I'd like to welcome everybody to the H.C. Wainwright 3rd Annual Virtual Cell Therapy Conference. My name is Andres Maldonado. I'm a senior analyst here at HC W, and on behalf of HC W and myself, welcome to our virtual conference. Continuing with our morning sessions, our next presenter is Dr. Gavin MacBeath, CEO of TScan Therapeutics. Welcome, Gavin. Thank you. Thanks for having me. Great. You know, for investors that are getting up to speed with TScan and all the progress it's made in developing novel TCR-T therapies, you know, I think a good starting point would be to provide an overview of the technology and maybe some broad commentary upon the pipeline advancements the company has recently made. Great. Sounds good. Yeah. For those that are not familiar with TScan, we started about six years ago, back in December of 2018. We were founded based on a technology developed at Harvard Medical School that enables us to discover the target of any T- cell receptor. What we did in the early years is study the T cells of patients that were responding to immunotherapy to really understand what the natural immune response is to cancer and what T cells are naturally recognizing in order to fight cancer. Using that information, we now have developed a pipeline of TCR-engineered T- cell therapies to treat patients with cancer. For those not familiar with TCR-T, it's very similar to CAR-T therapy, except we're engineering the patient's T cells with naturally occurring T- cell receptors. The T- cell receptor is the natural mechanism that T cells use to recognize cancer-specific antigens. Using this information, we've actually built our own manufacturing facility. We do all the genetic engineering here at TScan. We have two main clinical programs. Our lead program is a program in heme malignancies. This includes patients with AML, MDS, and ALL. For these patients, really the only curative therapy right now is to get a bone marrow transplant. In fact, transplants are curative for about 60% of patients. If a patient relapses following a transplant, the prognosis is very poor. About 80% of patients will die within two years of a relapse. Our therapy is designed to make transplant fully effective to essentially address any residual cancer that remains following the transplant so that it's completely eliminated and the patient doesn't relapse. We launched a phase I trial about three years ago. That trial has now most recently presented, we presented data at ASH in December. That data set included 26 patients that we've now treated with our engineered T- cell therapies, as well as 12 patients on a control arm. The results are quite remarkable. On the treatment arm, only two out of 26 patients have relapsed over the course of the running of this trial, whereas on the control arm, four out of 12 patients have relapsed. That's 8% on the treatment arm versus 33% on the control arm. A really strong treatment effect. Based on this data, we now have RMAT designation with the FDA. We've met with the FDA and have high-level agreement on a pivotal trial design. Our plans right now are to launch a pivotal trial in the second half of this year. That trial will focus on one of our products that enables us to address about 42% of patients that are undergoing transplant. It's called TSC-101. The primary endpoint for that trial will be relapse-free survival. Based on our current clinical sites and the rates of enrollment, we project that trial will take about two years to get to a top-line readout. We anticipate a top-line readout for full approval in the second half of 2027. We are in the process of gearing up for that right now. We've engaged a commercial CDMO that will do the commercial manufacturing. They'll actually do the manufacturing for the pivotal trial. We'll continue to enroll into the phase I study as we move forward. We also announced in December that we have a new product that we're developing that enables us to address additional patients. Right now, our product addresses the HLA type A*02:01, which is about 42% of the U.S. With our new product, we'll be able to extend that to A*03:01 and continue to build the program with additional TCRs to really broaden the set of patients that we can address with these therapies. That is really the update on the heme program. Our second program is in solid tumors. Solid tumors present a very different problem. Solid tumors are notoriously heterogeneous. Not every tumor cell in a tumor expresses a given antigen. We believe that the best way to treat solid tumors is to treat them with combination therapy with multiple different TCR-T cell therapies simultaneously. To this end, what we've been doing is building a collection of TCRs that address different antigens so that when a patient comes in, we can figure out what antigens are expressed in their tumor and then go to that collection and give them the best two or three TCRs that address their specific cancer. Right now, we have seven different TCRs that we've cleared INDs on. They're all in the same clinical trial. The way that trial works is that we first test each TCR individually to make sure they're safe on their own at two different dose levels. Once those TCRs have cleared dose level two, they then become eligible to be combined with any other TCR that's cleared dose level two. That's when we start multiplex therapy, which is at dose level three. We updated the street back in December on our progress on that trial. At that point in December, we announced that we had treated our first eight patients in that study with four different TCRs, that we already had cleared dose level two for two of our