Good morning, everyone, and thank you for joining us at our annual healthcare conference for Needham & Company. My name is Gil Blum. I'm a senior biotech analyst here at Needham, and it is my pleasure to have Adaptimmune's CEO, Adrian Rawcliffe, here with me. And Adrian will discuss the company's most recent advancements. And with that, Adrian, you have the stage. Thank you very much. I plan on talking for 15-20 minutes, and then there'll be plenty of time for any questions. So start off with, obviously, everything I'm going to be saying is covered by our standard disclaimer. For those of you who are unfamiliar with Adaptimmune, Adaptimmune has been the leader in engineered T cell therapies for solid tumors since its inception in 2008. That means that initially we had the best technical platform of engineering T cell receptors to be able to address targets on solid tumors. Then we had the first clinical data in a solid tumor. Then we had the best clinical data across a range of solid tumors. Now, what that means is that we have the first engineered T cell therapy products to treat solid tumors about to become approved by the FDA and commercial. And so a good way to think about Adaptimmune is in these three buckets. We have, as a function of the development over the last decade, two products that together represent a high-value sarcoma franchise. Cell therapies have been proven to work very effectively in soft tissue sarcomas and afamitresgene autoleucel targeting MAGE-A4 and lete-cel targeting NY-ESO are at the forefront of bringing engineered T cell therapy to the solid tumor space. We estimate that sales in launch indications in the United States alone from these two products could be up to $400 million, and we can address that at a reasonable margin of about 70% gross margin with a small and focused commercial footprint in the United States, based on the relationships that we've developed with these sarcoma centers of excellence over the last decade. That's just the front end of the rest of our engineered T cell pipeline, that address a range of solid tumors, much larger opportunities, for example, ovarian cancer, bladder, and head and neck cancer. I'll talk a little bit about how we're thinking about the pipeline behind our sarcoma franchise in a second. All of that's built on the fact that we have built Adaptimmune from the ground up as a cell therapy company. Why have we done that? We've done that because we believe that cell therapies, the development of cell therapies, and the commercialization of cell therapies will require particular capabilities, particular skills that will differentiate us from small molecules or biopharmaceutical companies. And we've had the privilege of being able to establish those capabilities and establish Adaptimmune as a pure-play cell therapy company, and we believe this gives us incredible advantage in this space. In particular, the investment we've made over the last eight years in manufacturing and CMC, including our facility where we make afamitresgene autoleucel. We've made afamitresgene autoleucel throughout the clinical development of afamitresgene autoleucel. Every patient in the pivotal trial was manufactured in our facility. All of the pre-BLA work was done in our facility. We will launch out of that facility, and we can manufacture to peak year sales out of that facility. That's an example of the investment that we've made that's going to make us successful as we seek to launch the first engineered T cell therapies in the solid tumor. Might seem obvious, why are we going after solid tumors? Because that's where the patients are. The cell therapies that have been launched to date, targeting CD19 and BCMA, are the CAR T therapies, are exclusively in the hematological malignancy space, which, despite only causing 10% of the deaths from cancer and despite relatively modest penetration, still are selling something around $4 billion worth of product. The remaining 90% is largely unaddressed with cell therapies, and there's a TIL therapy that's recently been approved by Iovance, but the first engineered cell therapies for these indications will be Adaptimmune's. and, our technology platform which engineers the T cell receptor, is uniquely suited to be able to develop robust responses and benefit from, T cells in the solid tumor setting. The starting point is these two subtypes of soft tissue sarcoma, synovial sarcoma and myxoid round cell liposarcoma. Synovial sarcoma is a disease that's diagnosed quite early in life. Average age of diagnosis is in the thirties. Five-year survival is 20%. So 80% of people who are diagnosed in the prime of their life are dead within five years. After first-line treatment with anthracycline-based chemotherapy in this metastatic setting, there is little else. Response rates for second-line treatments typically are around about 10%, high single digit, low teens. Myxoid round cell liposarcoma, diagnosed slightly later-... Also very poor prognosis on diagnosis and similar levels of similar treatment paradigm with chemotherapy as a first-line systemic therapy in a metastatic setting, and precious little after that point in