All right, everyone, let's go ahead and get started. Good morning. Thanks for joining us. This is the Fireside Chat with T Scan Therapeutics. Happy to have with me on stage CEO Gavin MacBeath. Gavin, thanks for joining us. Appreciate it. Thank you. Before we get started, let me read a brief disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, Gavin, maybe the best place to start is, for people in the audience not familiar with T Scan, if you could just kind of give an overview of, what the platform is, what the thesis is behind why you feel like it could be, useful in developing differentiated therapies for solid tumors and liquid tumors. That's probably the best place to start, and then we can go into specifics from there. Yeah, great. And thank you also for inviting us to this conference. Sure. Yeah, so, for those not familiar with T Scan, T Scan was started in 2018, and it was founded, really at a time when there was a revolution in cancer therapy, and that is the real success that we were seeing from engineered T cell therapies, coming out of Kite and Juno at the time. And so the realization that genetically reprogrammed T cells offers probably the best solution for patients with cancer. And so we set out to build a company that could generate engineered T cell therapies for cancer, but not using CARs, but rather using the naturally occurring T cell receptor. I think one of the things that was holding that field back at the time was that we really didn't understand what the full range of targets were for TCR therapy. T Scan was built based on a novel technology platform, which we call TargetScan, that enables us in a single high-throughput screen. It's a genome-wide screen. It enables us to figure out what the target of any T cell receptor is. When we started the company, what we did is we acquired T cells from patients that were responding to immunotherapy. If a patient responds to immunotherapy, it's because their T cells have now been unleashed and able to drive that response. We just acquired T cells from those patients, ran them through our platform to figure out what the targets of their T cell receptors were. That's the first component of our platform, is target discovery using this novel genome-wide screen. The second piece is how do you take that information and turn them into novel therapeutics? The second pillar of our platform is what we call ReceptorScan, and that's a technology that enables us to very efficiently screen literally over a billion T cells from either cancer patients or healthy donors to find the absolute best TCR for a given target. For example, if the platform has identified a novel epitope on a protein like PRAME, we would then screen over a billion cells to find the very best TCR for PRAME. A naturally occurring one, not an affinity-enhanced TCR, but a natural TCR. Then finally, the third aspect of the platform is how do we turn those into engineered T cell therapies? We need to build a manufacturing platform that enables us to take patients' T cells, genetically engineer them with these TCRs, and deliver that product back to the patient. As probably aware, in this whole T cell therapy space, your product is the process, right? So it's very important to have a process that gives you a really good T cell phenotype, and, you know, really potent T cells that you can deliver, 100% success rate, right? There's a lot of challenges with manufacturing. And so we did two things, building our manufacturing platform, which we called T-Integrate. First, we made the decision not to use virus in our manufacturing process. There's a lot of challenges associated with virus production, and variability. So instead, we focused on using transposons to engineer our T cells. So we have our own transposon system, and it has three advantages: one, it's lower cost of goods, two, it's faster development time, but three, it also enables us to deliver more genetic material than you can deliver with a lentivirus. And so that's enabled us to build enhanced T cell products where we don't just deliver the gene for the TCR, we're also delivering additional genes like CD8 and dominant-negative TGF-beta receptor that further enhances the T cells. And then we also built our own GMP facility, so we do all our own cell manufacturing at T Scan. So I'd say the you know high-level summary is a platform to discover new targets for TCR therapy, a platform to discover the very best TCRs to deliver to patients, and then a platform for manufacturing these products in a consistent and low-cost turnaround time directly at the company. Got it. Got it. Great. That's a great overview. With that, could we maybe dive into the liquid tumor pipeline then? TSC-100, TSC-101. First off, if you could just talk a bit about how the platform was used to identify these product candidates, and then we can talk a bit more about the programs from there. Sure, yeah. So, we realized from the beginning that TCR therapy really had broad applicability in cancer, so not just for solid tumors, but for heme malignancies as well. And in particular, there was a clear unmet need in the heme space around myeloid cancers, right? So, AML in particular. And there really wasn't a CAR T solution for it, nor could you just copy what had been done with B-cell malignancies for myeloid malignancies. And so where we used the platform here was not for target discovery. So the targets that we're addressing are