Adaptimmune Therapeutics plc (ADAPY) Earnings Call Transcript & Summary

Thank you everyone for joining us. I want to welcome you to Adaptimmune’s first virtual Investor Day. A lot about the company has changed since I took over as CEO about a year ago. In the first half of 2020, we demonstrated for the first time that our SPEAR T-cells can effectively attack a range of solid tumors offering benefit and hope to people with cancer. It’s this benefit in patients with advance solid tumors that places us at the forefront of the cell therapy revolution in cancer. From this position, we will launch the first engineered t-cell therapy for a solid tumor indication in 2 years’ time for people with synovial sarcoma in the United States. We’ll follow that up with additional indications starting with gastroesophageal cancers and develop a pipeline with subsequent products on the road to make cell therapy both curative and mainstream. This includes entering the clinic with our allogeneic or off the shelf platform representing we believe the future of cell therapies. These ambitions are supported by capabilities specific to cell therapy with a seamlessly integrate to convert the therapies that benefit patients in the clinic into products of value on the market and to ensure that the clear benefit to patients that we’ve seen translates to value creation for shareholders and this is what you’ll hear about today. Here, I’m going to lay out the four key value driver for Adaptimmune over the next 5 years. Firstly, we will have 2 products on the market which both recognize cancer through the same target, MAGE-A4. The first of these is ADP-A2M4, and we’ve seen transformational efficacy in patients with synovial sarcoma and we have the opportunity to launch this in the U.S. in 2022. This is an ideal size opportunity for a company like us to launch our first product in a patient population with very few effective therapeutic options. But this is just the first potential cell therapy targeting, MAGE-A4. In a moment, I will touch on the full size and scope of the MAGE-A4 opportunity which we believe to be very large indeed. But more immediately, our second product on the market will be our next generation MAGE-A4 targeting therapy, M4CD8, in gastroesophageal cancers. We’re going to start a registration directed trial in the first half of next year and subject to data, we could be launching this indication in 2024. Behind this, we believe that 2 further BLA filings will come out of our existing clinical pipeline over the course of the next 5 years and these will come from additional indications from our SPEAR T-cell targeting MAGE-A4 and our SPEAR T-cell targeting alpha-fetoprotein or AFP in liver cancer. We will also develop a robust clinical pipeline of cell therapies from our autologous and allogeneic research. We anticipate that 5 programs will start clinical development in the autologous setting. And as you will hear, the goals of the research team is to move the needle towards cell therapies becoming curative through our next generation of products and mainstream by expanding the number of patients that can be treated. We also anticipate that the first 2 products from our allogeneic or off-the-shelf platform will enter the clinic. This is another important component of what it takes to make cell therapies mainstream, by which we mean these therapies need to be readily available to large numbers of people with cancer. Our first allogeneic product into the clinic will use our engineered TCR targeting MAGE-A4, a TCR and a target we understand well. And we're announcing today that our second allogeneic product is against a new target for us, mesothelin, which is expressed in a range of solid tumors. This will also be our first HLA-independent T-cell receptor or HiT into the clinic. And it's part of a co-development, co-commercialization collaboration that we signed in January with Astellas. Delivering on these value drivers is supported by the whole company. And I've talked in the past about how Adaptimmune has been designed from the ground up as an integrated cell therapy company. This is based on our conviction that making cell therapies available to patients absolutely requires an integrated approach and a single-minded focus. As we think about this, we think about times in the past in biotech, where new modalities of therapy have arisen. We think about monoclonal antibodies or oligonucleotides. And integrated companies in those fields were just better equipped to solve the challenges of developing products in that new modality. And ultimately, integrated specialist companies were those who reap the value and benefits of that new modality. And I believe this translates directly into cell therapy. The idea of integration runs through the DNA of the company. It enables the delivery of each of these objectives. And it's what will enable us to build a business, not just a pipeline. I also want to point out that we are well capitalized to execute on these value drivers. At the end of the last quarter, we had $400 million available to us. And today, we extended our runway guidance into early 2023. The strategies to deliver on these 4 value drivers are going to be outlined by these senior leaders. This is a very talented team. And they represent the breadth of disciplines and the leadership required to make cell therapy a reality for people with cancer, from discovery and research through early and late-stage development and critically for us, patient supply. I'm not going to introduce them now because you will meet them all later individually. But as you see, they share my enthusiasm for the prospects of our cell therapies. I felt honored to lead them over the last year and as we look forward to delivering on everything we're going to talk about today. Now I'm going to take some time and just walk through each of the value drivers one by one. Starting with the first. Two products on the market targeting MAGE-A4. As I've said, the first of these is ADP-A2M4 for synovial sarcoma. Shortly, you will hear from Dr. Dejka Araujo. She's a world leader in the treatment of synovial sarcoma at the MD Anderson Cancer Center. And she will talk about the patients experience of the disease, the existing treatment options and the dire need for the benefits of cell therapy in this setting. You will then hear from Dennis Williams, who will talk about the durable responses we presented yesterday at CTOS with ADP-A2M4 in synovial sarcoma. This therapy has shown great efficacy in the Phase I trial and really does have the potential to be an extremely meaningful therapy for people with this terrible disease who have few other treatment options. Dennis will talk about our ability to execute rapidly on late-stage development. At the end of this year, we would have completed enrollment in our pivotal SPEARHEAD-1 trial. This is approximately 12 months after the first patient was enrolled and several months ahead of schedule. I want to point out that this was achieved amidst what we've all been experiencing for the last 8 months, the most disruptive global pandemic in a century. So despite the obvious challenges of conducting clinical trials in 2020, we remain on track to submit the BLA, gain approval for this therapy and to launch this product in the U.S. in 2022 for patients with synovial sarcoma. As you will hear later from Elliot Norry, we've validated MAGE-A4 clinically. In addition to sarcoma, first and next-generation products have demonstrated responses in patients with lung, head and neck, melanoma and gastroesophageal cancers. And we've seen anti-tumor activity in patients with ovarian and bladder cancers. We believe that the efficacy shown in gastroesophageal cancer, shown here in the blue stars on the plot on the right from our Phase I SURPASS trial can translate to an effective therapy for the thousands of late-stage gastroesophageal patients who are poorly served by existing treatment options. We will move towards a registration-directed trial in gastroesophageal cancers in the first half of next year. And I want to point out that this type of quick go/no-go decision-making is a particular opportunity in cell therapy development. And so this is something that Mark Dudley will talk about later. So I'm going to bring it all together in the context of our clinical pipeline. This shows our products targeting MAGE-A4 and AFP, which Elliot will touch upon later. You see the SPEARHEAD-1 Phase II trial, which will form the basis of our first approval in synovial sarcoma. And also the Phase II registration-directed trial in gastroesophageal cancers that subject to data would form the basis of our second product. You can also see the range of indications in the SURPASS trial with ADP-A2M4CD8, and you can see the ADP-A2AFP SPEAR T-cells being studied in liver cancer. We anticipate that these ongoing trials in multiple indications will lead to further registration-oriented trials and 2 additional BLA submissions in the next 5 years. Now I'd like to talk about why MAGE-A4 is such a significant cancer target. We've been screening across our trials for some years now. So we believe that we've got about the best understanding in the industry of this targets expression across a wide range of tumors. We estimate that up to 300,000 people in the United States and the EU are diagnosed with cancers each year that express MAGE-A4 at moderate to high levels. And this would place MAGE-A4 in the context of similar addressable population sizes for the subset of tumors, similar to KRAS or FGFR or BRAF. MAGE-A4's expressed in major tumor types. We talked about lung, head and neck, gastroesophageal and bladder cancer. And as a protein expressed inside the cell, it's a target that can really only be addressed through a T-cell receptor mechanism. We're in the lead clinically, and we'll have the opportunity for the first product on the market against this target in 2022. Now because our current SPEAR T-cell therapies targeting MAGE-A4 do so only in the context of HLA-A2, addressing the entirety of this population expressing MAGE-A4, i.e., all 300,000 patients, will require additional products targeting additional HLAs, and Karen Miller will touch on our approach to expand the HLA populations we reach in our efforts to make cell therapy mainstream later. More immediately though, we have the opportunity to benefit people having advanced or late-stage cancers with our products targeting MAGE-A4 in the context of HLA-A2. As Elliot will outline and as shown on this slide, using mortality data as a conservative estimate of people with advanced or late-stage cancer. Our current TCR therapies targeting MAGE-A4 and HLA-A2 have the potential to treat large populations, address significant unmet medical need and unlock huge value. Turning now to the third and fourth value drivers. 5 autologous and 2 allogeneic products into the clinic. We believe the future in our space lies in cell therapies that are both curative and mainstream. By curative, we mean that they give long-term therapeutic benefit, such that ultimately, patients do not die from their cancer. By mainstream, we mean available to broad populations of people with cancer. Now obviously, this is not a short-term goal. And these are both very complex, multifactorial challenges. However, our research pipeline is focused on products that have the potential to meaningfully move us towards these goals. Later, you'll hear from Helen Tayton-Martin, from Karen Miller and from Jo Brewer about how our deep understanding of the translational data is driving our next-generation approaches to improve T-cell performance against tumors with hostile microenvironments, thereby drive deep durable responses moving towards curative therapies. You will also hear about the multiple approaches to making our therapies more mainstream. These include SPEAR T-cells targeting additional HLA types to broaden the population, our HLA-independent T-cell receptors or HiT program to do away with the need for HLA typing full stop and our allogeneic platform to enable fully the off-the-shelf cell therapies. This brings us to the preclinical pipeline from which we anticipate the autologous and allogeneic products entering the clinic. Which includes a range of next-generation products targeting MAGE-A4 and AFP, including in-house constructs and those developed in partnerships, for example, with Noile-Immune's IL-7 CCL19 construct. It also includes T-cell receptors directed towards additional HLAs for both MAGE-A4 and AFP targets. Extending our HRA coverage is, as I've said, one of the ways we intend to broaden the treatment population. It includes our first foray into next-generation tumor-infiltrating lymphocytes or TILs, a partnership with CCIT, a leading TIL center, [ show ] that we're delighted to announce today, and Karen will give you more details. And it includes our HLA-independent TCR program that can recognize cell surface proteins without HLAs. One of these programs targets a cell surface protein, mesothelin, and it's being developed in our allogeneic platform in a co-development, co-commercialization partnership with Astellas. And we also have our fully owned allogeneic program starting with targeting MAGE-A4, which we aim to be our first off-the-shelf therapy into the clinic. This brings me to the connective tissue that we believe builds confidence that we can deliver on these value drivers. We talk about Adaptimmune as an integrated cell therapy company. The challenges and opportunities of cell therapy demand a particular set of capabilities. And Adaptimmune has been built from the ground up with the sole purpose to design, develop and deliver cell therapies. Across all aspects of the company, our capabilities are differentiated from those who might find in a small molecule or biopharm company. But it's not just the design of individual components that differentiates us. It's also the belief that integrating these capabilities, largely internally has unusually outside benefits in the cell therapy space at this point in time. And later, John Lunger and Mark Dudley will talk about those benefits of being integrated and specialized for cell therapy. Conceptually, this enables the virtuous circle you see on the left, with insights from one part of the organization impacting every other part quickly and in an iterative fashion. However, I like to think of it in simple terms as enabling us to operate faster, better, cheaper. And we'll talk through specific examples of this, including the speed of execution in our SPEARHEAD-1 trial, the speed of execution with our next-gen program, security and cost of vector supply and how we've driven significant cost of good savings across the manufacturing process. Ultimately, this is how we build a business, not just a pipeline. So here's an overview of the agenda today. In a moment, I'm going to hand over to Dr. Dejka Araujo, who is our lead investigator with SPEARHEAD-1. She will talk about her experience with synovial sarcoma and with cell therapies. And we'll then spend the rest of the time before the break discussing the clinical pipeline and the first 2 core value drivers: 2 products on the market and 2 further BLAs. We will also discuss our approach to development as an integrated cell therapy company and provide examples of specific tangible benefits this has generated. After the break, we'll delve into our discovery and research pipeline with translational learnings informing new approaches and an overview of our allogeneic platform. We'll take further questions. And after that, I'll wrap up. And with that, I'd like to introduce Dr. Dejka Araujo. Thank you.

