Ladies and gentlemen, thank you for standing by and welcome to the ALLOHA Cohort C Data Presentation. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question- and- answer session. To ask a question during the session, you would need to press star one one on your telephone, and you will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Gavin MacBeath, CEO of TScan Therapeutics. Please go ahead. Great. Thank you. Thank you everyone for joining us this morning. Very excited to be presenting updated data from our phase I ALLOHA study of TSC-101. Just to remind everyone, we are a publicly traded company, I will be making forward-looking statements this morning. Before we begin, I just want to give a brief overview of TScan Therapeutics. We are a next-generation, fully integrated T-cell therapy company. Our lead program, which we're focusing on this morning, is in heme malignancies where we're treating patients that are undergoing bone marrow transplants in order to prevent relapse. Before we begin, I do want to highlight our two other programs. We do have a program in solid tumors. This is in preclinical development right now. I'm excited to announce that we have recently met with the FDA using the INTERACT mechanism. Based on their very encouraging feedback, we now have a path to filing our first INDs, for both our PREM-TCR and our MAGE-A4 TCR, by mid next year. Very excited to be advancing that program through preclinical development. I also want to highlight our discovery program in autoimmunity, where we have previously disclosed that we've identified targets for pathogenic T-cells and systemic sclerosis, ulcerative colitis, ankylosing spondylitis, and Birdshot uveitis. I'm excited to also announce that we are now generating first-in-class T-cell depleting therapies, with a particular focus on ankylosing spondylitis and other spondyloarthropathies. With that, I want to introduce those that are joining me on the call today. We're very pleased to be joined by Dr. Ran Reshef, who's the Director of Translational Research at the Columbia University Blood and Marrow Transplantation Program. He's also the Director of the Cellular Immunotherapy Program at Columbia University. I'm also joined on the call today by Dr. Chrystal Louis, our Chief Medical Officer, and by Dr. Shrikanta Chattopadhyay, who's our Senior Vice President of Translational Research. With that, I want to move into a description of our heme malignancies program, then focus on the recent data update from our ALLOHA study. For those of you not familiar with our program, our program is focused on patients that are suffering from various types of heme malignancies, in particular, patients with myeloid malignancies like acute myeloid leukemia or myelodysplastic syndromes. Really the only curative therapy for these patients is to undergo a bone marrow transplant. In fact, transplant is very effective. Upwards of 60% of patients are completely cured by a transplant. Unfortunately for those patients that are receiving a transplant with reduced intensity conditioning, the risk of relapse is over 40%. Any patient that relapses, unfortunately the prognosis is very poor. In fact, most of those patients will pass away from their relapse within the first six months. Our program is to develop TCR engineered T cell therapies that target residual leukemia in the patient immediately following their transplant in order to eliminate that residual cancer and prevent relapse in those patients. Our lead product, TSC-101, is targeting an antigen in patients that have the HLA type A0201, which is the most common HLA type in North America. Just to remind everyone of the mechanism of this product. Any patient that has the HLA type A0201, again, about 42% of people in North America, their blood cells, all of their blood cells will be displaying an antigen called HA-2 on the surface of those blood cells, and that would include any leukemia cells as well. If that patient is paired with a donor who does not have that HLA type, who is A0201 negative, their blood cells will not be presenting that antigen. If that patient undergoes a bone marrow transplant, following the transplant, all of their new blood cells will be donor-derived, and so I've colored them in blue here. They will be HA-2 negative, whereas any residual cancer in the patient comes from the patient, and so those blood cells are HA-2 positive. What we do in order to treat these patients is we take T cells from the donor. Again, these are HA-2 negative cells, and we engineer them with a T cell receptor that targets that antigen. Immediately following the transplant, typically about three weeks after the transplant, we then treat those patients with those engineered T cells, and at that point, those T cells will only target HA-2 positive cells. In other words, any residual patient-derived cells, including leukemia cells in those patients, but they won't touch any of those new donor-derived cells, which are all normal, healthy growing, donor-derived cells. It's a way to target those residual cancer cells and prevent relapse in those patients. I just want to briefly recap the data that we've had on this program, and provide an update on that data before launching into what we term Cohort C of this trial. To remind everyone, this is the structure of the ALLOHA phase I trial of TSC-101. This trial included subjects with AML, ALL, and MDS, and we included a control arm in this study. In the control arm, as shown in yellow, patients undergo a regular hematopoietic cell transplant, and then we follow those patients. Whereas in the treatment arm, patients undergo a regular standard of care transplant, but then receive two infusions of our product. The first infusion occurs approximately 21 days post-transplant, and the second infusion occurs about 40 days after their first infusion, or about 61 days post-transplant. What I'm providing here on this slide is an update of the data from patients that have been in this study, many of these patients for over three years now. We launched this study over three years ago. The updated data includes 19 patients on the treatment arm, as shown in the green color above, and 19 patients on the control arm, shown in yellow at the bottom. What you can see from these data is that patients that have been treated with our product have remained on study and disease-free much longer than patients on the control arm. In fact, both of the patients that have been on study for over three years remain relapse-free on the treatment arm, whereas none of the three patients that have been on study or were enrolled over three years ago on the control arm are on study any longer. In fact, if you look at the two-year mark, five of the seven patients that have been on study for over two years on the treatment arm remain relapse free, whereas only three of the seven patients on the control arm remain relapse free at two years. Very encouraging long-term data from this study. I also want to highlight the fact that our product has a very attractive safety profile. All infusions of TSC-101 to date have been very well tolerated with no dose-limiting toxicities. On the far right, I just want to highlight the fact that this product has very long-term persistence. In fact, we have been able to observe engineered T cells in circulation in every patient in the study, including those patients that have been on study for over three years. Finally, at the end of last year, we reached agreement with the FDA on a