TCRs. Our plan is to continue to enroll into that study to treat at least a dozen patients by the end of the year with multiplex therapy at dose level three or higher, and be able to provide a substantive efficacy readout on that trial in the second half of this year. Great. Thank you very much for that very comprehensive overview. Two very interesting narratives here between the liquid and solid tumor programs. Let's start off visiting the liquid tumor program, TSC-100 and TSC-101. Could you give us a little bit more color on how they were developed and really what differentiates those profiles thus far from other post-transplant therapies? Yeah. Originally, the targets of TSC-100 and TSC-101, which are antigens called HA1 and HA2, were actually discovered at Leiden University in the Netherlands about 25 years ago. They were discovered in patients that were undergoing transplant therapy because it was discovered that certain patients really responded to donor lymphocyte infusions following transplant therapy. It was discovered that the patients that responded to DLI, that many of them were expressing these antigens, HA1 and HA2. Based on that discovery, they were seeing a specific graft-versus-leukemia effect in those patients. That is what this program is based on, right? A known phenomenon in the transplant space. Can we specifically engineer that graft-versus-leukemia effect that is observed in patients naturally? Based on the antigen, we used our own internal discovery platform, which we call ReceptorScan, to clone high- efficiency, high- affinity TCRs that address those antigens, HA1 and HA2, and then, of course, developed our own manufacturing process to engineer the T cells with those TCRs. That is really the genesis of that program. The way the product is administered is the patient undergoes an allogeneic transplant according to normal procedures. We are not modifying the procedures of the transplant. We are focusing on patients that are getting reduced- intensity conditioning. This is actually the majority of patients that get transplanted. It enables us to address not just young healthy patients, but older patients as well. The patient undergoes the transplant, and then as soon as their white blood cell count has recovered, which is typically about three weeks post-transplant, they then get their first infusion of engineered T cells. Essentially, we're administering the T cells when the disease burden is lowest, right? Immediately following transplant, which is the best opportunity to come in and mop up all residual cancer cells and completely eliminate them. I think what's unique to our program is coming in at that very early stage post-transplant to really complete the process, eliminate all cells that could lead to relapse. We think that's really why this program has been so effective. Great. No, very interesting. TSC-100 and TSC-101 have generated a pretty compelling efficacy and safety profile thus far. Could you help us? Can you walk us through some of the highlights of that data? Maybe also with the data in mind, can you start talking a little bit about the pivotal study design and a little bit of discussion on surrogate endpoints, the potential for surrogate endpoints for accelerated approval? Sure. Yeah. Walking you through the data first. Starting with safety, we're actually really excited about the fact that these products appear to be extremely well- tolerated. Obviously, patients undergoing transplant have a lot of adverse events that are related to the transplant itself. We have not seen any significant safety concerns added by our cell therapy on top of what the patients are experiencing from the transplant. We've seen very mild cytokine release syndrome, one patient with grade 1, one patient with grade 2 out of 26 patients. No incidents of ICANS, some of the typical adverse events from engineered T- cell therapy. An extremely well- tolerated product. From an efficacy perspective, as I said, the most relevant thing is, are we preventing relapse? Seeing only two out of 26 patients relapse over the course of a two- to three-year study is really remarkable. In addition, there are some biomarkers that we've been following in these patients to really understand how effectively the product's working. In particular, donor chimerism is a key biomarker for us. In a transplant, you're trying to replace the patient's blood cells with donor blood cells. Ideally, you want post-transplant, the patient, 100% of their cells to be donor-derived. If they have any patient-derived cells left over, those are the cells that could lead to the transplant. We're looking for 100% donor chimerism. If you have less than that, that gives you increased risk of relapse. What we've seen so far is that every patient in our study, within three weeks of getting their first infusion, have converted to complete donor chimerism. This contrasts quite dramatically with the control arm, where we see quite a few patients that have incomplete chimerism that then precedes relapse, and many of those patients have passed from their relapse. Donor chimerism has been a key early readout for us of the effectiveness of our product. In terms of the pivotal trial design, we originally thought that chimerism could be a potential surrogate endpoint for accelerated approval. As we worked with the FDA and with trial design, we had one key outcome in our discussions with the FDA, and that is that they agreed to our use of an external control arm in our trial. What this means is that we won't be doing a randomized clinical trial in which patients are randomized to the treatment arm versus the control