Good morning, everyone. My name is Dr. Dejka Araujo, and I am so excited to be here today. I am going to be talking about taking care of patients with synovial sarcoma and, in particular, the need for cell therapy. So just a little background information on synovial sarcoma. Most people have never heard of it. It is a very rare tumor. In the U.S. each year, there are fewer than 1,000 cases diagnosed. And one of the things about synovial sarcoma is it affects very young people. The median age is the third decade of life. So if we look at synovial sarcoma, just in general, the 5-year overall survival is between 66% and 74% depending on what paper you look at. If you look at the 10-year overall survival, it drops to about 48% to 61%. Myself and some of my assistants have been looking at data for particular locations of synovial sarcoma. So we have looked at patients who present with synovial sarcoma at the head and neck, for example. And the 5-year overall survival for that group of patients is 70%, and the 10-year overall survival drops to 50%. More recently, we looked at the patients who have synovial sarcoma, either primary of the hand or the foot. If we look at the 5-year overall survival, they do better than those with head and neck synovial sarcoma, the 5-year overall survival being 78%. And the 10-year overall survival not dropping much and being better than synovial sarcoma as a whole as well as head and neck with the 10-year overall survival being 73%. The next thing I'm going to do is talk about my personal approach, and you might be wondering why I don't talk about the approach in general. One of the reasons is I am one of the leaders in the field. As far as I know I've seen and treated more patients with synovial sarcoma than anyone. And so this is my approach. So first of all, I'm going to talk about patients who present with localized disease. So for those who present with a tumor that is less than or equal to 3 centimeters, I recommend local therapy alone. So that's either going to be surgery alone or a combination of surgery with radiation, and the radiation is given either before or after surgery. The reason why I don't recommend chemotherapy for these very small tumors is I had yet to see a case or in my retrospective reviews find a patient with a tumor that is less than 3 centimeters where they develop metastatic disease. However, if we turn to the patients who have tumors that are greater than 3 centimeters, these can be bad actors. And so I actually recommend chemotherapy for any patient with synovial sarcoma who presents with the tumor that is 3 centimeters or greater. And my recommendation is doxorubicin and ifosfamide for 6 cycles, which is going to be 4.5 months of heavy-duty chemotherapy. They also need surgery and depending on the location, radiation. If a patient has an amputation, there is no need for radiation. Now I'm going to share with you my approach to patients with metastatic synovial sarcoma. And this is very pertinent to this group because this is the population who would be potentially eligible for ADP-A2M4 or what I will call MAGE T-cell therapy. So I still recommend doxorubicin and ifosfamide at high doses for 6 cycles. And generally, as soon as I see a patient with synovial sarcoma, who has metastatic disease, I right away, have a lab drawn to see what their HLA status is. If they are positive for HLA-A*0201, I usually contact my research nurse and start planning the T-cell therapy. So my second line recommendation for those patients who are eligible for a T-cell trial is a T-cell trial. I will often use pazopanib as a bridging agent. If patients are not eligible on either because they don't have the right HLA type or because they have really bulky disease or fast-growing disease, for those patients, I will -- I generally recommend pazopanib second line. To give you an idea of how well pazopanib works, in the PALETTE trial, the overall survival was 12.5 months with pazopanib, and it was only 10.7 months with placebo. And if you see, it's not a big difference between placebo and pazopanib. Many of these patients need a third line and beyond. For those patients, I will recommend high-dose ifosfamide at a dose of 12.5 to 14 grams per meter squared. Trabectedin, gemcitabine and docetaxel, doxorubicin combined with dacarbazine or a clinical trial. A few words about some of the pertinent clinical trials for patients with synovial sarcoma. I enrolled many patients on the Phase III anlotinib versus dacarbazine clinical trial. This trial is actually currently closed for patients with synovial sarcoma. I'm hoping, fingers crossed, that it will be FDA approved. Another trial that is being run by some of my colleagues in the Phase I department, although it's actually a Phase II trial, is with a drug called erdafitinib. It is an FGFR inhibitor. I have yet to find a patient who's eligible for the trial, but I think it would be very reasonable. Another trial is a trial that one of my colleagues in my own department is running, and it is with an agent that is new. It's called sulfatinib, and synovial sarcoma is one of the subtypes that they're looking at. I have thus far enrolled 1 patient. I don't know the response rate yet. And sulfatinib is a small molecule inhibitor, and it targets VEGF. A trial that I have enrolled patients in, again, this is with my colleagues in Phase I is what I think of as sort of an off-the-shelf T-cell trial. Patients do not need to receive lympho-depleting chemotherapy, and they do not need to undergo apheresis with T-cell expansion. And this particular trial is targeting LAGE as well as NY-ESO-1. So what are some of the current and upcoming T-cell trials? So as some of you may know, I am the national PI on the Phase II study of ADP-A2M4 SPEAR T-cells in patients with advanced synovial and myxoid/round cell liposarcoma. One of my colleagues in our Phase I group is running a trial. It's another T-cell trial. This is targeting PRAME. The results are much more preliminary with this target then with either MAGE or NY-ESO. As I mentioned, I have a passion for T-cell trials in patients with synovial sarcoma because I think there's a real role for it. So I'm also the national PI on a GSK trial where the targets are NY-ESO and LAGE. So finally, what are my thoughts on the future of the SPEARHEAD-1 trial? As I mentioned, I'm very behind this approach. And my hope is that it will get FDA-approved sooner rather than later because there's a real need for it. And I would actually like to see it in the future, probably after it gets approved to move that to frontline therapy for patients with metastatic disease. And the reason I say this is I think this approach is going to work the best when the T-cells have not been affected by chemotherapy. And so let's say, I meet a patient, the patient has metastatic disease, I don't want to put them on the doxorubicin, ifosfamide because that's going to affect their T-cells, but I need to do something to control their disease. So for those patients, I would recommend putting them on pazopanib to control their disease prior to apheresis, if I need to, and then while their cells are being expanded. So if it doesn't get approved frontline, I would definitely recommend that the SPEARHEAD-1 approach is used second line. This isn't just coming from me. More and more patients are looking for approaches that do not include cycle after cycle of cytotoxic chemotherapy. Another idea that I have and I think there's definitely some data out there is so let's say a patient is on this trial. It works for a while, but then their tumors progress, but it's lung-only disease where there's progression. For these patients, I think there's definitely going to be a role for a second T-cell infusion with some low dose radiation therapy for the lung metastases. So my overall feeling is that T-cell trials targeting MAGE will become just part of the treatment algorithm for patients with metastatic synovial sarcoma.

