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Ladies and gentlemen, thank you for standing by and welcome to the Aloha 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-1-1 on your telephone, and you will then hear an automated message advising your hand is raised. And to withdraw your question, please press star 1-1 again. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Gavin McBeth, CEO of T-Scan Therapeutics. Please go ahead. Great. Thank you. And thank you, everyone, for joining us this morning. Very excited to be presenting updated data from our Phase 1 Aloha study of TSC-101. Just to remind everyone, we are a publicly traded company, and so I will be making forward looking statements this morning, So, before we begin, I just want to give a brief overview of T-Scan Therapeutics. So, we are a next-generation, fully integrated TCR T-cell therapy company, and 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. But before we began, I do want to highlight our two other programs. We do have a program in solid tumors. This is in preclinical development right now. But I'm excited to announce that we have recently met with the FDA using the Interact mechanism. And based on their very encouraging feedback, we now have a path to filing our first INDs for both our PRAME-TCR and our MAJ-A4-TCР by mid-next year. So very excited to be advancing that program through preclinical development. And then 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. And so I'm excited to also announce that we are now generating first-in-class T-cel depleting therapies with a particular focus on ankylosing spondylitis and other spondyloarthropid bees. So with that, I want to introduce those that are joining me on the call today. So we're very pleased to be joined by Dr. Ron Rashef, who's the Director of Translational Research at the Columbia University Blood and Marrow Transplantation Program. And he's also the Director for the Cellular Immunotherapy Program at Columbia University. I'm also joined on the call today by Dr. Crystal Lewis, our Chief Medical Officer, and by Drs. Shrikanta Chattopadhyay, who's our Senior Vice President of Translational Research. So with that, I want to move into a description of our heme malignancies program, and then focus on the recent data update from our ALOHA study. So for those of you not familiar with our program, our program is focused on patients that are suffering from various types of heme malignancies. And in particular, patients with myeloid malignacies like acute myeloids leukemia or myelodysplastic syndromes, really the only curative therapy for these patients is to undergo a bone marrow transplant. And, in fact, transplant is very effective. Upwards of 60% of patients are completely cured by a transplant. But, unfortunately, for those patients that are receiving a transplant with reduced intensity conditioning, the risk of relapse is over 40%. And 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. So 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. And our lead product, TSC-101, is targeting an antigen in patients that have the HLA type AO-201, which is the most common HLA-type in North America. So just to remind everyone of the mechanism of this product, any patient that has the HLA typ AO-211, again, about 42% of people in North American, their blood cells, all of their blood vessels, will be displaying an antogen called HA2 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 AO2O1 negative, then their blood cells will not be presenting that antigen. And so if that patient undergoes a bone marrow transplant, following the transplant, all of their new blood cells would be donor-derived, and so I've colored them in blue here, they will be HA2 negative, whereas any residual cancer in the patient comes from the patient, and so those blood cells are HA2 positive. And so what we do in order to treat these patients is we take T cells from the donor, again, these are HA1 negative cells, and we engineer them with a T cell receptor that targets that antigen. And now 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 HA2 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. So it's a way to target those residual cancer cells and prevent relapse in those patients. So 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. So to remind everyone, this is the structure of the ALOHA phase one trial of TSC-101. This trial included subjects with AML, ALL, and MDS. And we included a control arm in this study. So 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 undergoing 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. And so 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. So we launched this study over three ears ago, and so 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. And 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 had been on study for over three years remained relapse-free on the Treatment Arm, whereas none of the three patients that had been on study or were enrolled over three years ago on the control arm are on study any longer. And 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 remained relapse-free, whereas only three of the seven patients on the Control Arm remained relapsed free at two years. So 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 doseless limiting toxicities. And then 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 non-study for over three years. And then 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. And based on that feedback, we're actually launching our phase three study this month. So purpose of the call today is to really update people on this new cohort of patients that we enrolled in the study. And this new cohort of patients really is focusing on a new manufacturing process that we developed at the end of last year. So throughout this study, we've been using what we would call a phase one 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. It takes 17 days to manufacture the product. And in particular, there's a step on day nine of the process. It's the step in which we enrich the engineered T-cells, essentially purify them away from any non-engineered cells. And this step was traditionally very inefficient. We would, in fact, lose over 90% of the engineered cells at this step. And so 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. And then to enrich the engineered cells, we simply add methotexate to the culture media and only the engineered T- cells expand. And this process has much lower cost of goods. It's much more efficient. And in fact, it's a shorter process. We can now harvest the cells on day 12 rather than on day 17. So prior to launching our pivotal study, we committed to enrolling an additional cohort on our phase one study in which we would treat every patient using