pivotal trial design, which we will recap today in today's call. Based on that feedback, we're actually launching our phase III study this month. Purpose of the call today is to really update people on this new cohort of patients that we enrolled in the study. This new cohort of patients really is focusing on a new manufacturing process that we developed at the end of last year. Throughout this study, we've been using what we would call a phase I process, which has obviously been very effective. We've been able to manufacture product for all of these patients. However, this process is not what we would call commercial friendly. It's a fairly long process, takes 17 days to manufacture the product. In particular, there's a step on day nine of the process. It's a step in which we enrich the engineered T cells, essentially purify them away from any non-engineered cells. This step was traditionally very inefficient. We would, in fact, lose over 90% of the engineered cells at this step. At the end of last year, we developed a new manufacturing process, which we call our commercial-ready manufacturing process, as shown in the bottom, in which we've eliminated this magnetic bead purification of the engineered T cells and instead replaced it with a drug selection. We, in fact, engineered these cells to be resistant to methotrexate, then to enrich the engineered cells, we simply add methotrexate to the culture media, and only the engineered T cells expand. This process has much lower cost of goods. It's much more efficient. In fact, it's a shorter process. We can now harvest the cells on day 12 rather than on day 17. Prior to launching our pivotal study, we committed to enrolling an additional cohort on our phase I study, in which we would treat every patient using this commercial-ready manufacturing process. I'm pleased to announce that in total, we were able to treat 14 patients in this cohort. This cohort enrolled very quickly, really highlighting the fact that there's a lot of enthusiasm from investigators on this study. We were able to enroll and treat 14 patients in about three to four months. This chart is showing the characteristics of these patients. I just want to highlight the fact that this cohort of patients was actually a very difficult to treat patient population. In fact, 75% of this cohort still had detectable disease in their bone marrow biopsies that were taken immediately prior to transplant. MRD positive prior to transplant, which is quite a bit higher than what we had previously observed on the control arm of this study, where only 53% of patients were MRD positive prior to transplant. In fact, post-transplant, before they received our product, 86% of patients in this cohort still showed mixed donor chimerism, and I'll explain what that is in a minute, whereas that compares to only 76% of patients on the control arm. A very difficult to treat patient population in Cohort C. I'm pleased to say that we continue to observe a very good safety profile for this product. The safety is, in fact, very consistent with what we observed in those 19 patients previously treated in Cohort A of the study. I do want to just highlight one safety issue that arose with one of the patients on this study. The second patient enrolled in Cohort C actually had some very challenging safety issues immediately following transplant. They had chronic kidney disease, and coming out of the transplant, the conditioning therapy actually exacerbated that. They had to go on dialysis. They had quite a delay in receiving their first infusion of our product. They did eventually receive that first infusion and actually responded well to that infusion, as I'll highlight in a minute. Unfortunately, that patient subsequently developed sepsis and passed away from the sepsis, which was deemed not related to our product. It was related to transplant. As I said, in total, there were 14 patients treated in Cohort C. Obviously, these patients are relatively early on in their follow-up following their transplant. There is a way to assess how those patients are doing in the short term that we believe is very predictive of how those patients will do in the long term. I just want to highlight again the mechanism by which this product works. The patient immediately following the transplant will have a combination of new donor-derived blood cells, which are colored in blue, and any residual cells that are still patient-derived, including cancer cells, that are colored in pink. Again, our product is designed to target the patient-derived cells but spare the donor-derived cells. If this product is successful, we should completely eliminate all the patient-derived cells, and you should only have donor-derived cells detectable. The assay that's routinely performed on patients following transplant is to follow what's called donor chimerism. Donor chimerism is a measure of if there are any patient-derived cells still detectable in that patient. If this patient has no detectable patient cells or recipient cells, then as shown on the left, that patient is said to have complete donor chimerism, and that patient is obviously of much lower risk of relapse. If, on the other hand, as shown on the right, the patient still has some detectable patient cells, which would include either malignant or normal cells, that patient has what's called mixed donor chimerism, and that patient would be at an increased risk of relapse. In our study, we have been using a very sensitive assay to detect donor chimerism, which actually relies on next-generation sequencing and has a much lower limit of detection, a much higher sensitivity than the standard assay that's used clinically. In fact, what we've shown in our own study, this is data coming from our ALLOHA study focusing on all the patients in the study, both the treatment arm and control arm patients. What we've observed is that if patients achieve complete donor chimerism early on, and this is data derived from two months following their transplant, for those patients that have complete donor chimerism as assessed using this assay two months post-transplant, those patients have a much lower risk of ultimately relapsing, as shown in pink, relative to those patients that have mixed donor chimerism, as shown in blue. Based on that, we're able to assess how well these patients in this new cohort are doing on study. I'm very pleased to report that we had very strong data on cohort C. As I said, in total, 14 patients received product. I'm showing all 14 patients on this slide. What I'm showing you is quantitative chimerism data. The y-axis in each of these plots is the percent of recipient chimerism. Again, we're trying to drop that percentage down below the limit of detection of the assay, which in this case is 0.2%. If you focus on the patient in the top left, this is a patient that had a very difficult to treat cancer, TP53 mutated AML. In yellow diamonds is when they received their first infusions of our product. Initially, this patient had 4.5% recipient chimerism. They received their first infusion of product, immediately within three weeks of receiving that product, their chimerism dropped below the limit of detection of the assay, which is 0.2%. That complete donor chimerism has continued throughout every blood draw that we've performed on this patient. This patient has now been in study for over six months with complete donor chimerism. Now as you look across all 14 patients, you will see that, in fact, 13 out of these 