Hello. I'm Dennis Williams. I'm the Senior Vice President of Late Stage Development here at Adaptimmune, and I'm happy to speak with you today about our late-stage activities. As you have heard, one of our core value drivers is our plan to have 2 marketed SPEAR T-cell products targeting MAGE-A4. Today, I will speak about our first planned marketing application with ADP-A2M4 in synovial sarcoma. As you heard Adrian speak, we had a nice presentation at CTOS yesterday, and we are thrilled that Dr. Brian Van Tine was able to present updated clinical data from patients with synovial sarcoma treated with our therapy in our Phase I trial. Why is this data important? It's important for 2 reasons. First, this data shows how impactful our therapy may be. As you heard from Dr. Araujo, this disease is devastating. It's devastating for the patient, and it's devastating for their families. And outcomes remain unsatisfactory for patients who progress after standard of care first-line therapies. This is a patient population with a high unmet medical need for more effective treatment options. This is why this data is so important. This trial enrolled the patient population with an unmet need, as I just described. Our therapy resulted in a response rate of 44% and a disease control rate of 94%, and the responses were durable. As you can see the data on the slide on the right-hand side, it shows responses over time. And what you can see on the far right is 2 patients who remain in response 18 months after a single infusion. The second reason this data is important is the following: This impressive data has facilitated our late-stage development program, including the execution of SPEARHEAD-1. SPEARHEAD-1 is our Phase II registration-directed study in advanced synovial sarcoma and myxoid/round cell liposarcoma, and I will talk about this in more detail on the next slide. This slide depicts our journey over the past year, reflecting our commitment to execute rapidly and how the Phase I data has facilitated the late-stage program. This Phase I data was used to support key regulatory designations. These designations are important for 2 reasons. First, they provide external validation of the clinical data. Regulatory designations such as the Regenerative Medicine Advanced Therapy Designation, or RMAT, the European Orphan Drug Designation or the European Medicines Agency Priority Medicines Scheme or PRIME, require clear clinical evidence, demonstrating the ability to either address an unmet medical need or some advantage over available therapies. Only promising therapies receive these designations. Second, these designations enable expedited drug development through a number of incentives. These incentives include expedited reviews of marketing applications and enhance interactions with regulatory authorities, including formal meetings. In addition to these regulatory designations, the clinical evidence from the Phase I trial allowed us to initiate SPEARHEAD-1. As I mentioned, SPEARHEAD-1 is a single-arm Phase II study conducted at 24 clinical sites in 5 countries in North America and Europe. This trial is Adaptimmune's first registration-directed trial. If I reflect back 1 year ago, we just presented clinical data at the European Society of Medical Oncology in September of 2019 and then again at CTOS in November of 2019. After these scientific presentations, there was a great deal of enthusiasm for the potential of this treatment for people with synovial sarcoma. And to illustrate this point, the first patient was enrolled in SPEARHEAD-1 in December of 2019, approximately 1 month after the 2019 CTOS presentation. COVID-19 has had a profound effect in everyone's lives, and it is a great impact on the conduct of clinical studies. However, despite the pandemic, the SPEARHEAD-1 study has recruited extremely well. All 5 countries participating in this trial has contributed to enrollment. As of the end of this month, the trial is more than 80% enrolled. The trial is expected to complete enrollment around the end of the year where approximately 12 months after the first trial patient was enrolled. We are extremely proud of this achievement. We have initiated a number of early commercial activities. These have included patient journey in research in collaboration with patient advocacy groups, such as the Sarcoma Foundation of America. And we're very pleased to work with them. We've conducted some initial sarcoma market sizing. And we've had engagement in early scientific advice with U.S. payers and health technology assessment bodies to generate insights on payer evidence requirements. Here again, our execution of key deliverables including our pivotal trial has enabled our plans to submit marketing applications in 2022. Looking forward, we will be focused on marketing application submissions, approvals and commercialization of ADP-A2M4. We have the ambition to be the first engineered T-cell product approved in a solid tumor indication. But more simply put, our goal is to make a difference for people suffering with this disease and to make this therapy available to patients. Hard stop. If you remember anything I say today, that's the statement you should remember. [ Treatment ] of patients in SPEARHEAD-1 is planned to complete in the first quarter of 2021. And the data cutoff for the marketing applications is expected in the third quarter of 2021. Next year, we anticipate several meetings with regulatory authorities, including formal presubmission meetings. As I previously mentioned, our regulatory designations facilitate interactions with regulatory authorities. The goal of these meetings is to reach alignment with the regulatory authorities on the content of the marketing application. During 2021, we will be intensely focused on preparatory activities to enable successful marketing applications. Due to the rapid execution of SPEARHEAD-1, we are on track to submit Adaptimmune's first marketing applications, and we plan to submit in the United States and in Europe roughly in parallel in 2022. Additionally, we have partnered with a major companion diagnostic developer. And along with this partner, we plan to concurrently submit a marketing application for a MAGE-A4 companion diagnostic assay in 2022. We expect expedited regulatory reviews based on our RMAT and PRIME designations. We also plan to make significant investments in our commercial organization and to execute on a number of key commercial activities in 2021 and 2022. These activities will enable the successful product launch as soon as marketing authorizations are received. We are focused on creating innovative product and patient services. We plan to develop a fully vetted value story to support pricing strategy, which ensures patient access, payer buy-in and provider confidence. Our aim is a fully integrated commercial organization to enable the successful launch of ADP-A2M4 and to provide this product, this important therapy to patients with synovial sarcoma. The integrated capabilities we are building and the experience that we will acquire through successfully submitting marketing applications, securing approvals and executing a successful commercial launch will be invaluable to us as a company as these experiences and capabilities will facilitate our next late-stage program. That late-stage program is with ADP-A2M4CD8 in gastroesophageal cancers. Now I'd like to turn it over to my colleague, Elliot Norry.