this commercial ready manufacturing process. So 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. And so we were unable to treat all of them. And so this is a really good example of how we were to enroll and treat 14 patience in about three to four months. And so, this chart is showing the characteristics of these patients. And 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. So, MRD positive prior to implant, 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. And 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 patience on the control arm. So a very difficult to treat patient population in cohort C. I'm pleased to say that we continue to observe a very tolerant, you know, 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. So, 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, and so they had quite a delay in receiving their first infusion of our product. They did eventually receive that first infution 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 sepsi, which was deemed not related to our product. It was related to transplant. So as I said, in total, there were 14 patients treated in cohort C. So obviously, these patients are relatively early on in their follow-up following their transplant. But 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. And so I just want to highlight again the mechanism by which this product works. So 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-derieved, including cancer cells, that are colored pink. And so again, our product is designed to target the patient-derived cells but spare the donor-derive cells. And so if this product is successful, we should completely eliminate all the patient derived cells and you should only have donor- derived cells detectable. So the assay that's routinely performed on patients following transplant is to follow what's called donor chimerism. And donor chinerism is a measure of if there are any patient- derived cell still detectable in that patient. So 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 has obviously a much lower risk of relapse. If, on the other hand, as shown in the right, the patient still has some detectable patients cells, which would include either malignant or normal cells, that patient had what's called mixed donor chimaerism, and that patient would be at an increased risk of relapse. So 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. And in fact, what we've shown in our own study, this is data coming from our ALOHA 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 showed in blue. So based on that, we're able to assess how well these patients in this new cohort are doing on study. And I'm very pleased to report that we had very strong data on cohort C. So as I said, in total, 14 patients received product. I'm showing all 14 patients on this slide. And what I'm show you is quantitative chimerism data. So, the y-axis in each of these plots is the percent of recipient chimericism. And again, we're trying to drop that percentage down below the limit of detection of the assay, which in this case is 0.2%. And so, if you focus on the patient in the top left, this is a patient that had a very difficult to treat cancer, P53 mutated AML. In yellow diamonds is when they received their first infusions of our product. So initially, this patient had 4.5% recipient chimerism. They received their 1st infusion of product, and immediately within 3 weeks of receiving that product, their chimerizm dropped below the limit of detection of the assay, which is 0.2%. percent. And 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 chinerism. So now as you look across all 14 patients, you will see that, in fact, 13 out of these 14 patients all showed decreasing recipient chimerisim immediately following that first infusion. In fact, there was only one patient on the study, patient 10, that did not respond to product and their chimerism actually increased. So we've often shown these data using this type of chart. So in this chart, all the columns represent the 14 patients and the rows represent blood draws and chimerisim assay results that we've performed on these patients. So 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. And so what you can see in that first row is that 12 out of the 14 patients had incomplete chimericism following the transplants. So very difficult to treat patients with incomplete chinerism. And then the yellow diamonds indicate when they got their infusions of engineered product. And so 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. So in total, 11 out of the 14 patients achieved complete chimeris within three weeks. And then two of the remaining three patients actually showed improving chimericism following that first infusion. So I'm going to walk you through the various patients that did not immediately achieve complete chimerism. Actually, I'm gonna start with this patient, patient three, that did achieve complete Chimerism immediately following that infusion, but then subsequently their Chimerizm increased again. So 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, a 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. Yet 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. So they received dose level three rather than dose level four. Every other patient on this 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. And then 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 chimeris immediately, as you can see on the quantitative plot on the right, their chimerim has actually been steadily decreasing with every blood draw, and they have now received their planned second infusion of TSC-101. I also want to highlight that this patient actually has ALL. Again, P53 mutated ALL, very difficult to treat cancer, but we are not actually including ALL on the pivotal study. And then 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. But in fact, that patient is extremely close to achieving complete donor chimerism using this assay. Their chimericism dropped from 7% down to about 0.3% within three weeks. So we're obviously very optimistic about this patient. They've effectively achieved complete chimerisim. I also want to point out that the standard clinical assay has a sensitivity of between 2% and 5%. So by any stretch, you know, the standard clinical assay would show complete donor chimerism in this patient. So just to summarize the chimerisim data relative to the control arm that we had previously enrolled on the study and tracked using the same assay, on cohort C, only 14% of the patients in this cohort had complete chimerizim following their transplant before receiving product, whereas on the controlarm, 24% of patients had complete Chimerizm. And yet this 14% jumped to 79%, 11 out of 14 patients, three weeks following their first infusion, and 