplant in the last 20 years or 15 years. It's certainly the standard for how we do a haploidentical transplant, meaning a half-matched relative. It's become an emerging standard for how to safely do mismatched unrelated donor transplant. It's in current trials being compared ongoing in randomized trials to conventional tacrolimus/methotrexate in conventional matched transplants. You know, we're trying to figure out if the post-transplant cyclophosphamide platform, which is not perfect, but we're trying to figure out if that should be the standard of care and sort of in which donor setting it might be. The very attractive part of post-transplant cyclophosphamide is that it appears to be better at preventing graft-versus-host disease. Even when it's accompanied by tacrolimus, starting afterwards, you appear to be able to have a higher success rate of getting people off any immunosuppression in the post-transplant setting at a faster rate. The post-transplant cyclophosphamide platform is the most attractive currently that's easy to do, you know, if you wanna give a cellular therapy after transplant. There are other ways to do it that involve sort of graft manipulation, cell sorting, T cell depletion, but those involve much more complex technology and experience, whereas post-transplant cyclophosphamide involves just the ability to deliver chemotherapy after transplant. It's a huge advance. We're trying to figure out exactly where it should be standard of care and so forth. It's extremely attractive to use for cellular therapy post-transplant. Great. The next one I think is for you as well, Dr. Chen. Do you think ZUMA-7 and TRANSFORM could change the frequency of transplant in heme cancers? I mean, you're referring to CD19 CAR T cells from Kite and BMS respectively, and that's addressing a population of relapsed diffuse large B-cell lymphoma and the two trials presented at ASH comparing them to standard approaches. I mean, those we don't generally see those patients for allogeneic transplant. I do believe the CD19 CAR T cell therapy is a huge advance. I do believe it will reduce the number of autologous transplants we do for high-grade lymphoma. It may, if we can get a safe and effective product in adult ALL, reduce the number of allogeneic transplants for ALL. We're mainly talking about B-cell malignancies for those trials in high-grade lymphoma who were not taking the allo transplant right now anyway. It's not gonna affect the applications of this product in allogeneic transplant. It likely will contribute to the ongoing movement of reduction in autologous transplant, which we likely should reduce anyway because it's a very sort of primitive formula for treatment, even though it obviously is effective for that setting. Great. The next one. Boy, I'm not sure who should take this. Can you elaborate on any differences between the U.S. approach to treating these types of cancers versus how patients are treated in the E.U.? Do you think the E.U. market is open to a product such as TScan's? Probably that's for you, Dr. Chen, as well. Yeah. I mean, I think it. That's an interesting question. I think there's a couple of issues to address. Based on differences in healthcare systems, I think in America at least, we're transplanting many more older patients, and there are countries in Europe, based on sort of their policies, that there's an upper age limit for transplant. I think there's practical differences there. The transplant platforms themselves do vary, but for haploidentical transplant across the world, post-transplant cyclophosphamide or this platform you've seen here is by far the most common and standard regimen. There are a few pockets of places that are different. In China, which is not Europe, but in China, there's a different regimen for haploidentical transplant, at several large centers. There are smaller centers in Europe, such as in Italy, mostly in the pediatric population, where they use different forms of T cell depletion for haploidentical transplant. But for the vast majority of adults, post-transplant cyclophosphamide for haploidentical transplant is the standard globally. This approach here that you're seeing would have mass appeal internationally if it actually does show some success. In the conventionally matched donor setting, there are differences, but that would not apply for these products here. Great. Thank you. The next one is, what is the profile of patients that TSC-100 and TSC-101 may be used for, and what is the addressable patient population? I think I'll hand that to Sri. You know, Sri, maybe you could go through the numbers of patients that are eligible for a hematopoietic stem cell transplant and how a relatively small proportion of those actually get one, either because they have to have myeloablative chemotherapy or just because of safety concerns. Maybe you could address that. Yeah. There was a session at ASH, you know, over this weekend talking about access problems to allogeneic transplantation and how only one-third of patients who are eligible for allogeneic hematopoietic cell transplantation actually get it. There's a variety of different factors involved, including socioeconomic factors, geographic factors, and referral factors. The two big sort of referral factors are, one, that allogeneic transplantation is still quite toxic, and so, you know, not everyone is referred, as Dr. Chen had talked about. The second is that it may not be still fully effective, and so even, you know, the patients would have to be in a complete response in order to be even referred for transplantation. If they don't achieve a complete response, they're not referred. You know, these two are the big barriers, and that's why only one-third of patients who are eligible actually get transplantation. You know, the first question is, what is the patient profile that'll be eligible for treatment with this? We expect this product to be available to all AML, ALL, and MDS patients and currently who are HLA-A*02:01 positive, and