Thank you, Dennis. I'm Elliot Norry, Adaptimmune's Chief Medical Officer. You've just heard from Dennis about the opportunity to register our first-generation product targeting MAGE-A4 for the treatment of sarcoma. And you heard from Dr. Araujo about the importance of this treatment for people who live with a horrible disease and have few treatment options. In the next few minutes, I'd like to build on this and discuss what we believe will be the broader opportunity with the MAGE-A4 target. While this story starts with the treatment of sarcoma, this is really just the tip of the iceberg. Initially, this speaks to the opportunity to advance the product toward registration for the treatment of gastroesophageal cancers. And then in the not-too-distant future, it leads to further late-stage studies and BLAs in additional indications. You've seen the waterfall plot showing the compelling efficacy and durability from the Phase I trial of ADP-A2M4 in synovial sarcoma. But what about all the other tumor types? In the waterfall plot on the left here, you can see the patients with other tumor types treated in cohort 3 in expansion of the Phase I trial with the first-generation ADP-A2M4 T-cells. What is clear is that there are RECIST responses in lung and head and neck cancers and anti-tumor activity across a broad range of solid tumor types. I also want to point out the marked tumor reduction in a patient with urothelial or bladder cancer, shown in red on the far right of this chart. This patient had a 67% decrease in their target lesions, but had progression in association with brain metastases. And you can see that there's also activity in ovarian cancer and melanoma. Not shown here is another patient with melanoma treated with in the low dose radiation sub-study who had partial response as well. Turning to the next-gen CD8 alpha data that we recently presented at SITC on the right. There's further confirmation of the potential of SPEAR T-cells targeting MAGE-A4. There are RECIST responses in 2 out of 6 patients, another patient with head and neck cancer as well as a patient with esophagogastric junction or EGJ cancer. In addition, 5 out of 6 patients experienced tumor size reductions, further indicating that this is a very active product. Of particular relevance, all 3 patients with gastroesophageal cancers had tumor reductions. That's 2 with EGJ and 1 with esophageal cancer, indicated by the blue stars. These data have led us to plan for a Phase II study in this gastroesophageal family of cancers starting in the first half of next year. Similar to SPEARHEAD-1 with sarcoma, we intend for this new Phase II trial to be registrational, of course, pending results. So let's talk about the impact of our SPEAR T-cells targeting MAGE-A4 and what they can have for people living with cancer and in turn the commercial opportunity associated with this target. As this table builds out, you will see that we've compiled annual mortality data in the U.S. and EU as a conservative measure of unmet need. These are the people who are otherwise dying from their disease which is a more conservative estimate of the eligibility -- of the eligible patient population than incidents alone. If the data support moving into earlier lines of treatment or we're able to expand to additional HLAs, the number of eligible patients would be even higher. The one exception to how we've estimated the number of potential patients based on mortality figures is synovial sarcoma, where, as Dennis indicated, we've conducted extensive market research to better guide us with respect to the treatable patient population in these geographies. Starting with synovial sarcoma and myxoid/round cell liposarcoma then factoring in MAGE-A4 expression and HLA type based on our own data that we've collected in our trials to date, you can see that there is an eligible population of approximately 775 patients per year. As we progress the BLA planned for 2022 discussed by Dennis, this represents an opportunity for us to build our capabilities, particularly in the areas of manufacturing, regulatory, commercial and medical affairs. Next, let's head into gastroesophageal cancers, where we've seen encouraging activity with 1 response and all 3 patients treated showing tumor reductions. Using the same calculation, using data for patients with esophageal, esophagogastric junction and gastric cancers, you can see that the total eligible population quickly jumps to almost 8,000 patients annually. Regarding gastroesophageal cancers, I'd like to take a moment to highlight the unmet medical need for this patient population. The incidents and mortality are high, and these patients experience a particularly difficult set of symptoms, including pain, bleeding and difficulty eating which often leads to weight loss. Based on recent presentations at ESMO 2020, it's clear that the standard-of-care first-line systemic treatment for these cancers is evolving toward the combination of chemotherapy with PD-1 inhibitors. But even with this new approach to treatment, median overall survival is still less than 15 months. So these patients still need new and better treatment options. I'd like to talk about one of the patients treated in the SURPASS trial with esophagogastric junction cancer who had a confirmed partial response. This 31-year-old was diagnosed in July of 2018 and within approximately 1 year had progressed to 4 lines of systemic treatment as well as radiation therapy. He received relatively low dose of 1.2 billion transduced T-cells at the end of October 2019. After this single dose, he received no other anti-cancer treatment until his tumor progressed about 9 months later. Over this time, his tumor became progressively smaller with greater than 50% reduction which was accompanied by marked symptomatic improvement, including resolution of his abdominal ascites fluid and reduction in narcotic pain medication requirements. In the images on the right, you can see the mass in front of the spine on the upper images is already smaller at 4 weeks. And the lower images show reduction in both peritoneal thickening and ascites fluid. When you consider the very promising early data in the SURPASS trial, with all 3 patients with gastroesophageal tumor types having reductions in size, we are confident in our plans to address this unmet need by initiating a Phase II study in the first half of 2021 that could lead to a second BLA in 2024. If we bring in the other tumor types where we've already seen convincing evidence of responses in anti-tumor activity, that is head and neck, urothelial and lung cancers, it's apparent that this is really a very substantial opportunity to have a massive impact on the trajectory of these cancers for a large patient population. This is the reason we're focusing the ongoing SURPASS trial on these tumor types. Please note that we've only put the squamous cell lung cancer population in the table here, as it has the highest MAGE-A4 expression. And just to complete the picture, adding melanoma and ovarian cancer, which are also tumor types in our Phase I trials targeting MAGE-A4, we get to almost 40,000 eligible patients in the U.S. and Europe each year. Moving on to alpha-fetoprotein, or AFP-directed T-cell receptors, for the treatment of hepatocellular cancer. This spider plot shows the efficacy data that was presented at the International Liver Congress in August. The blue line represents the 1 patient who had a complete response out of 4 treated with the target dose of -- with target dose of cells in group 3 in expansion. This patient remained in complete response until week 32 when they developed a new lesion. This patient also had a marked reduction in their serum AFP level from over 5,000 to approximately 10 that lasted until the time of progression. This patient scans are on the right where you can see 2 target lesions at base line indicated by the red arrows that are completely absent at week 8. Also notable with this trial is that there has been no evidence of T-cell-related liver toxicity. And several other patients had transient reductions in serum AFP and/or mixed responses with some tumors getting smaller. Most have had stable disease for a period of time after treatment. This further supports our belief in the antitumor potential of this product. We've reported data in only 4 subjects at the target dose to date, and we continue to recruit patients into this trial to better understand the strength of this efficacy in a more meaningful number of patients. We are also exploring enhancements alongside the AFP-directed TCR, such as a combination with PD-1 inhibitor or a CD8 next-gen product, something Karen will mention later. When looking at the same type of calculation with respect to commercial opportunity, you can see that there is, again, a considerable potential patient population that would be eligible for treatment. In summary, adapting SPEAR T-cells targeting MAGE-A4 are capable of delivering meaningful responses for patients with a broad range of tumor types. The commercial opportunity with SPEAR T-cells targeting MAGE-A4 is substantial. Pending clinical data in our registration-directed trials, there is a clear pathway to our first 2 BLAs starting with synovial sarcoma in 2022, followed by gastroesophageal cancers in 2024. There is promising antitumor activity in several other cancers being studied in Phase I that can result in pathways to additional late-stage development and future market opportunity with both MAGE-A4 and AFP-directed T-cell receptors. You can see how this all comes together when looking at our clinical pipeline with respect to our current and planned clinical trial activity. We believe this is the foundation for a robust company that can address solid tumors with T-cell therapies. And with that, I will turn it over to John, who will discuss how we've built an integrated cell therapy company capable of delivering our commercial ambitions.

Thanks, Elliot. My name is John Lunger, and I'm the Chief Patient Supply Officer for Adaptimmune, which means I lead the team accountable for a successful process development, manufacturing and supply of our SPEAR T-cell products to patients. Before I go through my presentation, I'd like to share a short video that showcases the complex manufacturing that we do. Some of you may know as well and may have visited our facility in the Navy Yard, so this may look familiar. Nonetheless, I think it does a great job of showing how far we've come from an idea to secure delivery of our drug products. Every time I see this, I am humbled and amazed at what our teams have built over the last several years. [Presentation]

You've seen previously that these are our core value drivers for the next 5 years: 2 marketed products, 2 additional BLAs, 5 autologous products in clinical trials and 2 allogeneic products entering the clinic. We believe that the integrated company we have built will be the foundation to deliver these results. What do we mean by integrated capabilities and why are they important? The challenges of cell and gene therapy drug development are becoming more and more apparent, and I think this quote from Scott Gottlieb highlights it clearly. What he means is that the clinical benefits of cell therapy are clear but the challenging nature of the product and the manufacturing process means overcoming CMC hurdles is going to be much tougher than what we've historically seen with other pharmaceutical products. And those headlines clearly show that his views and ours are real. They are some of the recent examples where product issues have caused real problems for the industry, delays to product launches and supply chain challenges. The primary differences between traditional pharma and cell therapy development fall into 3 main buckets: Speed of new insights, the need for rapid understanding and implementation of these insights in the clinic in a constrained and immature supply base. A few years ago, we reached the conclusion that we needed to build integrated and largely internal capabilities to be a successful cell therapy company in the long term. This is even more important when you consider the complexity of tackling solid tumors. And Karen will tell you more later about how our translational science team learns from every patient we treat. Without these tightly integrated functions, I'm convinced it would be nearly impossible to deliver on the full promise of cell therapy. So what have we built? As you saw in the video, we have our T-cell manufacturing facility at the Navy Yard in Philadelphia, where we have the capacity to support up to around 300 patients per year. We can scale it up to approximately 1,000 patients per year with some investment to build out fallow space and increase our staffing. We are confident we have the capacity to deliver on our clinical trials as well as our initial commercial launches from this building. In the U.K., we have 2 facilities: one in Milton Park, south of Oxford, which is our headquarters along with research, process and analytical development; and in Stevenage, north of London, we have dedicated space in the catapult cell and gene therapy manufacturing center where we make lentiviral vector using a process developed by our research team in Milton Park. Our clinical development teams, our growing commercial team and our corporate teams are split between the Navy Yard and Milton Park. By leveraging people, facilities and integrated capabilities, we are building a business and not just a pipeline. It is a business that can quickly take scientific insights, design the manufacturing process and deliver the product to the clinic. With what we have built, we are able to execute this innovation cycle quickly. This is a key strategic advantage for us and will be of great value as we deliver results going forward. And while enabling the future is important, I have 2 case studies that illustrate how our integrated capabilities have already delivered value. The first one is about our lentiviral vector journey. When we first entered the clinic with our autologous T-cell products, we were using lentiviral vector sourced from a number of academic suppliers. At the time, vector cost per patient was extremely high, and the supply was variable and not very reliable. In 2017, we developed our vector strategy that included a mix of commercial-grade contract manufacturers along with developing our own internal vector capability. Over the last several years, we've executed on that strategy, and our vector costs per patient have reduced by more than 90%. In addition to contract manufacturers, we have our own manufacturing process, which ensures stability of supply as well as quicker implementation of new T-cell receptors. So for all intents and purposes, we have taken concern about vector cost and supply off the table. The second example is about T-cell manufacturing. And here, we face different challenges. In 2018, we had established our own manufacturing, but the process was not scalable beyond several hundred patients. It was not as reliable as it needed to be, and it was based on older lab scale technology. Using our internal and integrated capabilities in process and analytical development, manufacturing and supply and regulatory, we have made multiple improvements to our process over the years. We recently shifted to the single-use G-Rex Bioreactor. We have adopted our media to reduce vector use and upgraded our cell washing equipment. This has reduced our cost by more than 40%, improved robustness and given us a platform that scales the commercial-level volumes. Without these internal integrated capabilities, managing this level of change quickly and effectively would have been extremely difficult. We will continue to improve our execution and reduce cost as the pace of innovation in the manufacturing space continues. These case studies obviously involve manufacturing. Next, Mark Dudley will describe how this kind of execution has led to the rapid implementation of our next-generation ADP-A2M4CD8 SPEAR T-cells in the clinic. And later, Jo Brewer will talk about how everything we do in the autologous field is enabling our progress with allogeneic platform. We have built the capabilities required to deliver value and are in a position to meet the demands of the future. We're a business, not just a pipeline. We now have one of the most experienced CMC teams in the industry. We have secure internal manufacturing of both T-cells and viral vectors, and we had the systems, processes and infrastructure in place to both scale out as we expand our pipeline and up as we increase capacity as we move toward commercial. Even more importantly, what we have built to date has already delivered value faster, better and cheaper. We have shortened our processing times by over 25%. We have improved our reliability of manufacturing to approximately 90% and reduced our costs by more than 40%. And while we are still not done, the outcome of all of this means we improve the patient experience and enable wider access to all of our cell therapy products. Next, I'll introduce Mark Dudley.