actually very well-known targets in the space. They were discovered at Leiden University about twenty, twenty-five years ago. So HA-1 and HA-2 are the targets in that program.... But rather we used the TCR discovery platform, so ReceptorScan, to screen, as I said, over a billion naive T cells from healthy donors, to discover two very high affinity TCRs that form the basis of TSC-100 and TSC-101. And then secondly, that program enabled us to build out our manufacturing platform. So we developed the vectors that we used to deliver these products, and then got this into our GMP facility and started manufacturing product for the patients. So I can go into sort of how that program works, if that's appropriate? Yeah, sure. Maybe we could talk about how that program works, and also you alluded to the commercial opportunity here and the unmet need. If you could just kind of frame out what you think that addressable patient population could be for both 100 and 101. Yeah. So, this program is really focused on patients with AML, MDS, and certain forms of ALL, that are not currently addressed with CAR T therapy. And so right now, for those patients, the best therapy for them is to receive an allogeneic hematopoietic cell transplant. And in fact, transplant is curative for about 60% of patients. And so right now in the US, every year, about 7,350 patients with those diseases, go to transplant, and as I said, 60% of them are cured by that transplant. The big clear unmet need here is that if you relapse following a transplant, the prognosis is very poor. In fact, about 75% of patients will die within a year of relapse. So what we're set out to do is, can we make transplant more effective? Can we treat residual disease in the patient following the transplant so that they ultimately don't relapse and are completely cured by the procedure? The way our product works is the patient undergoes a transplant, standard of care transplant, but then, while they're undergoing the transplant, we engineer the donor's T cells with a TCR that recognizes only the patient's cells, but not the donor's cells. So we're taking advantage of natural genetic differences between the patient and the donor. The patient's blood cells are positive for this antigen, the donor's blood cells are negative, and so that way, we can have a product that specifically focuses on eliminating residual cancer without touching any of the new normal blood cells that are derived from the donor. And so with this program, right now, we have two different products, and between TSC-100 and TSC-101, we can address about 42% of patients that, in the US, are undergoing transplant therapy. So right now, a little over 3,000 patients a year in the US would, from a genetic point of view, qualify for one of those two products. In Europe, the market is about a similar size. There's a slightly higher percentage of patients with the HLA type that we're addressing in this program in Europe. And so we estimate that between the US and Europe, the addressable patient population, from a patient eligibility perspective, is about 6,000 patients a year. Now, there's certain criteria that they need to undergo and certain aspects of the transplant that need to be qualified in this, so right now, our clinical trial is focused on a subset of that, but we think ultimately, if our program is as successful as we think it is, then that's, you know, what we estimate to be the addressable patient population. Got it. Got it. That's helpful. And I think you were working your way here, so maybe this is the next best place to go, is the clinical data you have so far for TSC-100 and TSC-101. You presented data updates, including at ASH last year. If you could just kind of walk us through what you and the team thought were some of the safety highlights, some of the efficacy highlights, and then we can maybe talk about next steps from there, but a summary of the data would be helpful. Sure. So, let's say our current publicly disclosed data set comes out at May twenty-first of this year. So we did a public financing in May of this year, and so that's when we disclosed the most recent data cut. And so at that point, from a safety perspective, so at that point, we included a control arm in our phase 1 study, which is somewhat rare, but has been very helpful for us. And so there were eight patients in the control arm and eight patients in the treatment arm at that point. So from a safety perspective, of course, all of these patients are undergoing transplant therapy, so they are experiencing the usual adverse events associated with transplant, CRS, GVHD, you know, potential exposure for infections. And so to this point, we haven't seen any obvious imbalance in safety between the treatment and control arm. So we're not seeing any additional safety concerns in the patients that have received our engineered T cell product relative to the control arm patients. So we're, you know, really excited about the fact that the product doesn't appear to be adding any safety concerns. From an efficacy perspective, at this point, the data couldn't be cleaner. So on the control arm, we're seeing pretty much what you'd expect in this space. Average follow-up time over six months in the control arm, and out of the eight patients, three patients relapsed already. One of those patients passed away from their relapse. A fourth patient passed away shortly after the transplant. So out