time. These are rare indications representing probably about 2,600 cases between these two types of sarcoma in the United States, of which a subset will be addressable by Adaptimmune's therapies, afamitresgene autoleucel and letetresgene autoleucel. That subset defined by HLA or tissue type, and then also by expression of the target, either MAGE-A4 or NY-ESO-1. We estimate about 1,000 patients population will be addressable by these products. To put that in context, that's about twice as large as the uveal melanoma population that is addressable by Immunocore's KIMMTRAK, recently launched and very successful TCR bispecific therapy for uveal melanoma. So about 1,000 patients, of which 400 are addressable with our first product, afamitresgene autoleucel, and the remaining 600 incremental patients when we launch letetresgene autoleucel in about two years. I talked about the fact that we estimate in their launch indications in the U.S. alone, we estimate $400 million of peak year sales, and because of the manufacturing that I talked about previously, we have the opportunity to address that at a high margin of 70%. This can be a significantly valuable and cash accretive opportunity for a company like Adaptimmune. It's all based on transformative data out of the SPEARHEAD-1 trial for afamitresgene autoleucel. So bear in mind, standard of care in second-line synovial sarcoma is something like Votrient or other non-anthracycline-based chemotherapies. Patients also receive radiation therapy. They receive successive rounds of surgery, including amputations, all aimed at trying to delay progression, but nothing has shown the effectiveness of afamitresgene autoleucel. We showed a 40% response rate across 44 patients with synovial sarcoma treated in cohort one of the SPEARHEAD-1 trial. And importantly, these responses are durable, with a median duration of response of 12 months. That compares to median duration of response from existing therapies of a few months. And those responses, when they happen, produce significant patient benefit and extension of survival. So this Kaplan-Meier curve shows overall survival of the population of the treated population. The black line in the middle shows the full cohort one full population data, 44 patients, and you can see there that median overall survival is about 17 months. This is a single-arm trial. It's difficult to compare to historic rates. There was no control arm here, but typically, historically, patients who were in this similar situation, second, third, fourth, fifth, and beyond lines of therapy, would then to have anticipated survival of less than a year. But what's really remarkable in this is the, what happens to the responders. We still have not reached median overall survival for the responders, with a 70% probability of being alive at 2 years. letetresgene autoleucel targets NY-ESO. letetresgene autoleucel is our second product. letetresgene autoleucel comes behind afamitresgene autoleucel, by about two years. But in its pivotal trial, it has already reached the primary endpoint, for efficacy. This was a trial called IGNYTE-ESO. It recruited patients with synovial sarcoma and myxoid round cell liposarcoma, and the data here looks very similar to afamitresgene autoleucel. A 40% response rate, long duration of response. This data cut was at the interim analysis. Already, we had 18 responders out of the 45 patients at this interim analysis. We only needed 16 responders out of the full 60-patient dataset to meet the primary endpoint. So when we read out the primary endpoint later on this year, we are very confident that this will hit its primary endpoint, and therefore, we are moving forward to register this product in 2025, anticipate approval and launch in 2026. afamitresgene autoleucel is with the FDA at the moment. We have RMAT designation that entitles us to priority review, and the FDA accepted the file, on the 31st of January this year, kicking off a 6-month review cycle with a PDUFA date of August the fourth. The meetings that you would anticipate and the inspections have been scheduled and are occurring on time. We are including the mid-cycle review meeting, the inspections of our GMP facilities and that of our third-party suppliers, and we will give a further update on the status of this and our plans for commercialization at an investor day next, in little over a week's time, on the eighteenth of April. That's at our Navy Yard manufacturing facility and is also available remotely as well. We are planning to launch afamitresgene autoleucel on approval, and we are therefore taking the steps, including setting up diagnostic testing for to enable afamitresgene autoleucel to be prescribed and the CMC capability, capacity that we need to be able to ensure that we can meet the demand on approval. We anticipate launching in 6-10-... Authorized treatment centers. That's appropriate for a product of this size and scale, and we'll grow from there to about 30 treatment centers across the U.S. This map shows how those treatment centers overlap with the clinical trial populations for both afamitresgene autoleucel and letetresgene autoleucel. These are