I'm Mark Dudley, Head of Early Phase Development. The cell therapy landscape is rich with opportunities. At Adaptimmune, we have a deep pipeline that will lead to benefits from many people with cancer. We intend to have 2 additional BLAs with assets currently in Phase I or II trials. We plan to take 5 new autologous products into the clinic. Adrian established an early phase development unit to drive clinical proof-of-concept studies and to get the best products to patients in the shortest amount of time. The initial clinical safety and efficacy assessments of a new cell therapy as with any medicine represents an inflection point. A positive proof-of-concept trial results in direct transition to late-stage trial that provides definitive data for registration, marketing and commercial supply. T-cell medicines are unlike small molecules and other treatment modalities. Cell therapies can result in substantial regressions in heavily pretreated patients, as Dennis showed you, in patients with synovial sarcoma treated in our A2M4 pilot study. The large magnitude and high frequency of clinical responses enables the design of clinical trials with small numbers of patients. Proof of concept. In early phase, efficacy trials may be seen in cohorts of 5 patients, 3 patients. Deep data capture is also possible with very few patients. T-cells engraft after drug product infusion and become persistent within the patient's immune system. T-cells from the infused product recovered from peripheral blood or tumor reveal important correlates of clinical outcomes, as Karen will show later. This translational data in every individual patient derisks rapid go/no-go decisions. For instance, with the analysis of only a handful of patients with synovial sarcoma after treatment with A2M4 in our pilot trial, we committed to the Phase II SPEARHEAD-1 trial that Dennis described earlier, which we intend to use for registration and ultimately a marketed product. With autologous T-cell therapies, each patient treatment is based on a separate manufacturing line. Each patient is, in essence, their own product. This is very different from small molecule trials, in which a single product batch might supply all clinical trials in the product's clinical development. In early phase cell therapy trials, manufacturing changes and product innovations can be introduced into the clinical trial relatively easily, as represented by the innovation circle. Iterative trial -- iterative clinical trials employ small numbers of patients and enable near real-time product evolution. In the next few minutes, I will share a couple of examples of how this approach delivered results. A great example of this increased speed of execution is the next-gen ADP-A2M4CD8 program. These are the SPEAR T-cells targeting MAGE-A4 that are being used in the SURPASS trial and the planned Phase II trial in gastroesophageal cancers that Elliot talked about. The scientific rationale for this next-gen product is that CD4 T-cells with both SPEAR TCR and CD8 gain functions that may be important for anti-tumor therapy in patients. An example is shown in an experiment on the left of the slide. CD4 SPEAR T-cell activity is represented by the orange lines. In the upper graph, there is no target killing by CD4 T-cells, and the orange line shows the rapid growth of target cells. In the bottom graph, there is strong target killing by the next-gen CD4 SPEAR T-cells, and the orange line drops to 0 over time as the tumor cells die. To explore this next-gen product in patients with nonsarcoma tumors, we submitted the IND in May of 2019. The first patient was treated in October 2019. Six patients were treated during dose escalation, which finished in September 2020. This is an example of rapid execution, using integrated capabilities from research to the clinic, something John just discussed and Karen will discuss further. Three patients with gastroesophageal cancers were treated during dose escalation in the SURPASS trial with the next-gen A2M4CD8 product. As you heard from Elliot, 1 patient had a partial response, and the other 2 patients showed tumor reductions. Based on these data, we decided to start a new Phase II trial, which we intend to be registrational in gastroesophageal cancers in the first half of next year. That's IND filing for a proof-of-concept trial to initiation of a registration-directed trial in less than 2 years. These examples showcase how the unique features of T-cells can be exploited for rapid delivery of effective therapies for patients. Preclinical research informed an efficient trial design where even the lowest cell dose achieved a response. Translational research data and clinical results drove the commitment to late-phase development in the gastroesophageal indications. A new manufacturing process, including in-house vector, will enable rapid global scalability for the A2M4CD8 product after registration, as you heard from John. We could not have accomplished this without wide-ranging expertise and integration from across the company. Another great example of our ability to rapidly execute is evident in the introduction of AKT inhibitor during manufacturing, also intended to enhance T-cell potency. The SURPASS trial with A2M4CD8 continues to enroll patients with a focus on gastroesophageal, lung, urothelial or bladder and head and neck cancers. Each tumor indication is different. Some patients, whether due to the impact of systemic tumor burden or from prior lymphotoxic chemotherapy, have T-cells that are difficult to manufacture or that result in suboptimal product characteristics. Last year, we initiated a screen for compounds that could improve manufacturing attributes and found that AKT inhibitors showed promise. As you can see from the data on this slide, AKT inhibitor added during manufacturing improves the T-cell products. T-cell proliferation is increased on the left, and target license is enhanced on the right. These attributes may correlate with better therapeutic impact via strong T-cell persistence after infusion and potent anti-tumor function in patients. By August 2020, we had achieved regulatory approval for use of AKT inhibitor and are currently using it for patient products in the SURPASS trial with A2M4CD8. This project progressed from concept to clinical implementation in just 16 months. Cell therapy is unique in the ability to extract information from small numbers of patients and rapidly drive therapeutic improvements in iterative clinical trials. These examples demonstrate how resources from across our integrated organization are focused to achieve rapid decisions and rapid product evolution. In the next section, you'll hear about our rich pipeline of targets, platform improvements and next-gen products. Adaptimmune is committed to exploring the best of these with rapid and effective early phase clinical proof-of-concept trials, to deliver effective, accessible therapies to patients with cancer. Bill, over to you for Q&A.

Thank you, Mark. I'm Bill Bertrand. I'm the Chief Operating Officer here at Adaptimmune. Before I turn into the -- or dive into the questions, I just wanted to reflect a little bit. This really is an amazing time at Adaptimmune. You heard this morning a summary of our 5-year core value drivers. Really focused on the first 2 of those 4 value drivers, having 2 additional products on the market and 2 additional BLAs in the next 5 years. And what we really dive or dove into the first half of the session this morning is the significant market opportunity for our SPEAR T-cell therapies and the benefits that we can bring to people with cancer. So let's dive into some of the questions that have come in this morning. We will try to answer as many of them as we can in the time allotted. And -- but we will keep all the questions that have come in.

So first, turning to the session by Dr. Araujo. There's a lot of excitement and interest in the focus on synovial sarcoma. So this first question is for you, Dr. Araujo. Can you comment on how easy it is to convince patients to agree to cell therapy treatment and how easy it is to plan and administer the treatment?

Of course. So it's not difficult at all to convince patients. More and more patients are looking for treatment approaches that are less toxic than our usual doxorubicin and ifosfamide. So often, patients come to me and ask me, well, I want more therapy but not necessarily more cytotoxic therapy. There are some patients who do not know about T-cell therapy. And once explained to them what it is about, it is extremely easy to convince them. In answer to the second question about the ease of administration, if we compare giving a patient the lympho-depleting chemotherapy and T-cells to 6 cycles of doxorubicin and ifosfamide, it is much easier and less toxic.

Thank you, doctor. A related question has come in. What is your view of testing in a standard way every sarcoma patient and then any cancer patient for MAGE-A4?

So my current practice is any patient with synovial sarcoma who has metastatic disease, as standard of care, I go ahead and draw the blood test to see what their HLA status is. On my dream list is to have a test to see what their tumor expresses, whether it's for MAGE-A4, whether it's for NY-ESO. It is not standard of care yet. But I think in my lifetime, it will be.

Thank you. And one further question. In synovial sarcoma, is there overlap between MAGE-A4 and NY-ESO expression?

There is. So I've had some patients where, for whatever reason, maybe the MAGE-A4 trial wasn't up and running yet or NY-ESO trial wasn't available or in between, so I do have patients who are positive for both on MAGE-A4 and NY-ESO. And I have other patients who are negative for both or positive for just one. So I haven't seen a definite trend.

And one more question came in. You test all of your metastatic patients for HLA status. How common do you think this is at other centers? What percentage of patients, synovial sarcoma patients, are already being routed to centers that could administer a cell therapy?

So I don't think it's back, out in the community, it's not common at all. And I see some patients come to me who already have their HLA status, but for me, it's standard of care. So what I would say in other academic centers, it's being done some, but not as much. And what -- can you repeat the last part of the question?