100%, five out of five patients, two weeks following the second infusion. And that compares to only 53% on the control arm, which would be at the equivalent time point, about 80 days post-transplant. Now, 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 patient's. And then looking at some translational data, if you compare in blue patients who received 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 patient's seven days post-transplant was proliferating very well, expanding very well. In fact, had higher levels of KI67. In the top right, you can see, looking at the activation marker, CD28, that their T cells were more activated seven days post-infusion. And then finally, at the bottom, seven days post- Infusion had higher levels of Granzyme B, which is a marker of cytotoxicity. So 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. So at this point, I want to turn the call over to Dr. Rashef, who is going to comment on the patients that have enrolled in the study, as well as his view of these initial data that I've just presented. Thanks, Gavin. So 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. So I've been immersed in the cell therapy and transplant field for quite a number of years now. And 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 allogeneque 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 are aiming to really achieve plateaus and 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. And 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 HLAA-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 and 50 percent relapse risk depending on what conditioning regimen specifically we're using and what type of patients we're treating. And 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%. So that's really our benchmark for this type of strategy. We're starting at a very low point that somewhere between a third and a half of the patients are expected to relapse. And 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 in 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. But 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. Now, 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's 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. But to go into more specifics and use some maybe benchmarking data, TP53 mutation is by far one of the scariest ones that we deal with. And 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% to 20%. And 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. So there's 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. So, 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 Horrigan'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, Kevin 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. So 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. So 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. Rachev. So at this point, I want to turn the call over to Dr. Crystal Lewis, our chief medical officer, who is going to take you through the trial design for the Phase 3 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. Vachef 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 USDA with regards to what the trial design would look like, and in a very nice way, it mirrors what we were already doing. So we are going to be biologically assigning patients to the treatment or the investigational arm if they're AO201 positive and have an AO202 negative donor, and then anyone else would be participating in the control arm. And 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, it would not be a readout that would be 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 percent, that median follow-up would be too short from a regulatory perspective. And a readout within about two years is relatively quick for a registrational study. So our plan is at this point to not proceed with an interim analysis and wait for the full readout in about two year. Gavin, if you could go to the next slide. We did make some important protocol modifications between our Phase 1 and our Phase 3 study that we'll 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 one study, as Dr. Reshef mentioned, it's kind of an all comers, you get what you get. But our plan was to really tighten that up with regards to the registrational study in two different ways. So 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 prognostic genotypes that Dr. Reshef mentioned, including TP53, as well MECOM rearrangement. And then from an eligibility perspective, instead of it being a transplant-eligible population that we allowed within the phase one 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 one or complete response two or less than 5% blast, as well as those patients with MDS who have less than 10% blast. One question that we get quite frequently is because this is a bit of an open label study, how are we guaranteeing that we'll get control alarm patients onto the study. And so really working with Dr. Rishaf 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, and so there is the potential for those to be included as well. But we did have some discussion with the investigators to allow HMAs on the study with a caveat. So 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 menins or HMA's. And that's really to give the cells time to work. The other thing that we're doing is that we are asking investigators to go ahead and pre-specify. So, to acknowledge that the inclusion of these agents would be part of what is their standard of care transplant. And so, therefore, if it's pre- specified as part of standard of transplant, we just proceed. If it has not been pre-specific 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're 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. So from an enrollment perspective, we are going to be stratifying as we discussed. And then we are going to be looking probably every 10 to 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. And then we are going be using Cox proportional hazard 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? So for the phase one, 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. But what we saw with Cohort C actually really helps us to be encouraged by the addition of about nine to 10 additional sites, getting us to within 30 sites in the U.S. And 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. And now I will turn it back to Gavin, but 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 and now to a registrational company within such a short amount of time. Great. Thank you, Crystal. So at this point, I want to sort of highlight how we're also extending this program, not just to treat the 42% of patients that have the HLA type AO201, but ultimately virtually every patient that qualifies for a transplant. And so 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 