14 patients all showed decreasing recipient chimerism immediately following that first infusion. In fact, there was only one patient on the study, patient 10, that did not respond to product, their chimerism actually increased. We've often shown these data using this type of chart. In this chart, all the columns represent the 14 patients, the rows represent blood draws and chimerism assay results that we've performed on these patients. That first row at the very top shows their chimerism data immediately following the transplant but prior to receiving their first infusion of TSC-101. What you can see in that first row is that 12 out of the 14 patients had incomplete chimerism following the transplant. Very difficult to treat patients with incomplete chimerism. The yellow diamonds indicate when they got their infusions of engineered product. All of those columns highlighted in blue are the 11 patients on study that all achieved complete donor chimerism within three weeks following that first infusion. In total, 11 out of the 14 patients achieved complete chimerism within three weeks. Two of the remaining three patients actually showed improving chimerism following that first infusion. I'm going to walk you through the various patients that did not immediately achieve complete chimerism. I'm going to start with this patient three, that did achieve complete chimerism immediately following that infusion, but subsequently, their chimerism increased again. This was in fact an incredibly challenging patient to treat. They had a very aggressive form of cancer. It's a MECOM rearranged AML. In fact, rare form of AML, only 2% of AML shows this translocation, but this has a very low survival rate. This patient was also MRD positive prior to transplant and MRD positive following their transplant. Nevertheless, they achieved complete chimerism immediately following that first infusion. I also want to highlight the fact that this is the only patient on the study that didn't receive the highest dose level. They received dose level three rather than dose level four. Every other patient on the study received dose level four. The difference between dose level three and dose level four is that first infusion. They actually received fewer than half the number of engineered T cells at that first infusion than every other patient. As I pointed out earlier, patient 10 is the only other patient on this study where we saw increasing recipient chimerism. They appear not to have responded, for some reason, to this product. Patient number five, although they didn't achieve complete donor chimerism immediately, as you can see on the quantitative plot on the right, their chimerism has actually been steadily decreasing with every blood draw. They have now received their planned second infusion of TSC-101. I also want to highlight that this patient actually has ALL, again, TP53 mutated ALL, very difficult to treat cancer, but we are not actually including ALL on the pivotal study. Finally, the last patient to highlight is patient 12, which according to the chart on the left, you can see they had incomplete chimerism immediately following that transplant. In fact, that patient is extremely close to achieving complete donor chimerism using this assay. Their chimerism dropped from 7% down to about 0.3% within three weeks. We're obviously very optimistic about this patient. They've effectively achieved complete chimerism. I also want to point out that the standard clinical assay has a sensitivity of between 2% and 5%. By any stretch, the standard clinical assay would show complete donor chimerism in this patient. Just to summarize the chimerism data relative to the control arm that we had previously enrolled on this study and tracked using the same assay, on Cohort C, only 14% of the patients in this cohort had complete chimerism following their transplant before receiving product, whereas on the control arm, 24% of patients had complete chimerism. Yet this 14% jumped to 79%, 11 out of 14 patients, three weeks following their first infusion, and 100%, five out of five patients, three weeks following their second infusion. That compares to only 53% on the control arm, which would be at the equivalent time point, about 80 days post-transplant. Then I just want to end with a little bit of translational data. I just want to highlight the fact that the engineered T cells, engineered in Cohort C using that commercial-ready manufacturing process, continue to persist well in the patients. You can see very high levels of circulating T cells in the patients. Then, looking at some translational data, if you compare in blue patients who receive product manufactured using this new commercial-ready manufacturing process versus in black patients receiving the original manufacturing process, what you can see in the top left is that the product in the patients seven days post-transplant was proliferating very well, expanding very well, in fact, had higher levels of Ki-67. In the top right, you can see, looking at the activation marker CD28, that their T cells were more activated seven days post-infusion. Finally at the bottom, seven days post-infusion had higher levels of granzyme B, which is a marker of cytotoxicity. All very encouraging data showing that this new commercial-ready manufacturing process is working as well as the original process, in fact, is very active in the patients and persisting in these patients. At this point, I want to turn the call over to Dr. Reshef, who is going to comment on the patients that have been enrolled in the study, as well as his view of these initial data that I've just presented. Thanks, Gavin. As Gavin already introduced me, I'm just going to make a few comments. I'm a Physician Scientist at Columbia. I specialize in allogeneic transplant. I've been doing this for 11 years at Columbia, and prior to that for eight years at the University of Pennsylvania. I've been immersed in the cell therapy and transplant field for quite a number of years now. I think my perspective would start with taking a step back for a second and giving you a little bit of a sense of what the transplant community is focused on right now. There's no question that the major laser focus is on decrease of relapse after transplant. There's no question that allogeneic transplant is a curative strategy. We actually don't conduct allogeneic transplants if we don't think there's a chance the patient will be cured. We're not aiming to improve survival by a few months. We're aiming to really achieve plateaus in survival curves, showing that patients are cured. We have gone a long way in overcoming many of the transplant toxicities. Supportive care has dramatically improved. We don't see patients dying from fungal infections or CMV infections, and more recently has improved dramatically our ability to treat and mitigate the risk for graft versus host disease, which has been the biggest threat. That has been maybe not 100% resolved, but tremendous progress has been made to the point that we are extremely comfortable now even doing bone marrow transplants across HLA barriers, and I think this is critical for the understanding of kind of the niche where TSC-101 would fit. It is not a narrow niche. It is, in fact, the way we do transplants regularly because the differences in survival between an HLA identical, an HLA mismatched, or even a half-matched haploidentical transplant, there are almost no survival differences in the contemporary cohorts that we look