Yes, I can. If I can find this here, sorry, there's a bunch here on the screen. Now, I've lost that question. Sorry. Wait, here. What percentage are being routed to centers that could administer a cell therapy?

Sure. I think it's very common. So since this is not available yet out in the community and patients are interested in it, patients are being referred. And sometimes they are being referred from one academic center to another if the referring academic center does not have cell therapy or a particular cell therapy trial available.

Thank you, doctor. The next question is for Dennis Williams. And Dennis, it is related similarly to our SPEARHEAD-1 trial. So what sort of efficacy do you need to see in SPEARHEAD-1 for approval? And if you're done with the SPEARHEAD-1 trial at the end of 2020, why will it take 2 years to get this to the market?

Thank you for the questions. Let me just first start on how any product gets approved, right? So a regulatory agency looks at the totality of the data. Who were the patients? What's the magnitude of the response? What's the duration of the response? What's the overall benefit risk? Having said that, we feel very confident that we will be able to generate all the evidence to address those points in SPEARHEAD-1. So SPEARHEAD-1, we plan to -- we would expect it to look very similar to the data we saw in the Phase I trial. We feel very confident that, that would be able to secure approval. To the second question, so dosing of the trial will complete in the first quarter of next year. So that's when treatment will end. And as I mentioned, duration of response is important. There is a minimum amount of time we want to follow patients in this trial, both from an efficacy and from a safety standpoint. So when you add in that follow-up time, so we can accumulate duration of response data, that really has the data coming mature towards the end of the 2021 calendar year. And of course, there is time to actually write-up reports and submit those to the FDA. So hopefully, that addresses the question.

Thank you, Dennis. This is a question for Elliot. Elliot, what are the key learnings from the clinical experience in synovial sarcoma in terms of achieving the efficacy data? And how might that read through to our efforts in other solid tumor types?

Well, thanks. I think that the -- what we've learned with synovial sarcoma is exactly what we might expect to see with future tumor types. As Dennis just said, it's -- there's the issue of response rate, but it's really quite a bit more than that. It's duration of response. In some diseases, it can be even around duration of stable disease and how patients do progression-free survival. And then, of course, there are safety assessments. We have also learned and will continue to learn as we go through the process of registering the MAGE-A4-directed TCR for patients with sarcoma. We will build our capabilities and continue to learn so that, as we've said, in the manufacturing and commercial and regulatory areas, et cetera, those are going to be key learnings for us that really help us build on being able to bring future trials and products to the marketplace.

Thank you, Elliot. You can probably stay here for 1 second more. Are you confident that AFP is a viable target? How do you know that one response wasn't just a fluke?

So I think that the complete response is in part the validation of the target. But there's a lot of other evidence as well. We've seen several other patients have some reduction in their tumor size, although not a RECIST response. And we've seen several patients have a decrease in serum alpha-fetoprotein level as well. So I don't think that this is a fluke. Now to that end, we have seen 1 response in 4 patients treated with the right number of cells as we've dose escalated. So I do think that it's important for us to treat more patients at that cell dose and really define what the response rate is as well as the translational information that tells us why 1 patient might respond or relapse, et cetera. So there's definitely still a lot to be learned from the Phase I study. But I don't question whether the alpha-fetoprotein TCR is a valid mechanism. I think we've demonstrated that.

Thank you very much, Elliot. Continuing to scroll through the questions here, this might -- it's a good question for John. What is a good assumption for COGS per dose at the initial commercial manufacturing scale?

Thanks, Bill. I guess the short answer is we haven't guided on particular numbers related to cost of goods. I think the most indicative example I gave was the reductions that we've seen. I think the market knows where pricing may end up on some of these products and where COGS needs to be to be able to enable the business to be one that is viable, and we're definitely directionally going there.

Thank you, John. This is a follow-up question for Dennis. Dennis, is there a certain regulatory efficacy bar for the SPEARHEAD-1 program, either ORR and DOR?

Thank you for the question. The short answer is yes. The trial is powered to show difference over an historical response rate. So as I mentioned, historical response rates in second-line therapies is around the 15% range. So the trial is actually powered to show a response rate where the lower bound of the confidence interval would exclude that number. So the short answer to the question is yes. So we're looking to have a response rate that looks statistically different than what you would see in second-line therapy.

This is a question for Helen. Helen, you mentioned the collaboration with Alpine was mentioned on the slides that were presented this morning. What are the timings for when we intend to go into the clinic?

Thanks for the question, Bill. We'll obviously be coming to the pipeline, a preclinical pipeline, in the next section. And Karen will give you an indication of where all of our preclinical programs are at. I think at this stage, it's too early to tell, but you'll see that it's one of several that could also come to the clinic within the next 2 to 5 years. Thanks.

Thank you. I'm going to direct this question initially to Elliot, and then we can see if Karen or anyone wants to add on to this, although I do think some of this will also be discussed during the afternoon so -- or in the next session. Elliot, can you speak to the biomarker data presented at CTOS, specifically, how do we use those metrics to better identify potential responders as we move our clinical trials forward.

Yes. Thanks. So I think that probably the best the best indicator we have is that MAGE-A4 expression is important. And we've seen that MAGE-A4 has to be expressed at a certain level to see response. The number of patients is still small and explore -- we'll learn a lot more in the Phase II trial. But I think that, that's probably the key biomarker that we've learned we need to pay attention to.

Elliot, one more for you. Do you see the potential to warehouse patients with MAGE-A4 expression for treatment with cell therapy?

Well, I'm not sure I like the term warehousing patients. But I think what the question is getting at is, can we identify patients early on, manufacture for them and be ready to treat as soon as they progress on their other standard-of-care therapies. And I think the answer to that is yes. And we've explored that in some of our trials. And I think as we gain better experience as it relates to how to mainstream the treatment of our patients and deliver to a larger population as we develop sort of our expertise in treatment operations, then we'll find the right mechanism. And we've done this in many instances in trials where leukapheresis patient make their cells and just be ready at the time that they progress on their prior treatment rather than having to wait for manufacturing at that time. I hope that addresses what the question was.

And a bit of follow-up. Karen, could you respond as well on the CTOS question we had earlier?

Thank you, Bill. I was just going to make the comment that I will be discussing our translational capabilities in a little bit more detail in the second session this afternoon.

Perfect. Thank you. We have several other questions on translational and biomarker data. I'm going to hold those now because we're going to go into that in more detail during the next session of the day. But Adrian, one for you to maybe wrap up the question-and-answer session this morning. As we head into 2021, how much more data can we expect from the MAGE-A4 and AFP programs from the ongoing trials?

Thanks. And thanks for the question. We will obviously give updates on the ongoing trials during 2021. But the purpose of today's discussion was actually to set the horizon a little bit higher and a little bit further out. And that's why, although we will be giving data updates next year and we'll communicate some more specificity on timing as we go through the tail end of this year and into next year, the real purpose of today is not to say, well, when will we get the next update on a few patients, rather where is the company going and where do we see the significant value creation over the next few years as opposed to the next few months.

Thank you, Adrian. So we will now be taking a 10-minute break. And we have, again, cataloged all the questions, so we have those. And the next session after this break, we'll turn to the second of our 4 value drivers, the focus and move towards curative and mainstream therapies with 5 new autologous programs in the clinic, 2 new allogeneic products in the clinic. It really is an exciting time for Adaptimmune in the arena of cell therapy. So we will see you in about 10 minutes, roughly 9:40 a.m. Eastern Time. Thank you. [Break]