top sarcoma centers of excellence. They're also mostly top oncology centers of excellence, and they have experience with afamitresgene autoleucel from being involved in our clinical trials. We have a deep understanding of the centers and the prescribing physicians, and it's really important to understand that although we have two products, they will go through exactly the same commercial channels. These are the same centers, they're largely the same physicians, they will be addressed by the same commercial field teams and medical affairs field teams, and the significant commercial synergies in leveraging the infrastructure that we will build for afamitresgene autoleucel for letetresgene autoleucel. And by the time letetresgene autoleucel is approved in 2026, we will have all 30 centers stood up and ready to take letetresgene autoleucel on approval. I referred previously to our investment in manufacturing. The critical piece is that we can control this, but it also enables us to manufacture efficiently, hence why we believe that we can have an attractive P&L on these products, with a gross margin of about 70%, for afamitresgene autoleucel and letetresgene autoleucel. The overall timeframe for the supply of the patients is 4-6 weeks turnaround time, which is reasonably industry standard and completely normal, completely addressable, will enable us to address this patient population effectively. The sarcoma franchise that we seek to establish with our first indications for afamitresgene autoleucel and letetresgene autoleucel is, however, only the beginning of what that franchise could be. The $400 million sales that I referred to is in the launch indications in the U.S. alone. Obviously, there's the opportunity for further development of this into earlier lines of therapy, first-line therapy, either with or without chemotherapy. There's the opportunity for geographic expansion outside of the U.S. into Europe and beyond. There's the opportunity for development into other sarcomas that express MAGE-A4 and NY-ESO. There's the opportunity for sequential or combination therapy, and we have some experience of patients who have received significant benefit, the sequential treatment with NY-ESO and MAGE-A4 containing T-cells. Overall, we think that this franchise is highly valuable initially and has the opportunity to grow significantly. So that's our sarcoma franchise. Two products launching about two years apart, 2024, 2027, with $400 million peak year sales from about 1,000 addressable patients, obviously, deep penetration into that, at an attractive margin with a commercial footprint that we are absolutely confident we can deliver. That's the front end of our pipeline. So the top two lines on this slide, afamitresgene autoleucel and letetresgene autoleucel. Behind that, we have a pipeline of engineered T-cell therapies targeting a wide range of solid tumors. The most advanced behind afamitresgene autoleucel and letetresgene autoleucel is called uza-cel. It's basically a next-generation version of afamitresgene autoleucel. It uses the same T-cell receptor, and it's been engineered to be more potent with the addition of a CD8 alpha homodimer. The opportunity there was to do for non-sarcoma tumor types, what afamitresgene autoleucel did for sarcoma. And when we tested this in a phase 1 trial, in a phase 1 basket trial across nine different tumor indications, we showed that we recapitulated the response rate from afamitresgene autoleucel in sarcoma across a broad range of other solid tumors. So this is a 35% response rate. We see responses in bladder cancer, in head and neck cancer, in ovarian cancer, in gastroesophageal cancers. And the median duration of response is probably reflective of the fact that these are very, very late-stage patients. Nonetheless, we were able to identify 3 indications where we believe that there's the opportunity to move forward, and those are, indications are ovarian cancer, where we saw a 40% response rate, and where we have embarked on a phase 2 trial called SURPASS-3. SURPASS-3 is a 2-arm, 2 single-arm study, 1 with cells alone and 1 with cells plus nivolumab. Overall response rate and duration as endpoints, and that trial is recruiting and dosing patients as we speak, and we anticipate reading that trial out in 2025. Behind that, urothelial cancer and head and neck cancer are earlier, at earlier stage. We've had fewer patients, but we have shown significant response rates. Bladder cancer, 57%, head and neck cancer, well, three out of four patients responding, but all of those patients actually saw substantial anti-tumor effect, as you can see from that waterfall plot. What we need to do here is we need to get more patients throughout 2024 to understand the nature of the signal that we're seeing. We'd like the waterfall charts here to look a bit more like what the ovarian cancer in terms of the number of the patients, so 10-15 patients in these two indications. We are also targeting getting patients earlier in their treatment paradigm and in combination with standard of care pembrolizumab. So we will recruit those trials, those patients throughout the course of this