of eight patients, you know, really, you know, over half of them are either relapsed, have passed, or are impending relapse due to incomplete transplant. Whereas on the treatment arm, out of the eight patients that we treated, all eight patients are completely disease-free, no relapses. We, in fact, can't even detect any cancer cells, either in their peripheral blood or in their bone marrow biopsies. That's with an average follow-up time of 10 and a half months. At that point, two of these patients over a year. In fact, one of our first patients had p53 mutated MDS. This has an 80% chance of relapse within a year. That patient is out past a year, and continues to be relapse-free. Very exciting data, which is really what's prompted us to now initiate conversations with the FDA around a potential path for a pivotal trial, which we are looking to launch in the second half of next year. Got it. What do you think is the approvable endpoint here for a pivotal program? Yeah. So I think, you know, looking at the whole, transplant space, I think it's fairly well established that relapse-free survival is an approvable endpoint for a full approval in this space. So I think the biggest question for us, going into meetings with the FDA, is: Is there a surrogate endpoint that could potentially be used for accelerated approval? So I think that's the key question that we have, going into discussions. Earlier this year, we received RMAT designation from the FDA. This provides us with an opportunity to talk to them early about potential surrogate endpoints. And so, this year, we'll be meeting with the FDA to start discussing a pivotal trial design, and then we're hoping, you know, by the end of Q1 of next year to have a clear path forward in terms of what, you know, we'd agree on as a potential pivotal trial. Got it. Got it, okay. Initial thoughts on what that pivotal trial could look like from your perspective? I mean, what do you think would be a suitable data set to be able to warrant a quick path to market? Yeah. So it's really difficult to say without having that feedback from the FDA. I would say the three biggest things we're focusing on in that discussion is, one, you know, is there a surrogate endpoint that could lead to accelerated approval? There is no established surrogate endpoint in this space, so it's a bit of a big ask. But if we can agree on one, that would certainly save us some time. It's not the end of the program, obviously, if we don't have an accelerated approval. There's a very clear approval path forward with relapse-free survival as the, you know, primary endpoint. The second question, there'll be a lot of discussion around the control arm. You know, what's an appropriate control arm in this space? And then the third is, you know, just our statistical analysis plan is critical here. How are we treating these two different products that we have in the program? We feel they're very equivalent products, and so, you know, that's really the basis. So at this point, you know, it's difficult to comment on what the size of the trial would be or the length of the trial until we get that feedback from the FDA. Fair enough. Fair enough. And then for the ongoing study, I think you have an updated data cut plan for later this year. Correct me if I'm wrong. Yeah. So we intend on providing an update on the heme program at ASH at the end of the year. Got it. Okay. It's framing expectations for that, for that data cut. What are you hoping to see? What else do you, I mean, what are the open questions following the last data cut that you think that the next update can kinda help address? Yeah. So, this next data cut is gonna have a, you know, fair number of more patients, certainly than what we had in May, which was eight patients treated. We're aiming to at least infuse 20 patients by the end of the year. That doesn't mean we'll have follow-up data on all 20 patients. Obviously, every patient will have different lengths of follow-up. But those eight patients that were in that data cut in May, all of them were dosed before ASH of last year. So we'll have one-year follow-up on all eight of those patients. We'll have six-month follow-up on another handful of patients, and then lesser follow-up on the rest of the patients. So I think that's a much more mature data set, obviously, than we've presented so far. And so, you know, that, I think, gives us increased confidence, but it also starts to help us define what the effect size is gonna be, which helps with the, you know, the sizing of the pivotal trial. The other thing that we're looking to do by the end of the year is establish a commercial process for manufacturing for this program. So obviously, our process that we're using now is working fine, but we want to, you know, make it, you know, more robust, lower cost of goods- Mm-hmm ... something that's really suitable for a commercial setting. We have identified a commercial CDMO that we're working with, that has capabilities of commercial manufacturing both in the US and Europe, and so that's the other focus of the program between now and when we launch the pivotal trial next year, is to tech transfer that process to the commercial CDMO so that they can really run the manufacturing in the pivotal trial. Got it. Okay. From a real-world use perspective, is there anything, either from, like, an infrastructure perspective or from a training perspective, that a center would need