Good afternoon and welcome to the Adaptimmune Therapeutics virtual KOL event. At this time, all attendees are in a listen-only mode. The question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the Adaptimmune website following the conclusion of the event. I'd now like to turn the call over to Adrian Rawcliffe, Chief Executive Officer of Adaptimmune Therapeutics. Please go ahead, Adrian. Thanks, Dar. Good afternoon and thank you for joining us today to discuss the key findings from the pivotal IGNITE-ESO trial of lete-cel in patients with synovial sarcoma and myxoid round cell liposarcoma. I'm delighted that this call will feature Dr. Sandra D'Angelo, sarcoma medical oncologist from Memorial Sloan Kettering Cancer Center. She is an investigative clinician in both the SPEARHEAD-1 clinical trial, which was the pivotal trial for Tecelra, and the IGNITE-ESO clinical trial, which was the pivotal trial for lete-cel. She presented the data from the IGNITE-ESO trial at ASCO this year and last week at the Connective Tissue Oncology Society, or CTOS, meeting. She will explain the nature and current state of treatment of sarcomas. She'll discuss the data from both of these pivotal trials and expound upon what these therapies could mean for the treatment landscape in sarcoma. Before Dr. D'Angelo begins, I'd like to remind you of the positive results from the IGNITE-ESO trial. The trial met its primary endpoint. It demonstrated even better outcomes than the interim results we announced back in June, and it will form the basis of the BLA submission for lete-cel starting next year. The study achieved a 42% overall response rate in 64 patients treated. This included six complete responses, and the responses are durable, with the median duration of response in the MRCLS population currently just over a year, and in the synovial sarcoma population, it's just over 18 months, so today we want to focus primarily on lete-cel, but last week we also shared an update on the launch of Tecelra, and we're making great progress on that so far. We feel confident that lete-cel will both complement and expand our sarcoma franchise, which, as you know, is a key strategic focus for Adaptimmune going forward. With that, please join me in welcoming Dr. D'Angelo. Thanks so much. It's a pleasure being here, and I'm happy to provide a little perspective and share some information about sarcoma, laying the foundation for our present and future treatment options, and really focusing on cell therapy and the great impact it's had on the care of our patients in our clinics. So today I plan to talk a little bit about sarcoma, describe the disease, what the treatment landscape is, talk about the SPEARHEAD-1 trial and afami-cel, review the recently presented IGNITE-ESO trial data, and then highlight the impact of these therapies for our patients. So I'm going to start by way of background. Sarcoma is a heterogeneous group of malignancies. It arises in the bone and soft tissue and can really affect individuals of all ages. Synovial sarcoma comprises 5% of all types of sarcomas that present in our clinics. Sarcomas fall into kind of two main baskets of diseases. For the purpose of simplifying it, we have those sarcomas with simple genetic translocations. These are diseases that occur in a younger patient population, and examples of those are synovial sarcoma, myxoid round cell liposarcoma, which is relevant in the context of this talk. Sarcomas generally present with a painless mass. Occasionally, they can present in the metastatic setting. It's slightly more prevalent in females, and about 40% of cases arise in the extremities. The natural history is based on the type of sarcoma, the location, the size, the grade. The standard of care for decades has been surgery with or without radiation therapy, and sometimes we do use adjuvant chemotherapy or chemotherapy after initial presentation to reduce risk of metastatic recurrence. But the sobering fact is that about half of patients with those tumors that are greater than 8 cm will die of their disease. So I'm going to walk you through what our standard therapies are and how we got there. So aggressive chemotherapy is really the backbone of all soft tissue sarcomas. And ifosfamide was compared to doxorubicin. Ifosfamide was administered in two different fashions. And the response rates, as you can see here, range from 5%-10%. The progression-free survival, or the average time most patients were on this drug, ranged from two to three months. And the survival, as you can see, is less than 12 months. Ifosfamide is a fairly toxic drug, to just give you a little perspective, we typically administer this drug over three days. It's a day-long infusion. Patients will come into my clinic at 8:00 A.M., wait for their blood work, receive one to two liters of fluids, then receive the drugs, then additional one to two liters of fluids. And this happens three to five days in a row, depending on the center where you receive this treatment. And this is repeated every three weeks. And this type of drug comes with the typical chemotherapy side effects one would anticipate: hair loss, nausea, vomiting, which obviously we've gotten better at managing. Some unique side effects of ifosfamide can include kidney damage as well as cognitive deficits, confusion. Gemcitabine and docetaxel is sort of the next go-to regimen that we use in soft tissue sarcomas. This was compared to gemcitabine alone. The response rates range from 8%-16%. The progression-free survival is a little bit better, four to six months, and the survival is 12 to eight months. I put this here because it forms a standard therapy that we use in soft tissue sarcoma, but I'll highlight that it's not typically used in synovial sarcoma or myxoid round cell liposarcoma, and then there was a comparison of gemcitabine, docetaxel with doxorubicin, and here, again, the message is very similar. The response rates are under 20%. The progression-free survival is about five months, and the survival is about 14 to 15 months. When we look at second-line therapy, so beyond frontline, I have here three potential agents. The first one on the top is pazopanib. As As you can see here, the response rate's 6%. The survival is 12.5 months. The progression-free survival is 4.6 