year, and around the tail end of this year, we'll be making decisions about which patient populations and how to take those indications forward. So uza-cel has three indications, each of which has a really promising signal. Ovarian is the most advanced in a phase two trial called SURPASS-3. Opportunity for that to be on the market, potentially as early as 2028. So therefore, we're thinking afami-cel in 2024, letetresgene autoleucel in 2026, uza-cel in 2028. Behind that, we have two significant preclinical opportunities. First, targeting PRAME, which, as you may know, is a broadly expressed cancer testis antigen, expressed in ovarian, endometrial cancer, lung cancer, triple-negative breast cancer. We have selected a candidate, and we are moving towards the clinic with that candidate. It's a highly sensitive T cell receptor that triggers a killing at very low levels of target expression. We feel very good about the nature of that T-cell receptor, and we are currently determining which next generation approaches to take advantage of and completing the manufacturing necessary in order to be able to put that into the clinic. Obviously, we are paying attention to the competitive landscape in the, in the PRAME space, in particular, the, relevant cell therapy competitor, and we will take, all the information we can get from that in designing our development program for PRAME. We've not said which indications we're going to go into yet, but more information on that will be forthcoming in due course. Behind PRAME, slightly, is a, TRuC-engineered T cell, which we acquired when we combined with TCR2 last year. This targets CD70. Of particular interest in CD70 is AML and renal cell carcinoma, although there are other solid tumors that express CD70 as well. We have added a membrane-bound IL-15 component to enhance persistence of these highly sensitive T cells, and we anticipate moving that into the clinic slightly behind PRAME. The objective of this platform overall is to move from the left over here to the right, from sarcoma, where we can establish, with a relatively modest footprint, a significant franchise, and then into ovarian cancer with uza-cel, potentially, urothelial cancer and head and neck cancer, expanding the patient population so you can get cell therapy before adding PRAME and CD70, which have the opportunity to expand this from being, a relatively small population and a rare disease opportunity to being a mainstream treatment approach for the treatment of a range of solid tumors. The company itself is relatively well-capitalized at this point. We have approximately $150 million on the balance sheet, and because of the partnerships that we've had struck in the past, in particular with Genentech and other non-dilutive sources of capital, for example, UK government R&D tax credit, we have access to approximately $300 million over the next two years. Takes our runway into 2026, by which point we will have launched afami-cel and be staring down the launch of letetresgene autoleucel, as well as potentially having the first indications of efficacy from the SURPASS-3 trial of uza-cel in ovarian cancer. In summary, the afami-cel sarcoma franchise, with peak year sales of $400 million and two products. Front end of a pipeline representing the opportunity to take cell therapy for solid tumors mainstream, built on the fact that Adaptimmune is an integrated cell therapy company with the capabilities needed to discover, develop, and importantly, deliver cell therapies to patients who need. With that, I'll pause, and we'll go to questions, Gil. Thank you very much, Adrian. I'll be moderating the questions in the Q&A section, so feel free to type in your question, and, in the meanwhile, Adrian, maybe a good place to start... So you mentioned, you know, other competitors in the space, and one that definitely comes to mind is Immunocore with their bispecific. How do you think the dynamic between, you know, cell therapy and bispecifics evolve? I think that's a question that nobody really knows at this point, because at the moment, everybody's basing it on their understanding of what the technology platforms do, as opposed to real long-term data from clinical trials. So but with that caveat, let's speculate based on what the technology platforms do. I think the bispecifics and cell therapies just have fundamentally different, what if you were talking about small molecules, we'd call PK/PD. You know, the fact is that with a cell therapy, you have a T cell receptor that is tethered to your effector function, the cell. And so whenever that T cell receptor sees a target that has completes the, what's necessary to trigger a T-cell response against that target. And so therefore, we anticipate that because we have engineered the T-cell receptors to be able to recognize targets down to very low levels of expression, that the T-cells will be able to hunt down cancer to relatively low levels of target expression. That means that certain targets will be addressable by us, more easily than they will with bispecifics, where you need to decorate the cell with the bispecific and then encourage the immune system to come and