at. With that said, relapse risk remains our biggest problem, and the focus on reduced intensity conditioning is highly appropriate because this is where we struggle the most. Acute leukemia and MDS are diseases that mainly arise in older individuals. Median age is greater than 60. We have plenty of patients in their 70s and even in their 80s who would want to get a curative approach, and reduced intensity transplant is the only option for them because a full myeloablative transplant is impractical due to the heavy load of toxicity and potential even mortality as a result of how aggressive that procedure is. In the reduced intensity setting, without even looking what types of patients are enrolled in the study, we should anticipate somewhere between 35%-50% relapse risk, depending on what conditioning regimen specifically we're using and what type of patients we're treating. In fact, there are some conditioning regimens that we are trying to use less and less that have a relapse risk of greater than 50%. That's really our benchmark for this type of strategy. We're starting at a very low point that somewhere between 1/3 and a half of the patients are expected to relapse. If it's not already clear, relapse after transplant is nearly always lethal. The ability of these patients to get subsequent therapy is very limited, and the only curative therapy as their next option is another transplant, and very rarely non-engineered donor lymphocyte infusions, which rarely work and mainly cause a lot of toxicity. One more point I wanted to make, which is not completely clear when we're describing this as a post-transplant intervention, this is the first cellular immunotherapy that actually works in AML and MDS. The field has been struggling now for many years to find appropriate targets, appropriate interventions, modalities that would put the sufficient efficacy and not too much toxicity into the world of treatment of AML and MDS, either with or without a transplant, and we have not had a cell therapy that met those criteria so far to go into a registrational trial. This is truly the first one. I'm going to circle back to that later on when we talk about the commercial opportunity, because just to remind everyone, this is not an AML or MDS-specific intervention. It is targeting all recipient cells, and it would work pretty much in any disease, malignant and even non-malignant, if you're trying to attempt to completely eradicate recipient cells. Let's zoom in for a second on the types of patients who go on this trial. First of all, in the reduced intensity setting, it is really difficult to cherry-pick patients because it is typically used in older individuals, and older individuals would typically have adverse risk AML or adverse risk MDS. It is not usual to find favorable risk diseases in this older patient population. To go into more specifics and use some maybe benchmarking data, TP53 mutation is by far one of the scariest one that we deal with. In fact, in some transplant centers, you would not be offered a standard transplant for TP53 mutated AML or MDS because the outcomes are so dismal with a relapse risk that exceeds 60%, certainly in the reduced intensity setting, long-term survival in the range of 10%-20%. In fact, what's most concerning is that when you look at some of the TP53 mutated cohorts, you don't get really convincing plateaus in the survival curve. There is some suspicion that if we follow these patients long enough, we might not be curing any patients with TP53 mutated AML with a standard transplant. There's a lot of appetite in enrolling these patients on clinical trials, but also gives you a sense of how good the data looks if we're able to achieve MRD negativity, prolonged remissions in people who are more than a couple of years post-transplant without relapse. Another group that's worth mentioning is the MRD positive patients. Maybe the best resource to look at, if some people are familiar with, is Chris Hourigan's paper in the Journal of Clinical Oncology in 2020, which showed very clearly that in the reduced intensity setting, the risk of relapse for MRD positive patients pre-transplant is close to 70%. Which again begs the question that many transplant centers struggle with, should we even offer a reduced intensity transplant to people who are MRD positive if we might be kind of approaching the point of futility. Lastly, Gavin also mentioned one patient with MECOM rearranged AML, and that patient did achieve an early response, which I think is already impressive in and of itself, but did not end up having a favorable outcome on the long run. Let me just remind everyone, because MECOM had several names historically. It was EVI1. Many people still call it Translocation (3;3) or Inversion (3), which was identified about 15 years ago as a type of AML that has a 3% long-term survival chance. Really, the worst of the worst. Achieving even a brief remission in the MECOM rearranged AML, I would have to say that's a relatively major achievement, and it's not completely surprising that that might be a patient that has been a bit more challenging to treat. I think that kind of covers some of the descriptions of the patient populations, and I'll be, of course, staying on for the Q&A to respond to some more questions. Great. Thank you very much for those comments, Dr. Reshef. At this point, I want to turn the call over to Dr. Chrystal Louis, our Chief Medical Officer, who is going to take you through the trial design for the phase III study, which as I said earlier, we are launching this month. Thank you, Gavin. If you can go to the next slide. In this particular case, as Dr. Reshef mentioned, this is actually a super exciting time point for us as an organization, and I think our investigators who are participating on this trial, which is ultimately to get ready to launch the registrational study in this particular patient population using TSC-101. We had our end-of-phase meeting in October with the FDA, where, as Gavin has previously mentioned, we did get agreement with the FDA with regards to what the trial design would look like, and in a very nice way, it mirrors what we were already doing. We are going to be biologically assigning patients to the treatment or the investigational arm if they're A0201 positive and have an A0201 negative donor, and then anyone else would be participating in the control arm. With this associated biological assignment, we are looking at RFS as our primary endpoint. The trial is powered at 85% for a hazard ratio of 0.52, which essentially reduces relapse rates by about 50%, and we do anticipate that we'll need about 150 patients per arm. With the excitement that we saw within Cohort C and with plotting out the enrollment rates that we expect, we do anticipate a top-line readout in approximately 25 months. Because it would be a top-line readout in about 25 months, there was some discussion as to whether or not to conduct an interim analysis or not. We were a little bit concerned that at 50%, 60%, or 75%, that median follow-up would be too short from a regulatory perspective, and readout within about two years is relatively quick for a registrational study. Our plan is, at this point, to not proceed with an interim analysis and wait for the full readout in about two years. Gavin, if you could go to the next slide. We did make some important protocol modifications between our phase I and our phase III study that we will cover very quickly. As Gavin mentioned earlier, we