months. Eribulin, trabectedin, all these outcomes with these particular agents, the further you are from frontline therapy, the worse the outcomes, and generally ranging in the less than 10% range, at least with regards to response rate. Again, progression-free survival, as you can see here, it's anywhere from two to four months. The chemo highlights, obviously, the high unmet need in sarcoma for more promising therapeutic options. In the broader field of oncology, we've learned and we've seen promise within the context of targeted therapy and immunotherapy. Those specific approaches have really led to improvement in mortality in a number of different malignancies. As you can see here now, immunotherapy sort of forms one of the backbones in how we deliver care to our patients with cancer. Specifically, in the context of checkpoint blockade, this has been one of the bigger advancements in the field of immuno-oncology. But in the field of sarcoma specifically, checkpoint blockade is relatively ineffective for most sarcoma subtypes, actually. The response rates range less than 20%. And in the context of synovial sarcoma and myxoid round cell liposarcoma, essentially, these drugs are ineffective, and we don't really use them. And so even in the context of immuno-oncology, there's an obvious need to explore alternative options and do more and do better for our patients. And that brings us really to the focus of this presentation and the adoptive cell therapy. Adoptive cell therapy has really revolutionized the care of patients with hematological malignancies. And within that particular space, much of the advancements has been with chimeric antigen receptors or CAR T cells. CAR T cells target proteins that are found on the surface of the cancer cell. I'll highlight that the limitations of CAR T cells, despite the promise, is that only 20%-25% of proteins are accessible via the surface. Engineered T cells actually allow us to target a number of different antigens, and nearly 75% of proteins are accessible with T cell therapies, which offers a significant advantage over CAR T cells. And obviously, the two areas of focus in the context of my clinical practice are those that are applicable to those patients with sarcoma, specifically MAGE-A4 as a target with afami-cel, and then NY-ESO-1 as a target with lete-cel. The slides highlight a bit of the process with regards to how these products are manufactured, and I'll go into that in more detail in a bit. To focus a little bit more on synovial sarcoma, this is a disease that represents 5%-10% of all soft tissue sarcomas. There are about 1,000 cases diagnosed in the United States each year. This is a disease that affects young patients. The average age of presentation is approximately 40, and more than 50% of patients are diagnosed younger than 40. And 50% of patients actually will present with metastatic disease with synovial sarcoma, a little bit different than what I alluded to earlier. And oftentimes, there's a delay in diagnosis, largely because the broader oncological community is not familiar with sarcoma, and it can take time for patients to be diagnosed correctly. Honing in on some more nuances with regards to synovial sarcoma, similar to other sarcomas, this is a disease that has poor survival. To give you a perspective, the one-year survival is 60%, and only 20% of patients are alive at five years. And unfortunately, most patients probably would have passed away by the 10-year mark. And I talked a little bit about the standard chemotherapeutics that we use for soft tissue sarcoma and synovial sarcoma, at least those drugs that I mentioned already, doxorubicin, ifosfamide, those are chemotherapeutics that we use. And we know that these drugs can actually stop the cancer from growing and spreading, but chemotherapy is never curative. Chemotherapy comes with a lot of toxicity. And there's also this ongoing need to receive chemotherapy, essentially indefinitely. So once a patient develops metastatic disease, they start chemotherapy, and they'll cycle through one regimen. And when that regimen stops working, they'll go on to another regimen. And as I alluded to earlier, each time on the following drug becomes shorter. So the median time on frontline therapy can be as high as nine months in the best-case scenario setting. In the second line, it goes down to less than six months. And then third line is three months, and fourth line is two months. And we can see this sort of dismal, sort of devastating decline in survival within each line of therapy. So I'm going to shift gears and kind of highlight our interest in cancer testis antigen as potential therapeutic targets. An ideal drug for a patient with cancer is one that can effectively treat the cancer, but obviously not impact the normal tissue. Chemotherapy can treat the cancer somewhat effectively, but obviously all the side effects that we have to encounter are all a result of the chemotherapy affecting the normal tissue in our bodies. Cancer testis antigens are actually proteins that are found in a number of different cancers, but they're not expressed in normal tissue. And so that makes these targets very promising. Importantly, we also know that they're able to elicit a humoral and cellular immune response, meaning that our immune system can react to these antigens because they're not expressed in the normal tissue, and they're felt to be so-called foreign. So these biomarkers are actually effectively addressable by T-cell therapeutics. And by the sheer fact that they're found in these diseases at high numbers makes it attractive to sarcoma clinicians and to patients as well. And importantly, because they're not expressed in normal tissue, that also provides promise to these targets. So talking a little bit more about synovial sarcoma, I've mentioned much of this already. We know it's a disease that's found in about 1,000 patients in the United States each year. The tumors are highly expressed in MAGE-A4, and they also highly express in NY-ESO-1. Then myxoid round cell liposarcoma, it's a different sarcoma subtype. Similarly, it affects about 1,000 patients in the United States each year. It's similar to synovial sarcoma in that it affects middle-aged adults. The average age of presentation is around 40, and the survival is quite