in the future, we would expand this to other HLA types as well. What we would hope is that all patients who are not cured with chemotherapy, that is a portion of AML patients and ALL patients, would be able to get allogeneic transplantation in combination with this kind of cellular immunotherapy. We would hope that that kind of treatment would entail reduced-intensity conditioning and maybe even further reductions of intensity of conditioning and that these patients would get it from a haploidentical donor, which would obviously make it easier to use this particular product, but it would also be cheaper and faster for a transplant center to use in the future. Essentially what we are hoping is that in the future we would try to get- All AML, ALL, and MDS patients who are not cured with chemotherapy into transplantation combined with this kind of cellular immunotherapy to make transplantation safer, more effective, and ultimately more available to the maximum number of patients. Actually, maybe I could interject a little. This is Gavin MacBeath. So maybe just to put a few numbers on this. Right now in the U.S., the number of patients being diagnosed every year with AML, ALL, or MDS is about 35,000 patients a year. Of those, over 7,000 of them will go on to have an allogeneic stem cell transplant. As we sort of outlined in terms of the prevalence of HA-1 and HA-2, as well as the appropriate HLA type, between our two products, 40% of patients, about 40% of patients, would be eligible to receive this product, taking just all allogeneic stem cell transplants into account. Now, obviously, we're, you know, starting clinical development with haploidentical transplants with reduced intensity conditioning, so that, you know, represents a subset of those 7,000 patients. Nevertheless, that's the sort of targetable population currently undergoing stem cell transplant. You know, for all the reasons that have been outlined in this call, we anticipate that number of eligible patients would increase if the, you know, therapy is successful. I guess the next question is related, which is one of the most important emerging approaches that could make transplant less necessary in AML. I guess you know what I look at is one that actually will make it more used, which is reduced intensity conditioning, which allows more patients to get a stem cell transplant. But Gavin or Sri, would you like or Dr. Chen, would you like to address that? Can you repeat the question? What are the emerging- Sure. Sure. Yeah, sure. Dr. Chen, you're our guest of honor here. What are the most important emerging approaches that could make transplant less necessary in AML, specifically? I'll take the first stab at this question. I'm not sure they exist at the moment, at least nothing that I've seen that is reliably exciting. You know, we mentioned the CD19 CAR T cell revolution sort of for B-cell diseases. It's just that we haven't really found a reliable target for MDS and AML that we can develop that we think can replace transplant. All the efforts that have gone into making sort of more targeted therapies for MDS and AML oftentimes are paired with a rescue transplant because the collateral damage from such therapy involves destruction of normal hematopoiesis. B-ALL is a different story because you can target 19 in that type of B-cell phenotype as well. I think there will be therapies in B-ALL that obviate transplant. The success of BCR-ABL inhibitors for the Philadelphia chromosome B-ALL certainly is making headway into doing that, but we need prospective trials to define that because of how successful and curative transplant is for that population. For MDS and AML, you know, even though there's been, like, five newly approved agents for MDS and AML in the last couple of years, what they've all done is been able to help get more patients to transplant because of improved pre-transplant treatment. They've made overall outcomes more successful because they've achieved deeper responses pre-transplant. In the future, we'll see if incorporating some of those agents post-transplant, like this, you know, therapy, will improve outcome from that perspective as well. I don't think anyone in the field feels that any of these therapies will ultimately replace transplant. I haven't seen a really effective idea that will do that at the moment. Great. Gavin or Sri, do you have anything to add? Yeah. Just, sort of building on that point, that it really is this lack of available targets that I think underscores, you know, the issue being faced with myelogenous leukemias, right? As I sort of alluded to earlier, the reason that CD19 CARs were so effective in B-cell malignancies is that CD19 is a lineage-specific antigen. It's expressed at that, you know, uniform level, and at a very high level on B-cells, and that means it's a very good target. The problem is that you can't do the same thing with myeloid cells because if you were to target a lineage-specific marker on myeloid cells, then, you know, patients would have severe neutropenia, which is intolerable. That's why this approach of targeting antigens that are present in some patients, but not in their donors, provides a solution to that problem. It's a lineage-specific antigen, but because of the way a transplant works, the fact that your blood is now being replaced with genetically different blood, right, from a donor, you can actually take advantage of that feature and target a lineage-specific antigen in myeloid leukemias. That's why we think the analogy between what we're doing and the success of CD19 CARs is based on that you know, on that feature of lineage-specific antigens rather than cancer-specific antigens. Great. Thank you, Gavin and Dr. Chen, and thank you all for joining us. We're now at the bottom of the hour. We really appreciate this great group joining us. We're really excited about this program and, you know, we look forward to getting these INDs filed and starting to treat patients. Thank you all and stay in touch.