arm. Instead, the control arm will actually come from this pre-existing database in the United States. The CIBMTR is an organization that basically tracks every transplant that occurs in the U.S. Anyone that gets transplanted, their data goes into this database. In our pivotal trial, we'll be treating patients in our treatment arm. For every patient that we treat, we will find three patients in the CIBMTR database that match that patient's demographic, their age, their gender, their disease type, their risk factors, and that becomes the control arm for the study. It enables better matching between patients and control arm patients, but it also enables a much more efficient clinical trial. Because of that, we actually don't need a surrogate endpoint because based on the current 15 clinical sites that we're using in our phase I study, we believe that we can enroll the pivotal trial in two years. It takes two years to get to a top-line readout. The primary endpoint for the study will be relapse-free survival, and that will actually enable full approval of the drug. With a two-year study, there's really no clear incentive to try and have an early readout, a surrogate endpoint for accelerated approval. Great. Very helpful. At this point, I'd like to switch gears to talk about a lot of the inroads you've made with your solid tumor program. Obviously, a very different approach from the liquid tumor program, but can you walk us through the exciting multiplex therapy, what this means for solid tumors, and kind of give investors an overview of the technology, how it works, and where it can go in your eyes? Yeah. When we started to design the solid tumor study, we were really trying to understand what is the key limitation in solid tumors because we've seen very promising results from TCR- T cell therapy, both in the academic setting and at other companies. We often see deep responses. One of the things that has been challenging in the field is to get durable responses. We believe that one of the reasons that you don't get really long-lasting durable responses is because you're not addressing the entire cancer, right? Not every tumor cell is expressing an antigen. If you use just a single TCR, you could be killing most of the cells, but not all of the cells. It's those cells that aren't expressing the antigen that then grow back and lead to that relapse. We really, again, wanted to take our cue from nature. Nature, when you respond to cancer, does not just send a single T cell clone to fight cancer. The response is polyclonal, right? Different T cells addressing different antigens. We felt that the best way to treat cancer, and this is true of the entire history of cancer therapy, combination therapy has always outperformed single-agent therapy. Similarly, with TCR- T cell therapy, we believe that combination therapy or multiplex therapy is going to outperform single-plex therapy. To that end, our strategy from the beginning of the company has been to build a collection of TCRs, which we call our ImmunoBank, that addresses different targets and different HLA types so that we can match the TCRs to the patient's tumor biology and give them a combination of TCR-Ts. We talked to the FDA about this early on. They agreed with us that this was an approach worth pursuing. The trial design that we settled on is that for safety purposes, we would test each TCR individually at two different dose levels to make sure that each TCR-T is safe on its own. Once a TCR has cleared dose level two, it becomes eligible to be combined with any other TCR that's cleared dose level two. Dose level three is where the real action begins, right? We can start to treat patients with multiple TCRs simultaneously. It's also at what we believe would be our first effective dose. So far, as I say, we had our first patient dosed in May of last year. In December, we announced we've now dosed eight patients at that point. We had dosed patients across four different TCRs. Two of them had already reached dose level two and cleared that dose level. We also filed and cleared another IND in December for a MAGE-A4 TCR. We now have seven different TCRs in that trial. Our strategy is to try and move all seven of them through dose level two as quickly as possible so that we can treat as many patients as possible with multiplex therapy at dose level three and higher. Our plan is to update on the efficacy and the solid tumor program in the second half of this year once we've treated a substantial number of patients with multiplex therapy. Great. Very helpful. One of the most common investor questions we get is, how should we be thinking about the time it takes in identifying the right multiplex therapy for a patient until they get the treatment and how that timeline compares to the liquid solid tumor timeline as well? Sure. With the solid tumor program, obviously, there's a diagnostic step involved, right? We have to test the patient's tumor to see what antigens are expressed. Just to clarify for people that aren't familiar with TScan, the seven TCRs in our pipeline include TCRs that address five different antigens right now or five different target proteins. We have an HPV16- specific TCR. We have a PRAME TCR, a MAGEC2, a MAGE-A1, and a MAGE-A4 TCR. Those are the antigens we're addressing. In the solid tumor program, we want to test the patient's tumor first to see if it's expressing any of those antigens, PRAME or MAGE-A4 or HPV16, and then based on that information, choose the TCRs. Obviously, the diagnostic test takes a couple of weeks. The manufacturing for the TCR-T cell product takes, it's typically right now, just about a