dismal as well. Importantly, it actually highly expresses NY-ESO-1. I'll also point out that as a sarcoma specialist, my main interest and research focus and clinical practice is focused on synovial sarcoma, myxoid round cell sarcomas, and a number of different sarcoma subtypes. The promise of these antigens is that they're actually highly expressed among other different tumor types, just as an example, melanoma, ovarian cancer, lung cancer. And so these are targets that ultimately can be targeted within the context of other cancers as well. I'm going to talk a little bit about the SPEARHEAD-1 trial. So in order to sort of walk you through here, the first part of a patient journey initiates with screening. You need to be sure that the patient harbors a specific HLA blood type. And then you also need to be sure that the tumor expresses the protein in the context of SPEARHEAD-1. It was MAGE-A4. For that particular trial, patients older than 16 and younger than 75 were allowed to participate. I'll highlight that these are criteria that are consistent with how we've run synovial sarcoma clinical trials because these are the ages where the disease is present. Patients must have had appropriate performance status or be able to handle the treatment and have normal blood work. And then importantly, they must have had those standard drugs that I mentioned that offer some ability to treat patients, including the doxorubicin and the ifosfamide. So once we deem the patients eligible, we undergo a process called leukapheresis where we remove the blood. The blood is sent off to a manufacturing site for production of afami-cel. It's received back at the site. And once the product's received, patients initiate lymphodepletion chemotherapy followed by infusion of afami-cel. And in the context of this particular clinical trial, the primary endpoint was response rate or the percent shrinkage of the tumor. And obviously, after infusion, we monitor patients for safety and for efficacy with imaging studies. The study was comprised of two cohorts, cohort I, which obviously completed enrollment, and cohort II actually completed enrollment as well. These data were published in Lancet earlier this year. The characteristics are consistent with patients with this diagnosis. I'm not going to go into all the specifics and nuances of these specific characteristics. Needless to say, the trial enrolled patients that I would otherwise be seeing in my clinic and would typically be considered for this type of therapy. Here we have the results or the waterfall plot, which shows the decrease in tumor burden for patients. We can see here that the overall response rate was 39%. 17 of 44 patients had what we call a response rate, including a number of complete responses, as you can see here. The duration of response was approximately 12 months. As a reminder, sort of the best drug, the last drug approved in this disease was pazopanib. If you recall, the response rate to pazopanib is about 5%-7%. The progression-free survival to pazopanib and synovial sarcoma is about three to four months. These results are exceedingly remarkable for patients with synovial sarcoma. In looking at these plots here, what we see is that for those patients that derive a response, the survival is 16.9 months. The two-year survival of those that have responded is 70%. Again, just to kind of highlight, this is a marked improvement upon standard typical chemotherapy drugs that I otherwise would have access to. The findings of this clinical trial supported the use of afami-cel as an effective treatment option for those patients that are eligible. These data were used in the BLA filing for afami-cel. Based on these data, afami-cel was approved by the FDA on August 2nd for the treatment of synovial sarcoma, whose tumor harbors MAGE-A4 plus with specific types of HLA. And so this provides really a marked advancement in our field. And I already sort of highlighted this information, but we can see here the comparison of afami-cel to pazopanib. And pazopanib was last approved in 2012. That was the last advancement we had in our field. And so here with afami-cel, we're obviously significantly improving response rates, duration of response, survival, and so really encouraging data. I'm going to shift gears now and talk a little bit about NY-ESO-1. NY-ESO-1 is another cancer testis antigen and just a reminder, it's a promising way to treat cancers because these are antigens that are not found in normal body cells, but only found in the cancer cells. Of interest to me, obviously, again, is the high NY-ESO prevalence found in synovial sarcoma, which is also expressed at an 80% level, but also myxoid round cell liposarcoma, where expression, depending on the series, has been found to be as high as 100%. And again, I'm not an expert in these other diseases, but NY-ESO is also expressed in a number of other different cancer types. Honing in a little bit more on liposarcoma. So liposarcomas actually comprise 20% of all soft tissue sarcomas, and myxoid round cell liposarcoma is one form of liposarcomas that we see in the clinic. I already mentioned some of this, but myxoid liposarcoma, again, is a disease that occurs in younger patients. The average age is in the 40s. Oftentimes, it initiates in the extremities, and it can present metastatic about 40% of the time. Let's skip over this. The standard of care, similar to most sarcomas, is surgery with or without radiation therapy. We do sometimes use chemotherapy to try and prevent recurrence after initial curative therapy. The survival, you can see here in purple, is quite poor. As is often the case for patients that are seen in sort of academic centers, while standard chemotherapy forms a sort of backbone of treatment, we do use a number of other different ways to treat our patients, mainly in the context of clinical trials, because that's how advancements are made in the field. It's a cornerstone of how I approach care for patients at Memorial Sloan Kettering. For myxoid round cell liposarcoma, actually, this is a disease that responds to chemotherapy. It can shrink. If we look here, again, it's in the less than 20% range for most of the chemotherapeutics. Sometimes if we use two chemotherapies, for example, doxorubicin and Ifosfamide, the response