hematocritic stem cells. And so we have additional products that are all termed TSC102 that are targeting antigens from CD45 displayed on other common HLA types, including AO301, AO101, and A2402. And so, we plan as a company to launch our first phase one study of these products in Q4 of this year. We're initially launching the two products that have already cleared INDs, TSC102A03 and TSC 102A01. And 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. So we will also be including a cohort that includes non-Hodgkin's lymphoma in this trial, as Well as ALL. I also want to point out that this phase one 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. So we plan to update publicly on progress on these trials approximately every six months at major hematology conferences. So at this point, I want to sort of end by highlighting what we view as a company to be the substantial market opportunity presented by these products. And so 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. So 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. So 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. And so as part of their regular transplant journeys, these patients are identified, they're HLA-typed, and their donors are HLA type. 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. And then 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 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, so 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 AO201. That's 42% of the U.S. population. And then you needto 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. So 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 two-thirds of transplants use reduced intensity positioning. And 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 a third 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 mis-matched donor. And so, 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. And 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. And so overall, depending on how much market penetration is achieved with this product, we anticipate that somewhere between 700 and 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. So we actually anticipate an increase in the overall transplantation market by about 40%. And then finally, as we bring on other products in this program, TSC-102, AO-301, AO101, 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. So over time, we anticipate the addressible market in the United States alone as reaching somewhere between 2,000 and 6,000 patients a year. And then 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. So with that, I want to turn it over again to Dr. Rochef. I 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, Kevin. And I'll try to be brief so we have enough time for Q&A. But 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. And 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 nicht super effektiv 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. And 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. So 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. And 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-relapse 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, it 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. However, 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. So 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. But to develop a TCR, you only need the patient to have one specificity that is a match to your TCR. And it 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. And from there, you could start thinking about multiplexing TCR. They're not going to go there. It might be a bit premature, but certainly there are opportunities there. And 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 option for these other diseases, we're looking at an expansion that's well beyond AML and MDS. And I do know that this is not the immediate plan for T-scan, 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. And thanks again. So 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 1-1 on your telephone and wait for your name to be announced. And to withdraw your question, please press star 11 again and the first question will come from sam seleski with fly side capital your line is now open hey good morning everyone thanks for taking my questions and great work on today's update i guess too i guess for dr chef based on your experience as a transplant doc just how confident do you feel that tst 101 is adding clear benefit to patients based on the data to date. And then for the T-scan team, could you talk about the impact of the second dose versus the first dose in the previously disclosed data? And then what that could mean as we kind of fast forward and some of these patients get their second dose in cohort C? Thanks. Yeah, so 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 one level to start seeing what the patient outcomes are in a control situation, getting a standard transplant and otherwise meet the same eligibility versus patients getting TSC-101. I think there's a very, very great distance between the outcomes that we've seen in the control patients and the experimental arm patients. And while that may not still be reflected in plots and Kaplan-Meier plots, because a phase one will never be powered to really provide you the statistical significance for that, for that you need a registrational trial. There's quite a robust signal of efficacy. Let me just repeat one thing that Kevin mentioned. The chimerism essay that we're using, I actually presented data on it at the last ECT 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 chimerisim to a really dramatic degree. And achieving or converting from mixed chimerysim to full chimeresim has a hazard ratio of 6, 8, 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. So 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, well, cytogenetic relapse. A third dose that the company happened to have as residual cells, it was not even a very large dose. And within two weeks, the patient went back into remission. Now 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. Now, 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. And I'll just briefly comment on your second question, Sam, around the second infusions. So I would say in general, most patients achieve complete chimerism using this assay that Dr. Rochef 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. And so the purpose of that second infusion is to really increase persistence of the engineered T cells, as well as to address any remaining recipient chimericism that may be left following the first infusion. And, so we anticipate, you know, 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. Rochef just referred to, we have enabled that as an option on the