Hello. I'm Helen Tayton-Martin, Adaptimmune's Chief Business Officer and a co-founder of the company. It's my pleasure to welcome you back from the break to the second part of our Investor Day presentation, which is going to focus on our rich cell therapy pipeline. I'm going to take a few minutes to explain how we are grounding our strategy in 2 core themes, which we believe will be important for long-term success in cell therapy. This morning, you heard Adrian set out our vision for T-cell therapy in cancer, and the 4 pillars we believe will be the core value drivers over the next 5 years. This was followed by presentations from the team on our specific product candidates and the innovation we leverage in our fully integrated company to effectively bring products forward to the patients. In this session, we are going to focus on the second 2 pillars of our core value drivers, namely the approach we are taking towards future products in our pipeline and the platforms that enable them in both the current autologous and the future allogeneic setting. From a bigger picture view, we will be setting out how we intend to bring 7 further products into the clinic in the next 5 years. But to start, I want to take a moment to emphasize the 2 fundamental principles we believe will influence the success of future products in cell therapy for people with cancer. As you heard Adrian mention at the outset, these 2 overriding principles can be summarized very simply. Firstly, we want cell therapy products to be curative. And secondly, we believe these products need to be mainstream. But what do we really mean by this? By curative, we mean aiming for therapies that can provide long-term therapeutic benefit. They need to provide deep and durable responses and bring improved quality of life. To do this, we believe they need to break immune tolerance for initial but ultimately long-term immune control. They also need to be capable of countering and overcoming the many mechanisms of resistance that we are learning to understand, and in particular, in relation to our cell therapies. By mainstream, we mean therapies that are more broadly and biologically accessible to a wider number of patients. To be more biologically accessible, we want to go beyond the current tissue type for HLA restriction of our first products. And to be more broadly accessible, cell therapies need to be available in a more real-time and cost-effective way. They need to be safe to administer on a wider basis and affordable and reimbursable within the existing standards of care. So how are we thinking about achieving cures at Adaptimmune? The first thing that we are doing is leveraging the translational learnings that we are gaining on the cells we are making and how they perform and persist in patients. And how these attributes of the cells relate to responses. In particular, we want to learn how and why patients such as our ADP AFP patients who achieved a complete response in hepatocellular cancer and similarly, the sarcoma patients we have treated and those in a handful of other solid tumors you heard about earlier, have benefited from real and in some cases, durable responses. But the challenge is to decipher the biology and characteristics of patients' complex, especially in solid tumors. We're using a whole host of technologies to explore many of these parameters and that's illustrated in the middle panel of this slide, looking at the function and persistence of the cells in relation to response. But Karen is going to explain that a little more shortly. We are leveraging as many of those insights as we can to focus on specific mechanisms to improve our products, and that's indicated by the panel on the right, several of these feature in many of the second-generation approaches, which we will also cover. In terms of mainstream, one of our core areas of focus is broadening out the numbers of eligible patients who can receive our current SPEAR T-cell T-cell therapies given that they have shown benefits for HLA-A2 patients. But by making new, optimized T cells to the other HLAs, we are making the therapies available to considerably more patients. Beyond this, we're also making specific TCRs which can recognize cell surface proteins without HLA restriction at all, our so-called HLA-independent TCR or HiT platform that's illustrated by the graphic on the top left here. In terms of rapid and streamlined access to our therapies for patients, you heard John earlier described some of the ways we are making our current autologous therapies more cost effectively and rapidly available today. But ultimately, we're aiming to get to a true off-the-shelf supply with our allogeneic platform, and that’s illustrated by the lower left product flow. Jo Brewer is going to be explaining that in more detail, especially the huge strides we have made in producing functional stem cell-derived T-cells, which resemble the function and effect of our autologous cell products. And finally, as with many of the core areas of our R&D efforts over the company's history, we have leveraged key partnerships to optimize our strategic execution in core areas. And our stem cell-based allogeneic T-cell platform is another example. Here, we continue to receive considerable inbound interest from multiple partners. And that follows on from our strategic collaboration with Astellas announced at the beginning of this year. But before I hand over to Karen, we want to share you a very short video, which summarizes the work our teams do to design the cell therapies that ultimately may transform the lives of people with cancer. As was the case in our earlier video in John's section, many of you who know us well will be very familiar with what the video summarizes. But as I look back over the history of the company, it's incredible to see just how much innovation has been realized in the clinic. And so much work originating in-house by so many of our own scientists and the broader Adaptimmune team. These efforts have brought us to this moment when cell therapy is on the cusp of becoming more accessible and more mainstream. Enjoy the video. [Presentation]

Good morning, everyone. I hope you enjoyed the video, which features many of the scientists who work at our U.K. facility near Oxford. My name is Karen Miller, and I'm the SVP of Pipeline Research. This is the team that designs and develops our autologous T-cell products running through from early discovery to preclinical safety testing and IND. This morning, Adrian shared with you our ambitious goal to deliver 5 new autologous products into the clinic by 2025. And today, I'm going to talk to you about the research pipeline that we're building to enable us to achieve that. As Helen has just said, our research is driven by 2 overriding principles, that we want cell therapy products to be curative, and that we believe these products need to be mainstream. I'm going to cover the topics on the right-hand side of the slide to show you how, guided by these principles, we are building our pipeline. Our fundamental importance to our ability to deliver 5 new products to the clinic by 2025 has been the development of a comprehensive translational profiling capability. Now this slide is a busy slide, but it's an important one. It illustrates the wide range of profiling technologies that we use to evaluate the tumor and blood samples that are collected before and after treatment in patients and our manufactured products. We are using these profiling capabilities to extract as much information as we can from the clinical samples. This enables us to monitor how our SPEAR T-cells perform and persist in patients and to examine how the properties of the cells relate to clinical responses. We can then use this information to determine which characteristics of the cells drive better antitumor responses so that we can then build those properties into future products. The transition of both the CD8 alpha next-generation product into the clinic and the cell manufacturing improvement using an AKTi inhibitor that Mark has just described are both excellent examples of how we have already acted on translational data to drive product improvement. I'd now like to present some emerging data to further demonstrate the power of our translational profiling capability to drive our product improvements. The data I'm going to show you is from our Phase I ADP-A2M4 synovial sarcoma trial, and is a single cell analysis of gene expression in our cell products. These diagrams are 3-dimensional plots, where each dot is a data from 1 cell and the dots are positioned in space based on a combination of what the cells are expressing and the level of that expression. If you look at the diagram on the left, the blue cells in the manufactured products are from patients with evidence of tumor shrinkage and the red ones are those from patients with no tumor shrinkage. You can see straightaway that the expression pattern is different. And using this technology, we can probe any gene within the genome for expression to determine if it is associated with patient response. And if you now look at the diagrams on the right, we have looked at the expression of multiple genes that are involved in important T-cell functions such as proliferation, activation, cytotoxicity and immunological memory. The darker the blue color, the higher the expression. You can see that these markers seem to be expressed highly in many of the cells from patients who had evidence of tumor shrinkage and they appear particularly co-localized in the subpopulation of cells outlined at the bottom right of each cell map. If we now take this one step further to look at the function of the cells from this region, we are able to show that SPEAR T-cells expressing a gene that we have called Marker X in this plot are able to kill tumor cells better than those that do not express the marker. As you can see, this type of data is so valuable to us as we can use it to modify our products to express the markers that will enhance their function and which will drive a deeper and more durable clinical response. So having touched on the importance of our translational profiling capabilities to guide product development, I'd now like to summarize our pipeline approach to improving efficacy by designing and developing next-generation products. We firmly believe that engineering SPEAR T-cells to express molecules that will evoke a wider immune response and overcome tumor evasion mechanisms is essential to drive better efficacy of cell therapy products. There are multiple ways in which we can approach this, and these are summarized in the left-hand diagram, and we are exploring a number of these mechanisms. Through this work, we've now established a strong toolbox of next-generation approaches, some of which we've listed on the right-hand side of the slide. Our first next-generation product combining ADP-A2M4 with a CD8 alpha coreceptor has already progressed into the clinic, and Elliot has just shared the really promising clinical data from our SURPASS trial. We have also combined the CD8 alpha next-generation construct with our alpha-fetoprotein targeted therapy for hepatocellular carcinoma, which is now progressing towards IND. And to further strengthen our next-generation platform, we're also leveraging external partnerships, and we have 2 very productive collaborations with both Noile-Immune and the Alpine Immune Sciences. With Noile-Immune, we are exploring the combination of expressing a cytokine, IL-7, with a chemokine, CCL 19, to improve efficacy by enabling T-cells to function better, allowing better access of immune cells to the tumors and evoking a much wider and durable immune response. To illustrate just one aspect of the mechanism, I'd like to show you the image on the right-hand side of this slide. In a tumor, we expect that expression of CCL19 by SPEAR T-cells will induce the migration of more T-cells and dendritic cells into the tumor, and this should enhance killing. Here, we show that if we put our SPEAR T-cells, shown in green, at the top of the special chamber, they can migrate towards the lower chamber if there is CCL19 in there to guide them, and you could see that in the lower panel. I'm now very pleased to be able to talk about our partnership with the CCIT, the National Center For Cancer Immune Therapy in Denmark, which we are delighted to announce today. In this partnership, we are working with a group led by Inge Marie Svane, who is a leading expert in TIL therapy. Our aim is to develop next-generation tumor-infiltrating lymphocytes or TILs to improve efficacy in patients with cancer. And the first product we intend to take to the clinic will be a next-generation IL-7 TIL for people with melanoma. This partnership plays to our strength in TCR discovery and in next-generation product development by targeting multiple antigens in one product with the boost in efficacy from a next-generation construct. The fact that it's a personalized patient product also aligns well with our key principle to develop mainstream therapies that target a wider patient population. I'd now like to move on to share 2 more examples that illustrate our drive to develop more mainstream products. We recognize the importance of maximizing the value potential of our clinical products by increasing the treatable patient population. And we're doing that by developing TCRs targeting MAGE-A4 and AFP peptides associated with additional HLAs. If you look at the diagram on the left, you can see that with our current MAGE-A4 targeted products, we cover around 40% of the patients eligible to screening in our clinical trials. By developing additional products associated with HLA-A*01 and HLA-A*24, we can increase the reach to around 70%. Similarly, for AFP, we are developing TCRs to HLA-A*24 in addition to the products that currently target HLA-A*02. And now for the future, it would be even more desirable to avoid the need for HLA restriction altogether, which is why we believe that our new HLA-independent TCR or HiT platform has such promise. This is a highly innovative approach to generate TCRs that bind cell surface molecules independently of HLA peptide presentation. These are the same type of targets that CAR-T cells recognize, opening up this market for us and extending our target space to both intracellular and cell surface molecules. The HiT platform builds on our strengths in TCR discovery and will be competitive in the CAR-T cell market. And of course, being HLA-independent means that we could treat a much wider patient population. We have already obtained in vitro proof-of-concept for the platform, having generated TCRs to a known CAR-T target, mesothelin. These TCRs bind directly to mesothelin with a similar affinity to normal TCRs as shown in the graph on the left. We can also engineer these TCRs to optimize their binding properties. The graph on the right shows that when expressed by T-cells, the mesothelin HiT enables specific killing only mesothelin-expressing tumor cells. We're delighted to confirm today that mesothelin is the target for the first co-development project with Astellas, and this product will be developed within our allogeneic platform. We're also identifying HiTs to a variety of additional cell surface targets to bring into the pipeline in the future. One of these is GPC3, a target for hepatocellular carcinoma, which we'll provide more detail on in due course. And now I'd like to conclude with the slide of our research pipeline, as shown by Adrian earlier. Our pipeline, underpinned by the 2 principles offer cures and mainstream therapy to people with cancer, has the potential to yield numerous new and improved products, and expand the treatable patient population. With this strong pipeline, we are very confident in our ability to deliver 5 products to the clinic by 2025. The 2 products closest to the clinic are our next-generation CD8 alpha product targeting AFP and our next-generation IL-7 TIL through our collaboration with CCIT in Denmark. As discussed earlier, we also have a number of next-generation products at the preclinical stage. You can see that within this pipeline, we are building multiple opportunities to maximize the value potential of our current SPEAR T-cell products and to develop multiple new cell therapy products. As always, we continue to be strongly data-driven in building our pipeline, and we have a laser focus on selecting the best products to progress rapidly into the clinic. Of course, our pipeline also includes our groundbreaking allogeneic platform, which you are now going to hear about from Jo Brewer.