rate can be a little bit higher, but that comes with a significant higher cost with regards to toxicity, and again, progression-free survival, depending on the drug, is all within the two to six-month range. I'm going to talk a little bit about the IGNITE-ESO trial, which I presented just this past Saturday in San Diego at our Connective Tissue Oncology Society meeting. The eligibility of this study is similar to the SPEARHEAD-1 trial. You need to have the specific HLA, A*02:01, A*02:05, or A*02:06. The age is greater than 10. The tumor has to express the NY-ESO protein. Patients must have adequate performance status and normal organ function. They must have received prior chemotherapy, as already specified. The primary endpoint of this trial was response rate. Similar to the SPEARHEAD trial, a patient's journey initiates with screening followed by leukapheresis, where the blood's removed, sent off for manufacturing. Patients then receive the lymphodepletion chemotherapy followed by infusion of lete- cel. At that point, then we're monitored for toxicity as well as for efficacy with imaging such as CT scans. Here's just a breakdown of the patients. We screened about 400 patients. Half of those patients were found to be HLA positive. 150 patients then were found to be both HLA and NY-ESO positive. 98 went on to leukapheresis. 78 received the lymphodepletion chemotherapy. 77 received lete-cel. 64 met the product specifications as were defined in the clinical trial protocol. These are the baseline characteristics. Within the context of this trial, synovial sarcoma and myxoid round cell liposarcoma each respectively comprised about 50% of the enrolled efficacy population. About 56% of patients were male. The median age was 46. The median cell dose was 6.7 billion cells. All patients received prior systemic therapy, including 20% of patients who had received at least three lines of therapy. In the context of this trial, patients also received bridging therapy between the manufacturing process and the infusion of the T cells. Here we have the response rate, which was 42%. It was found to be 41% in synovial sarcoma with three complete responses. Similarly, it was 43% in myxoid round cell liposarcoma, and again with three complete responses. The responses seemed to be durable across both diseases. The median duration of response was 12.2 months. The duration of response specifically in synovial sarcoma was 18.3 months. In myxoid round cell liposarcoma was 12.2 months. With regards to side effects, not surprisingly, the side effects we see tend to be mostly related to the lymphodepletion chemotherapy. We give patients a chemotherapy to sort of make way in the body for the new cells. Most of these cytopenias are resolved over time. There was one patient who did have a complication, a grade 5 event related to the chemotherapy. This was a patient who had persistent low platelet count and ultimately developed hemorrhage in the lungs and passed away from this, and then other side effects related to the T cells. Most commonly, we saw cytokine release syndrome, which occurred at a more serious rate, what we refer to as grade 3, 12% of the time. Generally, this resolved with the interventions that we typically use to treat CRS, namely tocilizumab, which 80% of patients received. In addition, rash occurred in about 64% of patients. 35% of patients had grade three rash. The cases of neurological adverse events occurred in four patients, but they were all grade one events. There was one patient also that received T cells and had a number of different complications, including neutropenic sepsis and cytokine release syndrome, and ultimately passed away due to disease in the lung and this potential relation to the T cells. This study, this IGNITE-ESO study, also met its primary endpoint for efficacy, demonstrated a 42% response rate, 41% in synovial sarcoma, 43% in myxoid round cell liposarcoma. The duration of response was 12.2 months, 18.3 months in synovial sarcoma, 12.2 months in myxoid round cell liposarcoma. The progression-free survival was 5.3 months, 3.9 months in synovial sarcoma, 7.7 months in myxoid round cell liposarcoma. Patients all experienced adverse events, most commonly cytopenias, cytokine release syndrome, and rash, all of which were common and manageable. And then, importantly, these results actually represent another novel therapy for patients with synovial sarcoma and myxoid round cell liposarcoma. And the biologics license applications the FDA has also planned. And importantly, there are efforts to further understand mechanisms of response and resistance. And so from my perspective, in the context of sarcoma specifically, cell therapy has really led to exceedingly improvement in clinical benefit for my patients in an area of high unmet need. Again, to give you perspective, afami-cel offers a near 40% response rate. Pazopanib offers a response rate of 4%-15%, depending on the series. So it's really exceeded our standard of care options. The other important point is that cell therapy is a single infusion. You prepare patients for this journey, but ultimately, the cells persist for years. And this has a significant amount of advantages, especially for young patients. But importantly, it eliminates the need to continuously treat patients with chemotherapy every three weeks or every four weeks or whatever approach is needed based on the specific chemotherapy drugs. This safety profile is consistent and similar to that of chemotherapy. We know that T cell therapy targeting cancer testis antigen, it highlights the promise of using these cancer testis antigen as targets. And it's now approved for synovial sarcoma. And we hope we anticipate the same for myxoid round cell liposarcoma. And both afami-cel and lete-cel are really leading to alternative and more promising options for patients. And integrating these therapies sooner in a patient's journey is something that I anticipate for my patients. And I'll stop there. I'm happy to turn it over to the Adaptimmune team at this point. Thank you, Dr. D'Angelo. So at this point, we're going to take questions from the audience. So please hold for a brief moment. So our first question comes from Ernie Rodriguez-Dumont at Cowen. Please go ahead, Ernie. Thank you for taking our