two-week process to manufacture and about a one-week process to do all the release testing before the patient can get the T cells. The way we're making this faster, however, is we're separating those two, right? What we do is we actually do the diagnostic testing on patients before they're ready to receive our T- cell therapy product. While a patient is currently getting therapy for their cancer, maybe front-line therapy or second-line therapy, we get a tumor sample, we test them for PRAME, for MAGE-A4, right, for HPV16. If they are positive for the antigens that are in our product, then we know that they will qualify for the clinical study. We keep those patients in a database. When they progress on their cancer, if they progress, right, we already know they qualify for the study. They can be moved very quickly into our clinical study. At that point, we're looking at, again, a two-week manufacturing process, one week for product release, and they can get the product as quickly as possible. Three to four weeks from when they enter the trial to when we can actually deliver TCR-T cells to that patient. Great. As more multiplex data becomes available, how should investors be really evaluating these unique data sets? If you could touch upon how you think the evolution and the diversity of the safety profiles will be different from each other given the various combinations of multiplexing you guys are doing. How should investors be thinking about the totality of the data sets on an efficacy and safety perspective and in a more macro sense, how that de-risks the entire strategy? Yeah. Great question. We actually think that the safety profile for each of our TCRs for these different targets is actually going to be very similar to each other. The reason for that is that if you look at CAR-T therapy and TCR-T cell therapy, the primary safety issues have to do with, one, the lymphodepletion regimen. Patients receive lymphodepleting chemotherapy prior to getting engineered T cells. A lot of the safety side effects of CAR-T and TCR-T actually relate to the lymphodepletion, which would be the same for all of our products. The other key safety issues actually have to do with the T cells doing what they're supposed to be doing, right, which is getting activated. Cytokine release syndrome results from the T cells getting activated. They see their target. They pump out cytokines, right? That's cytokine release syndrome. That should be very similar from product to product for us. It's not target-dependent. There's not really target-dependent toxicity. It's more toxicity that results from either the lymphodepletion or the actual activation and activity of the T cells themselves. We believe that safety profiles are going to be very similar from TCR-T to TCR-T, which is why we think that multiplex therapy, the safety profile is going to be dependent on the total number of T cells, not how many you're having of each different TCR-T product in there. The efficacy, obviously, we're looking at response rates. We're looking at depth of response, duration of response. The bar is going to be different depending on the cancer. Obviously, the bar is higher with melanoma. We'd expect higher response rates there. In lung cancer, right now, the best therapies in late-line lung cancer are seeing response rates around 20%-22%. The bar is much lower in lung cancer than it is in melanoma, somewhere in between for head and neck cancer. That really depends on what cancers we're focusing on. What we've decided to do as a company is really focus in two key areas, right? One, because one of our TCRs addresses HPV16, we have a specific focus on HPV-driven cancers, which include head and neck cancer, cervical cancer, and anal cancer. That's one area of focus. The second area is in non-HPV-driven cancers. There, we're really focusing on lung cancer, head and neck cancer, and sarcoma. By the end of the year, you should see some focused efficacy data in those key indications. We've chosen actually not to focus on melanoma. There's a lot of activity in melanoma. We've now seen AMTAGVI approved and in commercial use coming out of IOVANCE. Immatics obviously has TCR-T cells being developed in melanoma. We feel that the key area that multiplex therapy can play a role is more in lung cancer, head and neck cancer, and sarcoma. Great. In the time we have left, 2025 is shaping up to be a big year for the company. What should investors have on their radar across the liquid and solid tumor programs or TScan? Yeah. In the heme program, obviously, our key focus is on getting this pivotal trial up and running. That will be a huge milestone for us to launch that pivotal trial. We will also provide updated data on our phase I study by the end of the year. That data will include, obviously, more patients treated as well as longer duration. The first eight patients on our study will have reached the two-year mark by the end of this year. Providing sort of longer-term follow-up data on our phase I study. We are also going to be introducing a new product, TSC-102, right, to expand to other HLA types. That is another key milestone for us on the heme program. In solid tumors, again, the big update there will be safety and efficacy update on multiplex therapy by the end of the year. Great. This was very informative and very helpful. I really thank you for taking the time. I know this takes a lot to prepare these presentations and really enjoy speaking with you guys. We look forward to future updates in the future. Thank you so much for joining our Cell Therapy Conference. Congratulations on all the progress. Great. Thank you for having me.