to be equipped with in order to be able to administer TSC-100 and TSC-101, if it's approved for commercial use? Yeah. So I'd say, you know, in a sense, this program is one of the easier cell therapy programs to roll out in a commercial setting, because one, the market is clearly very concentrated in transplant centers, right? And, you know, right now, the clinical sites that we're using for this study are the largest transplant centers in the US. In fact, 25% of patients that receive a transplant in the US right now receive a transplant in one of the clinical sites that are currently participating in our trial. So, the sites are getting well-versed with how to administer the product. But two, transplant itself is obviously a complicated procedure, and so we're adding very little complexity to an already established, you know, process for these patients. They're already familiar with doing the conditioning therapy, managing the toxicities associated with it, preparing, you know, doing the apheresis and the infusions. So all our product adds to the process is an additional apheresis for the donor, and then two IV infusions for the patient. One while they're still in the hospital, three weeks after the transplant, and then the second, we're looking to do as an outpatient procedure forty days after their first infusion. So very little additional complexity to the process in centers that are already well-trained to do these procedures. Got it. Okay. I'll ask you one final question on the liquid tumor program, and then we should pivot over to solid tumors. I guess when you take a step back and just look at the progress you've made with TSC-100 and TSC-101, from a platform perspective, what questions do you think the TSC-100 and TSC-101 data updates help you address? And what do you think are the key open questions in your mind still for TScan's overall approach with both TargetScan and ReceptorScan? Yeah. So I think, the success that we've seen on the heme program, for us, has validated the fact that, the TCRs that we're discovering at T Scan are clearly efficacious. This all came out of our own ReceptorScan platform, so that to us, de-risks the fact that, T Scan, you know, TCRs discovered at T Scan, are clinically active. The second is clearly the manufacturing. So, you know, using the transposon-mediated methods, knowing that we can produce, really effective and safe, product out of our own facility and with our own, transposon platform, I think really de-risks the solid tumor program as well. Obviously from a clinical execution perspective, we're building the clinical team, and they've been, you know, very effective at you know, rolling out now over a dozen clinical sites participating in the heme program. We actually have over fifteen clinical sites active in the solid tumor program. So we've been very effective at clinical execution on these programs. And then, oh, yeah, the last point is T cell persistence, right? So our translational data, what we've been finding so far is that the T cells that we've administered to these patients in the heme program are persisting. In fact, we can see engineered T cells past a year in the earliest patients at the lowest dose levels treated with our product. So that suggests that these naturally occurring TCRs are leading to an engineered T cell product that can persist long-term in these patients, which we hope is data that will translate over to the solid tumor program as well. Got it. Got it. That's probably a good segue to get into the solid tumor pipeline then. Before we discuss the specifics, maybe you can just walk us through the approach of developing multiplex therapy, T-Scan's approach of developing an ImmunoBank that you can use to kind of develop kind of multiplex solid tumor cell therapies, and then we can go into specifics from there. But it might be helpful just to kind of get your perspective on the overall strategy here. Yeah, thanks. So we are quite differentiated in this aspect in our solid tumor program. So as we, you know, moved into developing TCR therapy as a company, we felt that the key unmet need in the solid tumor space is the fact that solid tumors are notoriously heterogeneous, right? So not every tumor cell in a solid tumor expresses a given target, and HLA loss occurs in tumor cells, which would make them resistant to a single TCR. We also note that the natural immune response to cancer is polyclonal. You don't just make a single clone of a T cell to fight cancer. You come in with a multitude of TCRs. And in fact, TIL therapy is taking advantage of that, right? It's a naturally multiplex product, that's clearly been effective, at least in melanoma at this point. And so based on all of those considerations, we put together a strategy for treating patients with solid tumors in which we would build a collection of TCRs, and these are all the best TCRs, right? We know they're safe, we know they're effective, we know they're high affinity. We'd build a collection of TCRs that address different targets that are commonly expressed in cancer and different HLA types, because TCRs have to be matched to the HLA type of the patient. So this collection is what we call the ImmunoBank. And then the strategy in treating a patient is that when a patient comes in, we would get a sample of their tumor, test their tumor to see what targets are expressed in their tumor, what HLA genes are still intact in their tumor