are not including patients with ALL in this population. We clearly expect that it would work, but to improve the homogeneity of the patient population, we did decide to actually remove ALL from this particular registrational study. From an enrollment perspective, as with any phase I study, as Dr. Reshef mentioned, it is kind of an all comers, you get what you get. Our plan was to really tighten that up with regards to the registrational study in two different ways. From the first perspective, we are going to be stratifying patients on this particular study with regards to their disease type, as well as the poor prognostic genotypes that Dr. Reshef mentioned, including TP53 as well as MECOM rearrangement. From an eligibility perspective, instead of it being a transplant-eligible population that we allowed within the phase I setting, we are going to streamline it to be more consistent with what you would expect from a registrational study and have AML patients who are in CR1, CR2, that being complete response I or complete response II or less than 5% blasts, as well as those patients with MDS who have less than 10% blasts. One question that we get quite frequently is, because this is a bit of an open label study, how are we guaranteeing that we will get control arm patients onto the study? Really working with Dr. Reshef and the rest of our investigators, we did decide that we would continue to allow for maintenance medications for those patients with targeted mutations like IDH1, IDH2, or FLT3. The menin inhibitors have now been approved, there is the potential for those to be included as well. We did have some discussion with the investigators to allow HMAs on the study with a caveat. The caveat for menin and HMA is that because we know that cytopenias are associated with these particular products, anybody who would be getting it on the treatment arm, we are asking for there to be a bit of a delay between their last TSC-101 infusion and the initiation of menin or HMAs, and that is really to give the cells time to work. The other thing that we are doing is that we are asking investigators to go ahead and pre-specify, to acknowledge that the inclusion of these agents would be part of what is their standard of care transplant. If it is pre-specified as part of standard of care transplant, we just proceed. If it has not been pre-specified and then subsequently started post-transplant, we would consider that an event with regards to the EFS analysis, which is one of our secondary endpoints. Gavin, if you could go to the next slide. The other thing that we are going to do is really work consistently with our investigators and with our DMC to make sure that we are able to achieve balance between the two arms. From an enrollment perspective, we are going to be stratifying, as we discussed, then we are going to be looking probably every 10- 15 patients enrolled on the treatment and control arm to make sure that there's balance between the associated arms, and then potentially have to toggle off enrollment into one of the strata if it looks like we're getting a significant imbalance between, for example, disease type or between poor prognostic features. From a statistical perspective, we're also going to look at balance on the back end. We are going to do separate models when we analyze the data to look at the AML population and the MDS population, again, to make sure that we're seeing efficacy results across both of them. We are going to be using Cox proportional hazards models to also help us evaluate any potential imbalance that may remain after all of the things that we've done. The last piece is when we look at that 0.52, we do feel that we ultimately conservatively powered the study, as when you look at the initial Cohort A data and then the encouraging data that we see with Cohort C, we do believe that that is a hazard ratio that would allow us to have good clinical benefit, as well as one that we think we can achieve with the current product. The last slide I wanted to cover is a question I do get quite frequently, which is how many sites are we bringing on board? For the phase I, we had approximately 20 sites, even though, if I'm being honest, there were probably about six or seven that were our very invested high enrollers. What we saw with Cohort C actually really helps us to be encouraged that by the addition of about 9- 10 additional sites, getting us to within 30 sites in the U.S. As you can see on this map, covering really a lot of the geographical area within the U.S., including all of the big centers across the country. We are very comfortable with the idea that our enrollment projections are correct, leading us to that 25-month readout. I will turn it back to Gavin, just complete my assessment here by saying that ultimately we are super excited to be at this point. It is always a transition when going from a preclinical company to a first in human company, to a registrational company within such short amount of time. Great. Thank you, Chrystal. At this point, I want to highlight how we're also extending this program, not just to treat the 42% of patients that have the HLA type A0201, but ultimately, virtually every patient that qualifies for a transplant. To extend this to other HLA types, we've developed a general strategy as a company, and that is to target antigens that are derived from the protein CD45, which is a lineage-specific protein that is expressed in virtually all hematopoietic cells, including hematopoietic stem cells. We have additional products that are all termed TSC-1 02, that are targeting antigens from CD45 displayed on other common HLA types, including A0301, A0101, and A2402. We plan as a company to launch our first phase I study of these products in Q4 of this year. We're initially launching with two products that have already cleared INDs, TSC-102-A03 and TSC-102-A01. This study also allows us to expand to other types of transplant, including transplant conducted with myeloablative conditioning, as well as to new disease types. We will also be including a cohort that includes non-Hodgkin lymphoma in this trial, as well as ALL. I also want to point out that this phase I trial of TSC- 102, as well as the Cohort C data that we shared today, will also provide continuous news flow over the next two years. We plan to update publicly on progress on these trials approximately every six months at major hematology conferences. At this point, I want to end by highlighting what we view as a company to be the substantial market opportunity presented by these products. I want to start by highlighting a feature of this program that isn't well appreciated, and that is that this is very different from CAR T therapy, in that patients actually seamlessly are incorporated into their current transplant journey. Rather than having to get referrals from community centers to major academic centers to get treated, these patients have already been referred by their treating oncologist to transplant centers in order to get a bone marrow transplant. It's very different in that respect. We know exactly where the patients are. They've already been referred for transplant, and there's actually only about 120 transplant centers in the U.S. that are conducting allogeneic transplants for AML and MDS. As part of their regular transplant journeys, these patients are identified, they're HLA typed, and their donors are HLA typed. They undergo a screening process to identify eligible donors. That patient will