questions. And thank you, doctor, for that excellent overview. My question would be, based on the data that you showed in the first line and later lines and what lete-cel and Tecelra has produced so far, do you think there is potential for these drugs to be taken into the front line? And how would that look like? It would be front line for chemo or neoadjuvant or adjuvant therapy? What do you think would be the best way of approaching that? Yeah, that's a great question. I think integrating these therapies sooner in a patient's treatment journey is better. I envision a world where I can screen a patient that presents with a primary large synovial sarcoma and perhaps be ready to go as soon as metastatic disease develops. In the neoadjuvant and adjuvant setting, while we sometimes use chemotherapy for these diseases, it's certainly not standard of care for these diseases as of yet, and while integrating these therapies into neoadjuvant and adjuvant setting may be more complex due to the practicality of manufacturing and all these kinds of things, it may be more challenging, but at the time of metastatic recurrence, that is the time we would use these therapies. Earlier at the time of metastatic recurrence probably would be most ideal. Thank you. In that second line setting, what do you foresee or in your own experience, what you've seen has been the biggest obstacle to therapy once these patients have been tested positive and the decision that the therapy is adequate has been made from there to actually getting the therapy? What has been the biggest barrier in your experience? Thanks. To be honest with you, I don't have a lot of obstacles to share from that perspective. Once we know that a patient qualifies, it's really been a streamlined process, all really in the context of the clinical trials, which most sarcoma centers have been involved in. We've developed a real sort of keen level of expertise to execute these therapies. That's actually consistent with the broader field of adoptive cell therapy. There are skilled physicians that do this and know how to do it well. And so it's been a relatively seamless process, at least from my perspective. Thanks again for taking our questions. And thank you for the presentation. Thanks for the questions, Ernie. Our next question comes from Paul Jeng at Guggenheim. Please go ahead, Paul. Hey, guys. Thanks for taking our question. This is Paul for Michael Schmidt. For Dr. D'Angelo, just assuming lete-cel is approved, how would you expect to use Tecelra versus lete-cel in a synovial sarcoma patient, for instance, who's positive for both biomarkers? Among your colleagues, do you think there's the greater familiarity with Tecelra might play an outsized role in driving that use later on, or are there nuances in the data that might dictate treatment decisions? Actually, the data look quite similar in synovial sarcoma. I think that these are both viable options. I do think that the antigen expression probably will guide one versus the other. Ultimately, having two potential options, from my perspective, is better than one. And whether we integrate one therapy first and then another one later, that can be an approach to consider. So I think that having these options gives patients actually more access, which has been a long, long desire for a disease like synovial sarcoma. Great. And then maybe just a follow-up. Any thoughts about potentially sequencing one therapy after another for a qualifying patient? Sure. I mean, I think that if a patient derives clinical benefit and has responded to one, then certainly you can consider targeting the alternative antigen with the alternative agent. I would be cautious, though. If a patient's benefiting from one agent, I wouldn't necessarily go to the next unless there's an obvious need to, because obviously, we want to make sure that the intervention will be beneficial for the patient. Great. Thanks very much. Thanks for the questions, Paul. Our next question comes from Tony Butler, Rodman & Renshaw. Please go ahead, Tony. Yeah, thanks very much. Dr. D'Angelo, appreciate the time today. Two questions, if I may. One is, I may get the exact numbers incorrect, but the relative difference is important. I think you said that in the IGNITE-ESO trial, 98 patients underwent leukapheresis, 77 actually received cells, even though that may be off in the exact amount. The question is, what happened? Why the difference between the two? What happened to those particular patients? Did they simply opt out of wanting to have cell therapy? And then the second question, if I may, is, when you think about the side effect profile of cell therapy versus what you see in patients with chemo, regardless of the outcome, can you actually speak to the differences? I understand what you said about, "Here are the side effect profiles of A versus B." I understand that. The question is, how do you think the patient responds to those side effect events for one versus the other? Thank you. Yeah, sure. That's a great question. So with regards to the sort of fallout with regards to the patients that underwent leukapheresis that actually went on to T cells, there was a number of different reasons why those patients did not go on to receive the chemotherapy. Some was patient preference. Some was MD preference. Some was the patient didn't meet criteria as defined in the protocol. Some patients' disease was too aggressive, and they were unable to make it to the T cells. Remember, I told you that 20% of patients had already received at least three lines of chemotherapy, and each time, duration of therapy, each line away from front line, obviously, outcomes do get worse, so that addresses your first question. Now, remind me your second question. Sorry. Yeah, no. On the chemotherapy. Sorry. Okay. Yeah, yeah, yeah. Sorry. So chemotherapy side effects, you get diagnosed with cancer, and patients receive chemotherapy on a regular cycle. Typically, it's every three weeks. And so the way it works is that I see someone in clinic, I give them chemo. Within 7-10 days, they have what we call cytopenias. That's when they drop their blood counts. That's when typically they feel the worst because not having immune cells creates a lot of fatigue, sores in your mouth. Ultimately, that gets better, only