find that. And our hypothesis is that that will take a larger amount of- likely to take a larger amount of target expression. And so I think in target selection, these will be different where they work best. I also think that there's a potential for this to work differently based on the, based on the tumor type. You know, where can cells get to versus where can bispecifics get to? And then also, I personally think that it's likely at the end of this, that T-cells are a lot more potent, but will need a narrower target expression and narrower target, narrower set of targets, and are likely to be given as a one-off therapy, whereas bispecifics can obviously be given multiple times over time and probably have a broader range of targets that they could get to without off-target effects. So I just think they're gonna be fundamentally different risk-benefit profiles in the solid tumor setting. And I think we're gonna need to work that out as to how patients can best benefit from these in different indications, and there's even the potential, which I think people will explore, of using them in combination and/or in sequence. Okay, and thank you for that. So maybe a question about your two lead assets in sarcoma. From a pricing perspective, do you expect them to be like for like as they're coming into the same patient population, or, you know, do you expect any differences with the approval of your second gen? So, I think the first two products in the first indication, in the first indications, the pricing is going to be quite similar. These are rare diseases, we'll be treating a few hundred patients with these therapies in the United States. I think uza-cel is slightly different, because uza-cel is going into a much larger patient population. So and so I, I... And I think you see that dynamic in these discussions about where TILs are priced, for example. Yeah, TILs are priced at about the level of CAR-Ts. Representing, I think, quite a large market for melanoma, for the first TILs. You know, we're slightly different for our first products because of the rarity of the indication. But I think as the field evolves, the pricing will represent the opportunities in the indications that are being launched in. And as those get larger or more mainstream, the prices will not necessarily remain at the sort of premium levels for orphan indications. The other thing to really think about is, as the volume goes up, the cost of goods should come down, and in particular, then we can evolve the process over time and bring the cost of goods down. So I think by the time you are treating tens of thousands of patients, you should have your cost of goods down to a level where you can not only enable pricing that can get to a broader, allow broader level of access. And I don't just mean that in the U.S., I actually mean that on a global basis as well. Okay. And when you're thinking about additional HLA types, specifically for your lead assets, is there a specific, you know, guideline of, you know, geography or nationality where there are more, or how are you considering this? Yeah. So the way that we think about this is how could you get to high percentages of patients across a range of geographies, of relevant geographies? And so obviously, the first one being HLA-A2, is simply because that's 40%+ of the European and U.S. population. So that makes sense. But as you do those trials, you realize that there's quite a drop-off rate with the HLA, and then there's a further drop-off rate. So from a pure efficiency of the clinical trials, actually having access to multiple HLAs would be useful. So even before you start thinking about this commercially, from a clinical development efficiency, multiple HLAs make a lot of sense. We think if we could get to so that actually it was significantly more likely than not that a patient would have an HLA type to which you had a TCR 70%+, then that would make the clinical trial efficiency a lot better, and it would also obviously make the commercial potential of this range of therapies much more significant. The thing to recognize, though, is, at least at the moment, these are different products, and so therefore, we anticipate that whilst you can de-risk a target to some extent in the context of cell therapy, they are going to require separate development programs. You're gonna have to show risk, benefit, and safety for each of them as you go forward. Now, there are a good ways and efficient ways of doing that, but that's how we're thinking about it. And it turns out that if you pick four or so HLAs, you can get to that sort of level of coverage in a quite wide range of geographies, actually. You need to pick up things like HLA-A24 to do that for some of the populations in the Far East. But if you pick those, you can get to 70%+ across a range of geographies. Maybe a bit of a hypothetical. Given you've shown proof of concept both in MAGE-A4 and NY-ESO-1, how about combining them? Yeah. Yes, we-- So on the fundamental basis that a multi-target strategy is probably, has probably some advantages, which I think is intuitively correct, although nobody's got clinical data to really show it. We