undergo a regular transplant at a transplant center, which is already well-versed in cell therapy, because transplant is a form of cell therapy. While they're still in the hospital recovering from their transplant, those patients will typically receive their first infusion of TSC- 101. Patients at that point are typically discharged. They go home, and then when they're scheduled to get their second infusion, that is largely now being performed as an outpatient procedure due to the very tolerable safety profile of TSC- 101. In terms of the number of patients that are eligible to receive the product, by the time we launch this product in 2029, we're anticipating a top-line readout in the study in mid-2028, which would enable a product launch mid-2029. About 7,000 patients with AML and MDS in the United States will be undergoing allogeneic transplant at that point. To qualify, you need to have the HLA type A0201, that's 42% of the U.S. population. You need to identify an A2 negative donor, which based on the donor types that we're allowing in the phase III study, we anticipate being able to do about 80% of the time. What that means is that about 2,350 patients a year in the United States will qualify for this product based on their HLA type. Now, to receive our product, you would undergo transplant with reduced intensity conditioning, and the current practice, about 2/3 of transplants use reduced intensity conditioning. You would have to be paired with a donor that is either a haploidentical donor, which is typically a child of the patient, or a mismatched unrelated donor, which is identified through a database search. Currently, about 1/3 of transplants use either haploidentical or mismatched unrelated donors. However, as Dr. Reshef pointed out earlier, the outcome for patients is really very similar, whether they have a matched donor or a mismatched donor. If our product is successful and we're able to drop relapse rates by 50%, we would anticipate that physicians would naturally try to identify haploidentical or mismatched unrelated donors for their patients so that their patient would qualify to receive TSC-101. In fact, we also anticipate that patients that might otherwise have been given myeloablative conditioning, would instead receive reduced intensity conditioning in order to receive our product, with on-label use of our product. Overall, depending on how much market penetration is achieved with this product, we anticipate that somewhere between 700-2,000 patients a year in the United States would receive TSC-101, and that would obviously increase over time as more and more people use our product. We also anticipate that due to the success of other agents that are enabling patients to go to transplant, in other words, to achieve the CR necessary to qualify for transplant, as well as the introduction of our product, that we would actually see an increased number of patients undergoing transplant in the United States We actually anticipate an increase in the overall transplantation market by about 40%. Finally, as we bring on other products in this program, TSC-102, A0301, A0101, and A2402, that this would actually more than double the addressable patient population based on the other patients that would qualify to receive this type of cell therapy. Over time, we anticipate the addressable market in the United States alone as reaching somewhere between 2,000-6,000 patients a year. Finally, just a word on pricing. We have done some initial pricing work and anticipate that this product would price in the range of other cell therapy products, which would be around $700,000 for the treatment. With that, I want to turn it over again to Dr. Reshef. Don't want you to take my word for it in terms of what we think the potential uptake of this product would be, but to hear from a transplant physician that is routinely treating patients in this area. Thanks, Gav in. I'll try to be brief so we have enough time for Q&A. First of all, I completely agree with you that this is an intervention that is already disrupting our donor search algorithm. The historical notion that you should only or mainly focus on looking for donors who are HLA matched or HLA identical siblings is outdated at this point, simply because the outcomes of mismatched and haploidentical donors has become so similar, almost identical to the outcome of HLA matched donors that you should really not prioritize that anymore. There's broad recognition that that's the case. Then we're kind of stuck with a donor search algorithm that focuses on donor age, which is a surrogate demographic for the health of the immune system and is not very specific and is not super effective in selecting the best donors. When you have an intervention that is tailored to a certain donor mismatch between the recipient and the donor, we will go look for that mismatch specifically. This already allows, it's already somewhat of a paradigm shift, but it is already happening in any center that's participating in this trial very seamlessly. Our coordinators are looking for specific donors who would be appropriate for us to be able to give patients TSC-101. When you have an agent or a transplant process that has the likelihood of improving transplant outcome, reducing relapse risk, you will prioritize the donor that would make it feasible for the patient to receive such a product. I think that's a very realistic prediction because it's already happening. The second thing to point out, which Gavin also mentioned, is the conditioning paradigm. Reduced intensity transplants were developed in the 1990s to reduce toxicity because transplant killed people from non-relapsed mortality regardless of their underlying disease and to advance it to older ages and reduce mortality and morbidity even in younger patients. The thought was that by reducing the intensity of the transplant, you will save a lot of the toxicity without impairing too much of the efficacy. Turns out that that was not the case, in a head-to-head study, when you head-to-head compare a standard transplant, reduced intensity is quite inferior because of the elevated relapse risk. If you take away the elevated relapse risk, this paradigm needs to be revisited, and it's quite possible that what we can achieve is a win-win situation where you have TSC-101 improving the efficacy, reducing relapse risk, and you have an opportunity to reduce the transplant intensity because you wouldn't need a myeloablative conditioning. While the study is focusing on reduced intensity because this is where it's easiest to show an improvement, and this is where the greatest unmet need is, I would have to say that there is a much broader application and a potential for shifting patients who are originally planned for an ablative transplant to receive a reduced intensity and then sail through that at a much easier manner. Lastly, I completely agree with Gavin's premise about exponential HLA scaling. The HLA system always appears extremely complicated because we have multiple loci and multiple HLA specificities. To develop a TCR, you only need the patient to have one specificity that is a match to your TCR. Turns out if you do the math, that you can cover more than 95% of the world's population by developing a fairly small and very manageable number of TCRs, and you may even run into the situation where you have patients who will be appropriate for more than one. From there, you could start thinking about multiplexing TCR. I'm not going to go there. It might be a bit premature, but certainly there are opportunities there. I think circling back to something I said at the beginning, while I'm very excited that this is the first effective cell therapy in AML and MDS, this is a truly disease-agnostic platform. We don't do transplants broadly in lymphoma and myeloma and other diseases because their efficacy is subpar. If we can have an agent that would actually allow us to revisit transplant options for these other diseases, we're looking at an expansion that's well beyond AML and MDS. I do know that this is not the immediate plan for TScan, but I'm just planting the seed in your minds that the potential for expansion here is, I would say, even conservatively presented in Gavin's slides. Thanks again. At this point, we're going to open it up for Q&A. Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. The first question will come from Sam Slutsky with LifeSci Capital. Your line is now open. Yeah. Hey, good morning, everyone. Thanks for taking my questions and great work on today's update. I guess for Dr. Reshef, based on your experience as a transplant doc, just how confident do you feel that TSC-101 is adding clear benefit to patients, based on the data to date? For the TScan team, could you just talk about the impact of the second dose versus the first dose in the previously disclosed data, and what that could mean as we fast-forward and some of these patients get their second dose in Cohort C? Thanks. Yeah. I'll start with the first part. I'm extremely confident that there's well above just the signal of efficacy. One thing that benefited this trial from the get-go was that it does have a control arm, so it allows you, from the phase I level, to start seeing what the patient outcomes are in a controlled situation, getting a standard transplant, and otherwise meet the same eligibility versus patients getting TSC-101. I think there's a very great distance between the outcomes that we've seen in the control patients and the experimental arm patients. While that may not still be reflected in Kaplan-Meier plots, because a phase I will never be powered to really provide you the statistical significance for that, you need a registrational trial, there's quite a robust signal of efficacy. Let me just repeat one thing that Gavin mentioned. The chimerism assay that we're using, I actually presented data on it at the last TCT meeting in February from an unrelated, very large real-world cohort and observational trial. Extremely predictive. The sensitivity of 0.2% in donor chimerism elevates the sensitivity of measuring chimerism to a really dramatic degree, and achieving or converting from mixed chimerism to full chimerism has a hazard ratio of six, eight, or 10 when you compare those patients who achieve it and those patients who do not when it comes to predicting relapse and even overall survival. I do think the data are very compelling. I would also remind one thing that has been disclosed in the past. We at Columbia have given TSC-101 to a patient, with [overt] cytogenetic relapse. A third dose that the company happened to have as residual cells, it was not even a very large dose. Within two weeks, the patient went back into remission. That, without lymphodepleting chemotherapy, without any other therapy, no HMA, no maintenance, no targeted therapy, that is the most clear evidence that the product directly eradicates recipient cells, including leukemic cells. That's a one patient, but I think it's a story that's worth highlighting. It was presented in the past. I'm happy to provide more information about it. I'll just briefly comment on your second question, Sam, around the second infusions. I would say in general, most patients achieve complete chimerism using this assay that Dr. Reshef just described within three weeks of receiving their first infusion. However, there have been a couple instances in our trial, including two instances in Cohort A, and it looks like about two instances in Cohort C, in which it just takes patients a little bit longer to achieve complete chimerism. The purpose of that second infusion is to really increase persistence of the engineered T cells, as well as to address any remaining recipient chimerism that may be left following the first infusion. We anticipate continued benefit being derived from that second infusion, which is why it is a scheduled infusion and part of the standard regimen that patients would receive. In terms of that third infusion that Dr. Reshef just referred to, we have enabled that as an option on the pivotal study, just as it was an option in the phase I. Patients that have impending relapse due to either chimerism or MRD status would be eligible to receive a third infusion in the pivotal trial as well. Thank you. The next question is going to come from Selena Zhang with Morgan Stanley. Your line is now open. Hello. Selena on for Max. Thanks for taking our question. What should we expect to be reported with the cadence of updates for Cohort C in terms of efficacy and additional patients? The cadence of data, we will provide data updates every six months, likely a large Hematology Conference in December of this year, and then another International Hematology Conference in the middle of the year next year. Essentially every six months, we'll provide updates. At the end of this year, there will be over six months of follow-up on every patient in Cohort C. At that Hematology Conference in June of next year, there will be over a year follow-up on every patient in Cohort C. We'll continue to provide updates on the control arm as well. Great. Thank you. Thank you. The next question will come from Andres Maldonado with H.C. Wainwright. Your line is open. Hi, guys. Thanks for taking my question and appreciate the granularity on the event. Maybe one question for Dr. Reshef to start off. In the context of perhaps, let's say, the TP53, in terms of antigen escape. For TP53 mutated patients, which are still in complete chimerism at six months, can you talk a little bit about is it the graft versus host leukemia effect basically indifferent to the cancer's mutational status, perhaps as long as the HLA-II presentation is still intact? I guess at baseline, how are you thinking about the potential for antigen loss as an escape route for those particular patients? Then, second one for Gavin and team. You touched upon on the chimerism speed versus endpoint. If you could maybe give us a little bit more color on, given that Cohort C is converting faster within the three weeks, is the speed of decline its own predictor of relapse, or is it just a faster path to the same endpoint? Thank you very much. Thanks for that question. I'll respond very briefly. It's, of course, a very complex question and trying to understand resistance mechanism and analyzing who are the patients who failed and why they failed. We're very limited due to the numbers of patients that have been treated. It is a question that I am very interested in and we have some ongoing thoughts on how we should approach that because we have a lot of samples from patients. The real answer to your specific question is that I don't think that's known, and I certainly don't know what the mechanism is in either TP53 mutated patients or others. It's very clear that TP53 mutated patients are inherently resistant to the chemotherapy and radiotherapy used for conditioning. Whether they have a very potent graft versus leukemia effect from the graft itself before the TSC-101 