for it to get worse again because I'm going to see that patient in clinic at that third-week benchmark and start the treatment all over again. So there's a chronicity of symptoms and side effects that really emulates the chronicity of having to receive these drugs. Now, when we shift gears with lete-cel, afami-cel, any cell therapy, you receive high-dose chemotherapy once, again, in order to prepare the body for the administration of the T cells. During that window surrounding that administration of the chemo and then followed by the T cells, you get a lot of the cytopenias that patients would get with chemo, albeit the doses are higher and the duration of that decrease in blood count will last longer. And then on top of that, you can get this sort of cytokine release syndrome, which is where you have that sort of inflammation in the body. Now, all of that typically will resolve within a week after infusion of T cells. Most patients recover their blood counts. The CRS would have resolved by then. And then that patient, in theory, no longer needs any therapy. So for me, the biggest advancement is that you do this once. It's done properly and correctly in the hands of physicians and teams that do this. And then if you fall into the category of patients who benefit, you don't need any additional therapy. So this approach is sort of unprecedented. Even with checkpoint blockade, like drugs like Keytruda and Opdivo and all those kinds of drugs, you still need to treat those patients every two to three weeks. Those patients need to come to clinic and get drug every two to three weeks. So cell therapy is promising because it's a sort of one-and-done infusion. And once you sort of overcome that peri-infusion period, which is roughly about 7 to 10 days, then that patient's done with their therapy. So it's a marked difference in how we approach care. It eliminates the need to chronically treat someone and chronically deal with the side effects. Thank you. So our next question comes from Jonathan Chang at Leerink. Please go ahead, Jonathan. Hi, guys. Thanks for taking the questions. Dr. D'Angelo, can you discuss the readiness of your center to treat patients with Tecelra in the commercial setting? Do you foresee any potential bottlenecks to treating patients with Tecelra? And how much of a learning curve is there, if you had to guess, for other centers to utilize these T-cell therapy options for patients? Thank you. Yeah, at MSK, we were actually one of the first sites to open these T-cell therapy trials. And so we are nearly ready to go. We've begun screening and are about to execute some additional logistics to get the therapy up and running. But we are screening and identifying potential eligible patients. The administration of all Adaptimmune cell therapy actually requires specific centers that are deemed centers of excellence to give this therapy. Many of these centers have, in conjunction, sarcoma centers of expertise. And so the two sort of go hand in hand. And generally, these are going to be high-volume academic centers. So you're not going to get this therapy administered in a local clinic, not because they can't do it, just they can't meet the requirements that are actually mostly deemed by the FDA and the broader adoptive cell therapy community. There's going to be key centers throughout the United States that are equipped to be able to do this. And these are centers that otherwise are administering, let's say, CAR T cells in our bone marrow transplant centers. It's all kind of comes hand in hand. Got it. If I could just ask, are you able to provide any color on what you mean by some of the additional logistics that you're seeing on your end? Oh, it's more just transitioning my own internal teams, like from my research team to my standard of care team, sort of a handoff, essentially. There's no logistical barriers at all, actually. The nice thing is that many of us that have been involved with these clinical trials are part of the same team that's going to administer the standard of care, afami-cel, so me being one of those physicians at MSK. And so, yeah, there's no barriers. It's just more of a sort of logistical handoff from one team to another, which already has essentially taken place. It's just some fine-tuning of a few of the details. That's all. Understood. Thanks for taking the questions. Sure. So our next question comes from Arthur He at H.C. Wainwright. Please go ahead, Arthur. Hey, Dr. D'Angelo. Thanks for the presentation. I had two questions. So one is regarding the patient achieved a complete response. Could you give us more color on those? Because if I calculate right, there's a significantly higher rate of the patient that you compare to the ASCO presentation reach their complete response in these presentations. Are you referring to lete-cel? Yes. Yeah. So in the context of lete-cel, there were three complete responses in synovial sarcoma and three complete responses in myxoid round cell liposarcoma. So six total in the context of lete-cel. I don't understand what you're comparing it to. So it seemed like so for the new additional 19 patients, you get four additional complete responses compared to the ASCO presentation. So is there any special for the patient baseline for the new additional patient? So we haven't really delved into clinical factors or things that correlate with complete response versus not. At least in the context of afami-cel, we know that using this therapy sooner is probably better. We'll see if that pans out with lete-cel. We haven't really delved into the clinical features that suggest more robust responses or not. It's an ongoing area of interest and research. Gotcha. Thanks for that. My second question is regarding the MRCLS NY-ESO positivity. It seemed like you mentioned there's 100% of the HLA-eligible patients in the lete-cel study get these NY-ESO-1 positive. Is this a kind of outlier number, or you think relatively it's kind of getting close to the real world percentage-wise? Yeah, with regards to myxoid round cell liposarcoma, there's been a number of publications out there which have really highlighted that NY-ESO is expressed very high and across the board in the disease. If you look, depending on the publication, it could be in the 90-plus% setting. So these