think that would be-- we think that would be a great idea. And I think we anticipate that as we think-- if you think about it, we've got the... We've got high-affinity engineered T-cells now against MAGE-A4, NY-ESO, and PRAME, actually, all cancer testis antigens with large levels of overlap. You could very much think about a combination approach. I think this, getting into that be-- the first step to get into that is probably sequential treatment. And we are starting to build experience, largely anecdotally, honestly, about patients who have received NY-ESO or MAGE-A4, then go on to get the other one in the sarcoma setting. And it does seem that patients are able to get benefit from having these sequentially, which tells you something important about escape mechanisms. That escape mechanisms might not be fundamental to the underlying ability of the T-cells to attack the cancer. They may be related to target, or they may be related to the specific cells that you put in to the patients. So I think sequential will come before widespread combination, but we are quite interested in combination, and probably see sarcoma as the place to start with that, given the response rates and target expression that we've seen. All right. Maybe a bit of a more challenging question, I'm sure, and is on a lot of investors' minds. I mean, you're one of the pioneers in this space, maybe the pioneer in the space, and you don't seem to be getting a ton of credit for what is technically almost an approved product- Yes ... despite the fact that we have good evidence, especially from Immunocore, that a small population, in a really small population, could be a significant product. What do you think the disconnect is? So I think you've absolutely hit on where we think the opportunity is. Let me just start there, and I come back to why I think that people might not be recognizing the opportunity. You know, 400-- we're trading at 1x, 1x sales of two products that are largely clinically de-risked, and you know, what the first of which is midway through an approval cycle. The history of cell therapy said that while there is the opportunity for delays, there hasn't been a single cell therapy that's been filed that hasn't been approved so far. And so we're quietly confident that we'll be able to have appropriate interactions with the FDA, and that we'll get approval on time, and we anticipate being able to launch. So we think this is, relatively speaking, lower risk. And you're spot on. Immunocore have absolutely shown the way in terms of a small indication, deep penetration, this being an oncology rare disease sort of opportunity, where you're not really competing, trying to convince people to give this product versus something else. You're basically trying to identify the patients for whom this is the product that they need. And so all of that's true and why we think there's this opportunity. And, you know, to put a fine point on it, depending on how you think about the size of that opportunity, that's worth, you know, $5 a share, and we're currently trading at a lot less than that. So there's opportunity there. Why, why is that happening? Why, why is there that disconnect? I think there's possibly two reasons. One, I do think people are wary about cell therapy. I think they while it is true that there's only been delays, and actually after filing, relatively short-term delays, I still think people think of this as a black box. They don't understand it. It is really- The Iovance experience. The Iovance experience. Yeah. And the fact that something can always go wrong. Mm-hmm. I think the other reason is, frankly, we've been at this for a long time. Now, we look at companies that actually are really successful at putting products on the market, and they are distinguished by the fact that they've been at this for a long time, but that does give people the opportunity to get bored with the story. We think this is a really interesting pivot point, because as we shift to become commercial, it's a different dynamic for us as a company. But at the same time, we've been public since 2015 and around since 2008, and we think that's what you need to do to be a successful company. We looked at Alnylam and Exelixis and Incyte and all these other companies that I was interacting with when I worked at my previous employer in a BD capacity back in the early 2000s, and they're now hugely successful biotechnology companies with multi-billion dollar valuations on the basis of products. That we, we think that's what's important, and we're sort of at that sort of pivot point where we're moving from R&D into it actually providing benefit to patients in the commercial setting, and that's what it takes to create real value in this business. Yeah. Maybe as a final point there, it does seem that investors are now more a show-me story for companies, especially given the last two years. Yes. There's definitely- We live in Missouri now. Yeah. There's definitely- Yeah ... an opportunity here. All right, Adrian, I think we are almost at time, and I wanted to thank you for, for coming and presenting for us today. Thanks. Thanks, Gil. Thanks, everyone.