cells, and then for each patient, we'd go to the ImmunoBank and select the best two or three TCRs from that Immunobank that match the antigens that are expressed in that patient's tumor cells. And that becomes what we call a customized multiplex therapy. So in a way, it's a form of combination therapy. In fact, the history of cancer has shown that combination therapies are always more effective than single-agent therapies, but we're just doing that with T cells, right? With different TCR-engineered T cells. And so our strategy has been to discover targets, discover TCRs, and then move them all into the same clinical study. Right now, we have six different TCRs, all in our same phase I clinical study. And then from a clinical trial design, we reached agreement with the FDA that we would be able to mix and match these TCRs in any two-way combination in our trial. But first, we start by testing each TCR at two different dose levels as single-plex therapy, because we want to make sure that each TCR is safe on its own before we start combining it with other TCRs, so dose level one is half a billion T cells. Dose level two is two billion T cells. Each TCR is tested at those two dose levels, and then once a TCR has cleared dose level two, it becomes eligible to be combined with any other TCR that's cleared dose level two. At dose level three, each patient is going to receive two different TCRs on the same day, just successive infusions of those two different T cells. Then we're also introducing a repeat infusion of that 28 days later. Dose level three is where we're really going to be testing the core hypothesis of the solid tumor program. Do patients that are receiving multiplex therapy have deeper responses, better response rates, and ultimately longer duration of response? Got it. You know, at scale, once this approach is commercial, how long do you think the process could take from identifying the right therapy, the right multiplex therapy a patient needs, working on that therapy through the ImmunoBank, getting it back to the patient? How long could that process take, and how much longer do you think it'll be, if longer, versus kind of the current kind of vein to vein time that's often quoted for liquid tumors? Yeah. So there's nothing fundamental about multiplex therapy that makes it have a longer vein to vein time than singleplex therapy, right? So the process for making the engineered T-cell therapy is the same. The patient gets apheresis. That apheresis product gets sent to our manufacturing facility overnight. We then engineer the cells. But for multiplex therapy, we simply split the apheresis product into two different portions, in parallel, manufacture the TCR-T cells, fill the bags, freeze them, and send them back to the sites for IV infusion. We're looking to get the overall manufacturing time down to, you know, about two weeks. Release assays have to occur, so typically within three weeks is when the product would be ready to administer to the patient. I would say that's the manufacturing process for preparing the actual product to deliver to the patient. Mm-hmm. The patient obviously then has to undergo lymphodepletion. Right ... before they receive the engineered T cells. So vein to vein time is, you know, also you have to add on the lymphodepletion period. But overall, you know, about a two-week manufacturing product process with a one-week, you know, product testing and clearance. The other aspect of all of this is identifying the patient and what TCRs they're- Right - going to get. Right? And so that's where these biomarker assays come into play. We want to test them for what targets are expressed, whether they've lost HLA genes. What we're doing functionally in our clinical trial is we're separating those two processes. We're screening the patient separately from treating the patient. So basically, we're screening patients while they're currently on therapy, right? So a patient may be receiving frontline checkpoint therapy. While they're receiving that therapy, we get a tumor sample, we test them to see if they would ultimately be eligible for our clinical trial. So all of that testing is done when the patient's not yet even ready to join our trial. So we know whether a patient's ready or not, so that in the event that they progress on their cancer, we can move them rapidly into the clinical protocol. So that's why I'd say, our overall process for our phase I study is very similar to other companies in terms of the turnaround time necessary to treat a patient. Got it. Okay, and then for the phase I study you have underway right now, could you just kind of walk us through the protocol and how you're thinking about the pace of patient enrollment going forward? Yeah, so we announced, was it four months ago, something like that, that we had dosed our first patient in the trial, but at the time, we also reminded people that we have six different TCRs in that trial, and that for those first two dose levels, those six TCRs can all move forward in parallel, right, so we're not sequentially testing one, making sure it's safe, and then moving to the other. All six function independently, and so because of our screening protocol, because we've been screening patients for all six targets in the study, we anticipate this trial to enroll fairly efficiently, right, and so what we're aiming for is, by the end of this year, to have advanced the majority of these