pivotal study, just as it was an option in the phase one. So 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. And the next question is going to come from Selena Zhang with Morgan Stanley. Your line is now open. Leah, 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? Yeah, so the cadenceof 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. So essentially every six months we'll provide updates. So at the end of this year, there will be over six months of follow-up on every patient in cohort C. And then at that hematogy conference in June of next year, uh, there'll be, um, over a year follow-op on every patient in Cohort C and we'll continue to provide updates on the control arm as well. Great. Thank you. Thank you, and the next question will come from Andres Maldonado with HC Wainwright. Your line is open. Hi, guys. Thanks for taking my question. I appreciate the granularity on the event. Maybe one question for Dr. Rochef to start off. You know, in the context of perhaps, let's say, the TP53 in terms of antigen escape. So for TP53 mutated patients, you know, which are still incomplete chimerism, you Know, at six months, you Now, 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 HLA2 presentation is still intact? And I guess at baseline, And, you know, how are you thinking about, you know, the potential for antigen loss as an escape route for those particular patients? And then second one for Gavin and team, you touched upon the chimerism speed versus endpoint. So if you could maybe give us a little bit more color on, given that cohort C is converting faster within the three weeks, you know, 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, but 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 TC-101 even goes in, that's debatable. The proof is in the pudding. Most of these patients relapse, and most of these patients relapsed very early, within three to six months after transplant. So 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, but obviously we do need to do a deeper dive into those specific patients who have failed to see if it's antigen lost, 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. And then just to address the second question around the rate at which patients achieve complete donor chimerism. So 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 chinerism 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. So 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. And so 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. And that dose level for the difference between that and dose level three is really that first infusion. So patients are receiving roughly twice as many engineered cells at that first Infusion as most of the patients received in cohort a. So I think the rate at which we achieve complete donor chimerism does come from, you know, 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. And 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. And then also, can you talk about the manufacturing success rate? You guys noted about 90% with the commercial ready process, but wanted to see if there's any additional color we could get there. Yeah, so just to answer both questions. So that patient, 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 kind of investigating if there were any features of that patient that distinguished them from the other 13 patients that clearly had very rapid responses to the product. And then the second question was around the manufacturing success rate. So we're actually extremely pleased with what we saw in cohort C, so gained 90% success rate in manufacturing. So, you know, we're always continually improving our processes at T-SCAN, and so we anticipate that manufacturing success rate to only increase as we continue through the pivotal trial. But 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. And we actually made more cells than needed so that we actually have backup doses for every patient coming out of the manufacturing process. So for cohort C, stored backup doses für every patient. And 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 side, they would be eligible for a third infusion, and this manufacturing process enables enough cells so that that third inf fusion would be available, hopefully, for every patient. Thank you, and congrats again on the success. Thank you. Thank you! And as a reminder, to ask a question, please press star 1-1 on your telephone. And the next question comes from Tara Bancroft with TV Cohen. Your line's open. Hi, thanks, and good morning. So my first question, I guess, is for Gavin, the company. Maybe you can elaborate a little bit more on what happened with patient three's initial dose. You know, you said it's half the number of target cells. Just curious what went on there. And maybe your level of confidence and uniform dosing being achieved across all patients in the future and especially in commercialization. And then for Dr. Vyshev, those are really helpful comments on, you know, how you'd use the treatment, what you see is the market and the size of it. But I'm curious to hear what you're looking for in phase three 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. So I'll address the first question. So this was actually scheduled as per protocol. So patient three was actually the first patient in the study that had a mismatched unrelated donor. And so 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. So dose level three was weight-based dosing, and that first infusion was smaller at dose level 3 than it was at dose number 4. Unfortunately, the patient also happened to have a very low body weight, and so that patient ended up receiving about 300 million cells at their first inf fusion, as opposed to 800 million cells that every other patient in the cohort received. But again, 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. And Dr. Rochef, 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 three trial with improvement in relapse-free survival clearly driven by reduction in relapsed would be sufficient impetus to create the commercial opportunity that I described, revisiting the conditioning paradigm, revisitting the donor selection algorithm, which is already happening. Of course, in a phase three 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. But of course, at the phase three level, we're going to have to learn more about this. Okay, great. Thank you both so much for your thoughts. Thank you. And 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. So, again, I want to thank Dr. Rochef for joining us this morning for his insightful comments. And again, very excited to be moving forward with this product. And so, I just want to reiterate that we are on track to launching this phase three 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