even goes in, that's debatable. The proof is in the pudding. Most of these patients relapse, and most of these patients relapse very early, within three to six months after transplant. I would argue that there is no potent GVL response before you infuse TSC-101. It does seem, based on the efficacy data so far, that TSC-101 is agnostic to the mutational makeup of the cells. That, of course, remains to be seen by collecting more patients. There's no true mechanistic reason why TP53 would be connected to antigen loss, not that I can think of, obviously we do need to do a deeper dive into those specific patients who have failed to see if it's antigen loss or is it something about the functional persistence of the cells. There could be various mechanisms of escape, no different from other interventions in the CAR T field or the cell therapy field in general. I hope that answers the question. Great. Thank you. Then just to address the second question around the rate at which patients achieve complete donor chimerism. I'd say, there's not a distinct difference between that in Cohort A and Cohort C. We are seeing rapid conversion to complete donor chimerism in Cohort C, as you note. I would say one of the key reasons why this product is so effective, is that we are treating patients when they have very minimal disease burden. Immediately coming out of the transplant, is when the patient's going to have the fewest number of recipient cells, including the smallest number of leukemic cells. I think this product is very effective because we are getting them a high dose of TSC-101 at that point where their recipient cells are really at their lowest. I will say that in Cohort C, we were treating patients at dose level four, which is the dose level that we are targeting for every patient in the pivotal study. That dose level four, the difference between that and dose level three is really that first infusion. Patients are receiving roughly twice as many engineered cells at that first infusion as most of the patients received in cohort A. I think the rate at which we achieve complete donor chimerism does come from essentially hitting the cancer hard, as early as possible, so that we can completely eliminate any residual cells. Great. Thank you very much. Thank you. The next question will come from Gil Blum with Needham. Your line is open. Hi, all. This is Jonathan on for Gil. Congratulations on the update. I just had a quick question about patient 10. Were there any features from the non-responder that would indicate a reason for this? Also, can you talk about the manufacturing success rate? You guys noted about 90% with the commercial ready process, wanted to see if there's any additional color we could get there. Yeah. Just to answer both questions. That patient number 10 that had MDS, we don't at this point have any specific hypothesis as to why their chimerism did not decrease following transplant. We're still investigating if there were any features of that patient that distinguish them from the other 13 patients that clearly had very rapid responses to the product. The second question was around the manufacturing success rate. We're actually extremely pleased with what we saw in Cohort C. Again, 90% success rate in manufacturing. We're always continually improving our processes at TScan, we anticipate that manufacturing success rate to only increase as we continue through the pivotal trial. It's also important to note that all of the product was in spec. Every release criteria was met for every product that was delivered to patients. We actually made more cells than needed so that we actually have backup doses for every patient coming out of the manufacturing process. For Cohort C, stored backup doses for every patient. That again, plays into what we're planning for the pivotal study in which most patients will receive their scheduled two infusions, but for any patient that has either increasing chimerism, as assessed at the site, or MRD positivity as assessed at the site, they would be eligible for 1/3 infusion, and this manufacturing process enables enough cells so that third infusion would be available hopefully for every patient. Thank you, and congrats again on the success. Thank you. Thank you. As a reminder to ask a question, please press star one one on your telephone. The next question comes from Tara Bancroft with TD Cowen. Your line's open. Hi, thanks and good morning. My first question I guess is for Gavin, the company. Maybe you can elaborate a little bit more on what happened with patient threes initial dose. You said it's half the number of target cells. Just curious what went on there and maybe your level of confidence in uniform dosing being achieved across all patients in the future and especially in commercialization. For Dr. Reshef, those were really helpful comments on how you'd use the treatment, what you see is the market and the size of it. I'm curious to hear what you're looking for in phase III, to achieve that level of use and maybe even what would change that outlook in either direction from the data. Thank you so much. Great. Thank you, Tara, for your question. I'll address the first question. This was actually scheduled as per protocol. Patient three was actually the first patient in the study that had a mismatched unrelated donor. Per protocol, we stepped back a dose level down to dose level three in order to treat that patient, just because it was a new donor type. Dose level three was weight-based dosing, and that first infusion was smaller at dose level three than it was at dose level four. Unfortunately, the patient also happened to have a very low body weight, and that patient ended up receiving about 300 million cells at their first infusion as opposed to 800 million cells that every other patient in the cohort received. That was per protocol based on the introduction of a new donor type. I do want to point out there were four other patients in Cohort C that also had mismatched unrelated donors, and all four of those other patients achieved and maintained complete donor chimerism within three weeks of receiving TSC-101. Dr. Reshef, if you want to address the second question? Yeah. I don't think it's very sophisticated. I think that a positive result in the phase III trial with improvement in relapse-free survival, clearly driven by reduction in relapse, would be sufficient impetus to create the commercial opportunity that I described. Revisiting the conditioning paradigm, revisiting the donor selection algorithm, which is already happening. Of course, in a phase III trial, you're going to also start looking at patient subsets and things like that. There's nothing specific about the product that would suggest that there will be differential efficacy in various patient groups. Of course, at the phase III level, we're going to have to learn more about this. Okay, great. Thank you both so much for your thoughts. Thank you. I am showing no further questions in the queue at this time. I will now turn the call back over to Gavin for closing remarks. Great. Thank you. Again, I want to thank Dr. Reshef for joining us this morning, for his insightful comments. Again, very excited to be moving forward with this product. Just want to reiterate that we are on track to launching this phase III study this month, and look forward to sharing exciting results as we move forward. Thank you, everyone. This does conclude today's conference call. Thank you for participating, and you may now disconnect