data are pretty consistent with what's out there. Thank you. Thank you for the question. Sure. Thank you for the questions. So our next question comes from Yanan Zhu at Wells Fargo. Please go ahead. Oh, great. Thanks for taking our questions. A question for the doctor was wondering, it sounds like these patients could be fast progressing. What percentage of the patients, the second-line patients at your clinic, second-line or later patients, do you think are eligible to be prescribed Tecelra without the risk of losing those patients during the waiting period? Yeah, can we start with this question? Yeah. I mean, I think the way I would address that question is that in my clinic at Memorial Sloan Kettering, I'll be screening the patients at the time of initial presentation, and so by the time they get to second-line therapy, I would know if they qualify and probably would have already integrated this into their treatment plan. If we look at the data in the context of lete-cel, 20% of patients that had received at least three lines of therapy were actually enrolled in the clinical trial with lete-cel, and I believe it was another 20%. I have to go back and look at the table. I'm not remembering it off the top of my head, but I believe it was another 20%, actually, so certainly, we can get our patients to this therapy. The other important thing is that while we screen them, we can actually treat them with standard systemic therapy, and one of the points that I made is that both synovial sarcoma and myxoid round cell liposarcoma, they both respond to chemotherapy. Chemotherapy can stop the cancer from growing and spreading. Chemotherapy can shrink the cancer. But the important distinction here is that even though it can shrink and it can stop the cancer from growing and spreading, the duration of benefit is not going to be forever with these standard drugs, and the side effects, obviously, are high. And so the messaging here is that we need to use these therapies sooner rather than later, and all of us in our sarcoma community are aware and know that. And we're going to be aggressively screening patients at the time that we meet them. As soon as someone comes into my clinic, part of my standard workflow will be to screen these patients, similar to how next-generation sequencing is used, right, to identify targets in a number of the different cancers. That's great to hear. In terms of manufacturing turnaround, I'm not sure whether lete-cel manufacturing time is different from Tecelra. Could you or the company comment on that? And would that play a role in a selection of either one for the patient if they qualify for both? I'm going to defer to the Adaptimmune team there. I mean, from my perspective, I haven't been involved in the development of both of these clinical trials for a near decade. I don't think that that's going to play into it at all. But if someone from Adaptimmune wants to comment. Happy to. So the manufacturing turnaround time for lete-cel is very similar to the turnaround time for Tecelra. And we don't anticipate that that would be a driving factor in the choice between the therapies we want to give first. Got it. Lastly, if I may ask the doctor to have a sense of patient population, the size of it, I was wondering what percentage of patients, incident patients, actually have curable disease through surgery or plus radiation for both synovial sarcoma and myxoid round cell liposarcoma? Right, so for synovial sarcoma, about 15%-20% of patients will present with metastatic disease, and for synovial sarcoma, for those patients that present with tumors greater than 8 cm, half of those patients will die of their diagnosis. What dictates recurrence and metastatic disease coming back is primary tumor size, so tumors less than 5 cm, less likely to come back. Greater than 5 cm, higher incidence of recurrence. For myxoid round cell liposarcoma, the metastatic presentation is a little bit higher. It's probably closer to about 40%, but the same kind of general rule applies. The bigger the tumor presentation, the more likely that this will come back and spread. And patients with the small tumors, is that a significant proportion of all the presenting patients? I mean, I don't know that we've looked at presentation of the disease based on primary tumor size and what that breaks down. Remember, these are relatively rare cancers. I think most comfortably, I could say that, again, about 20% will present metastatic. But we really haven't broken it down by size and rate of recurrence at that granular level. Got it. Very helpful. Thank you. Thank you for the questions. So our next question comes from George Farmer at Scotiabank. Please go ahead, George. Hi. Thanks for taking my questions. Dr. D'Angelo, you make this in your presentation, you talk about how chemotherapy is used for treating this disease. Frankly, it doesn't really seem to do much of anything. How do we get this treatment into earlier lines of therapy without having to go through a full multiple course cycle of chemotherapy? That's number one. Number two, is it possible maybe to, given that at least in your clinic, it seems inevitable these patients are going to get either afami-cel or lete-cel? I mean, does it make sense to do the leukapheresis before they even begin chemotherapy? You raise a couple of important points. The obvious that chemotherapy, nobody likes to receive it. Most of us don't like to administer it. As a medical oncologist, though, I spend a vast majority of my day doing that, giving patients chemotherapy. Because chemotherapy allows us to bridge what I tell my patients is that chemotherapy is the bridge to the next clinical trial or the next promising option. So I think aggressive screening and leukapheresis sooner rather than later is essential. When I look at all the trials that I've run in this space and where we are today, I will tell you that 10 years ago, I was doing this later. Now, I'm screening patients very, very, very early in their treatment journey. Now, the question about adjuvant and neoadjuvant therapy was already raised, meaning can we give this before surgery or can we give this right after surgery? I don't think this is a therapy we're going to give in the absence of disease. Do I envision this being an option for a