six TCRs through dose levels one and two. If we can get to the end of the year and have had established safety on five or six of these TCRs, and, you know, what we're also hoping to do by the end of the year is treat our first patient with multiplex therapy. If we can get there by the end of the year, that sets us up for, you know, a very interesting twenty twenty-five. Because at that point, all the patients that are coming in, or the majority of them, are going to be receiving multiplex therapy. And so twenty twenty-five is the year in which we can start treating patients at what we view as the effective dose, right, dose level three, and start testing the core hypothesis of the company, right? Does multiplex therapy provide an advantage over singleplex therapy? Really, looking to treat, you know, ten plus patients by the end of the year to advance to those first two dose levels, and set us up for success next year. Got it. So it sounds like, the first set of mature multiplex data is next year? Yeah. So the first set of real data on multiplex therapy would be next year. Yeah. When that data is available, what's your guidance on how to best interpret that data set and try to glean, I guess, proof of platform for the solid tumor part of the company from that data set? Should people be looking for better durability? Should people be looking for depth of response, differentiated safety? What are the guideposts you think are fair to keep in mind there? Yeah, so ultimately we're looking for two things, right? So better depth of response, right? Because if a tumor is heterogeneous, if you're only addressing some of their tumor cells, you're only going to kill, you know, 20, 30, 40% of their tumor, right? If you're addressing 80% of their tumor cells, you should have a deeper response. So one, deeper responses, but two, increased durability of response, right? We think that these rapid relapses in some of these programs with single TCRs is due to all the tumor cells in the tumor that aren't expressing that target and are leading to the relapse. So I think those are the two key metrics, deeper responses and longer duration of response. But as a reminder, we are also addressing a broader range of tumor types in this study. So we are seeing patients with melanoma, but we're also seeing non-small cell lung cancer, head and neck cancer, ovarian cancer, cervical cancer. We're really focusing on cancers that have immune-rich environment. So we know that T cells get into those cancers. They have response to checkpoint therapy, so we know it's a conducive environment for T cell function. But some of these cancers are more heterogeneous, for example, than melanoma, right? So a lot of the really encouraging data, particularly for PRAME, has come out of melanoma, where we know that PRAME is very uniformly expressed at very high levels in melanoma. The same is not true in non-small cell lung cancer, where PRAME is much more heterogeneous. And so it's these other types of cancers, like lung, where we really feel that the multiplex therapy is going to be critical, right? That patients just aren't going to respond to singleplex therapy, but if they give them a multitude of TCRs in cancers like lung and head and neck, that's where we're going to see the, you know, sort of the biggest bang for our buck. Got it. Okay. We have about a minute left. Maybe I'll pivot a little bit and ask you a question on kind of broader platform applicability. Do you think there's a role for T Scan's platform outside of oncology? I certainly hope so, because we have a partnership with Amgen to discover the targets of T cells in Crohn's disease. The platform, as I said, was founded on this platform that enables rapid target discovery. The company was founded on this platform that enables rapid target discovery. We've recently expanded the platform to discover the targets of not just Class I MHCs, but Class II MHCs as well. Diseases like Crohn's disease are known to have a heavy T cell component, and it's Class II TCRs that are driving that. We formed this partnership with Amgen about a year plus ago to acquire T cells from patients with Crohn's disease, sequence their TCRs, run them through our platform, and discover novel targets. And I think this is going to open up a whole new area of therapy and autoimmunity, because right now, all the therapies are fairly blunt tools. We're just treating inflammation. If we can treat the source of that inflammation, if we can figure out, you know, treat the cause of autoimmunity, I think that, that's a whole new wave of therapies, and knowing the target is the first step in doing that. Got it. Great. In closing, just remind us of your current cash balance, the associated runway, and I guess the amount of pipeline development contemplated in that runway. Yeah. So we ended Q2 with just shy of $300 million in cash and cash equivalents. And so this gives us runway into Q4 of 2026. And so we continue on track with that. This gives us the cash necessary to run both the heme and solid tumor program and launch that pivotal trial. So I think we're in really good shape right now. And now it's sort of a execution phase of the company as we kind of move both of those programs forward. Great. Great. And with that, probably a good place to close out. Gavin, thanks so much for joining us. Really appreciate your time. Thanks, everyone, for joining and listening in. Great. Thank you.