patient who presents with a very large primary tumor where I know that there's a very high risk of recurrence? I think that would be a very viable option. Obviously, the question would first need to be asked in the context of a clinical trial. But using this as sort of first line or very close to first line, right, where I meet a patient, I screen them, I start standard chemo during manufacturing, and then I give it to them immediately, that's basically what most of us are going to wind up doing, right? You need to allow the four-week manufacturing period. And for most patients, most physicians may not want to necessarily keep the patient off chemo while we wait that short period of time. And to give you just some perspective, when I meet a patient, I typically like to get standard therapy going within two weeks of presentation. And so manufacturing is about four weeks. So we're not sort of that far away. For select patients, we probably can do this front line for the right patient, right? Now, again, everyone's different. And it's the level of expertise we have caring for sarcoma patients that's going to guide the comfort level of waiting for manufacturing versus just giving someone a few cycles of chemotherapy to so-called hold them over and then get them to T-cells. So I think that's going to be very doable. And honestly, that's a lot of how the trials evolved over time. And you can see the evolution that the lines of therapy were less as the field progressed if you compare some of the earlier trials that we were running back in 2014 or 2013. Yeah. All right. Thanks very much. So I think that's all the live questions that we have. We have several written questions. But in the interest of time, I think I'm just going to ask one. If you did write in a question, thank you very much for doing so. We'll probably follow up with you to make sure that we can end promptly here. But the next question comes from Graig Suvannavejh at Mizuho Securities. And he's asking, helping us to gauge the uptake rate of Tecelra once some of these logistical hurdles, is there anything other gating that you can see from your side as to something that would prevent very quick uptake of Tecelra? And then secondly, once all of that has been put in place, by the time lete-cel comes to market, would you anticipate a much more rapid uptake within the market given the experience, or are there similar hurdles that you would need to go through on your end before you would start using that? So I want to just be cautious in saying that there are no hurdles. I think it's more, as I said, a sort of transition of power here. Our clinics at Sloan Kettering are set up with a number of different teams. But my team, I have an outpatient nurse, and I have a clinical trials nurse. And again, we're just sorting out who does what here. It's a very simple handoff here. So there are no hurdles. I just want to make sure that that's clear. I could tell you that I probably get five to 10 emails a week from international patients, colleagues reaching out. And so I think there's already plenty of knowledge and information out there that these drugs are now that afami-cel is available and sort of ready to go. At MSK, we're leveraging our experience as an adoptive cell therapy site in launching these products in a commercial setting, and many centers that have these adoptive cell therapy teams are the same sites that are going to have afami-cel and lete-cel. Obviously, each time you do something, the process becomes easier and more efficient, so yes, I imagine lete-cel may be somewhat easier and more streamlined. But I'm not seeing any kind of hurdles to provide this to our patients, and the word's out there. Also, the great thing about sarcoma is that our community is a pretty small community, and it's a tight-knit community, so we're good about getting the word out and getting patients into our clinics seen quickly. To give you perspective, there's 12 people that do the same job I do at MSK as medical oncologists caring for sarcoma patients. Everyone's sort of ready to go and excited about getting this to our patients. And then one last one, a follow-on to that one from Graig was, given the similar dataset that you just showed for lete-cel in the two different subtypes, would you expect any kind of difference in the rate of uptake between synovial sarcoma and MRCLS? By rate of uptake, do you mean like integration into the clinic? Yes. I think that's what it's referring to. Yeah. Yeah. Got Got it. No. I mean, I think that obviously today, right now, what I have is afami-cel, and all of my patients are going to get afami-cel. And in the future, curious to see if any clinical factors evolve over time with lete-cel that can maybe guide that decision-making. I don't think that'll be the case. I think one of the great things is that we will have access to two different options for our patients. And I'm excited to be able to make that choice myself and not have someone make that choice for me. And it's wonderful to have a number of different ways to treat these diseases. This is a tremendous advancement. All right. I think we're going to wrap it up there. And on behalf of LifeSci, thank you, Dr. D'Angelo, for doing this. Thank you to everyone for listening and for all the great questions. I'll turn it back to Adrian for some closing remarks. Thanks, Garry. So I want to thank Dr. D'Angelo as well for her insights, for taking the time to walk us through the landscape, but also for the work over the last decade that she and her team at Memorial Sloan Kettering have done to enable us to get Tecelra and lete-cel to this point. It's people like Dr. D'Angelo and the team at Memorial Sloan Kettering and the care teams and oncologists at the other institutions that we've partnered with over that time period that have made this happen. We are looking forward to continuing that partnership with the entire sarcoma community that Dr. D'Angelo talked about to continue to make these absolutely groundbreaking medicines available to more people with sarcoma. Thanks also to everybody on the call today. Thank you for your time. Thank you for your interest. And please don't hesitate to follow up if you have any other questions that we can answer. So thank you ever so much and have a great day.