Hello. I'm Jo Brewer, and I'm the SVP of Allogeneic Research. I lead the off-the-shelf program that Ad and Helen were talking about earlier. So an allogeneic platform will enable us to get our therapies to more patients more quickly, part of our ambition to make our treatments more mainstream. We aim to have 2 products in clinical trials by 2024. The first one will use the same MAGE-A4 targeted TCR that we're using in our current trials. That way, we can test our allogeneic platform in a known clinical context, and we can compare it directly to our autologous products. And this is a huge advantage for us, having both types of products under one roof. The second program will use the mesothelin HiT that Karen was talking about earlier. And this will be the first of 3 products that we are going to co-commercialize and -- co-develop and co-commercialize with Astellas. We expect that these products will be the first stem cell-derived, engineered TCR T-cell therapies to make it to the clinic. So why did we decide to build an allogeneic platform using stem cells rather than healthy donor blood cells? We believe that gene editing stem cells provides a flexible platform whilst minimizing batch-to-batch variation. We want some allogeneic products that we can control so that we can make reproducible products. And one major factor that introduces variability is the source of cells that you use. So with our platform, we create a line from a single donor, we edit it, and then we use that to make stem cell banks. And this gives us control over our starting material so that each manufacturing run starts with the same cells. With healthy donor-derived starter material, the cells come from multiple people, and this will always be a source of variability between batches. So what are the advantages of combining stem cells and gene editing? With our platform, we do all of the edits upfront at a small scale before expanding those clones and making banks. And we can perform multiple rounds of knock-ins and knock-outs in an iterative fashion. And the ability to keep adding extra edits makes our program very flexible. But going back to the clone each time limits the variability that might impede the GMP manufacturing. And this flexibility will be incredibly powerful for future product development cycles, and it allows us to modify the cells to suit based on what we learned from our patients. It also overcomes some of the vector size issues that limit the changes we can make in our autologous platform. Screening the clones after we've edited allows us to check for anything that we don't want to come into the final product, such as translocations or any off-target edits. This scenario is completely different to a healthy donor platform, where you're required to make multiple edits in a large batch of cells from an apheresis product. Bulk editing always yields the mix products, where many of the cells are only partially edited and they contain only some of the desired modifications. And the higher the number of edits that you want to do, the higher the number of possible partial combinations, and in turn, the smaller the number of cells that actually contain all of the edits. And this is a big limitation when using healthy donor starting cells. So with our platform, every cell in the product has every edit and this, again, gives us better control with the product. Lastly, I want to focus on being GMP manufacturing ready. Everybody has already told you the importance of being an integrated company, and this is also true for our allogeneic program. The research team has been working with a dedicated process development team from very early on and GMP compatibility has been at the front of our minds as we aim to the clinic. So the research process that we've produced uses defined media without using human serum. And serum, as I expect many of you know, is a well-known source of variability and potential viral contamination that can confound GMP production. Similarly, we don't use any feeder cell lines to support the culture. This eliminates yet another potential contaminating element and it helps smooth our path to GMP manufacturing. All of these factors combine to give us greater control of the product. There are 3 broad areas to think about when genetically modifying an allogeneic product compared to an autologous one. Firstly, potency. For our first allogeneic product, we're using that same MAGE-A4 targeted TCR currently in clinical trials. And we expect to add further next-gen modifications to improve the product in the future, just like we do with our autologous platform. However, unlike the autologous system that relies on lentiviral vector, editing in the allogeneic platform will allow us to introduce multiple changes at once. Secondly, safety. It's absolutely vital to make sure that we control the endogenous TCR or preferably get rid of it altogether. And this will prevent GvHD in our patients. And thirdly, persistence needs to be addressed. Allogeneic cells are noncells and will be rejected by the patients. This is something that we don't have to worry about with our autologous platform because patients receive their own cells. But to reduce the risk of rejection with the allogeneic cells, we have to knock-out beta 2M, which stops class I HLA, that's HLA-ABC, from getting to the cell surface. So this helps the allogeneic cells escape from the patient's T-cells. And then we also knock-in HLA-E so they aren't targets for the patient's NK cells either. We know from our autologous products that persistence is likely to be a very important factor for efficacy, particularly with solid tumors. This is one of the reasons that we are focusing on generating a T-cell platform rather than an NK cell one. T-cells should have a longer life span in patients after delivery than NK cells, and we really think that matters. So we have built a process that mimics early T-cell development in a dish. Normally, T-cells were developed through the embryo in early life, but we've reduced this to a timescale that's workable for manufacturing. The stem cells start in a completely pluripotent state, meaning that they have the capacity to differentiate into any cell type that's found in the human body, depending on the cues that they receive. And the trick here is to get them to differentiate in the way that we want them to. So for us, that's alpha beta T-cells. Complex 3D structures self-assemble in the early stages of the process, as you can see here. This is one of the key differences with our platform and others. These structures support the T-cell differentiation pathway without the need for a feeder cell line, and this is a clear advantage as we move towards GMP manufacturing. Each step along the way reduces [ names ] of cell types that can develop. What you're looking at here is a red tubular structure, which is like a blood vessel in a dish, and the green stain cells are actually inside this vessel. Now these are blood precursors at this point and those green cells could go on to be red blood cells or T-cells, B-cells or NK cells or macrophages, but we push the cells down the T-cell differentiation pathway. And in the final panel, you can see CD3 staying in green, which just confirms that we've made T-cells at the end of our process. So are these CD3 T-cells functional? Do they kill like our autologous cells? So here, you're looking at some killing curves similar to the ones that Mark showed earlier. On the top panel, you can see our first-generation autologous products in purple. The black line shows a tumor line growing during the assay, and this is the control. And when we add the autologous T-cells at 24 hours, you can see that the purple line starts to head downwards a little bit later as they kill. The line going downwards shows that the tumor cells are dying. On the bottom panel, you can see the red line tracking our allogeneic cells. It shows that not only do they kill the cancer cells but also that they do it faster than the autologous cells on the top graph. You can see the red and black lines clearly separate 6 to 9 hours after the cells are added because the allogeneic cells are primed and ready to go. I've not shown the data here, but the allogeneic cells only kill cells where the MAGE-A4 target is present and the right HLA type is present, so exactly like the autologous cells. So the cells that we're generating with this process are potent killers, and they maintain their TCR specificity, which is really important as we move to the clinic. So our process can be broken down into 6 stages on the journey from stem cells to becoming T-cells. The cells become more specialized and more restricted in their fate decisions at every step. By the end of Stage 3, their fate is fixed on becoming blood cells, those were the green cells that I showed you in the red vessel before. Then Stages 4 to 6 are skewing the cells to become the T-cells that we're after. So we can track this process using the same sort of single cell gene expression analysis that Karen was showing you earlier. Here, we have our autologous products, and each dot represents the gene expression profile of a single cell. And the closer the dots are together, the more similar the cells. So let's see how the allogeneic cells compare. The stem cells start off looking quite different, they pop-up over here at the top of the plot. Then as you get to the end of Stage 3, they sit down here at the bottom, and those are the blood precursor cells still quite a long way from the autologous product. At Stage 5, getting towards the end of our process, the cells are getting closer to becoming T-cells, and you can see the gene expression profile is getting a bit closer. And at the end of Stage 6, the profiles are actually touching. So the profiles are not identical, and that's okay. We're not aiming for identical. We won't need to see how these allogeneic cells work in patients, and we can take those data into account as we try and make the best products that we can. But our ability to check the biology after each edit, check the process and compare back to our autologous learnings is hugely beneficial, and this enables us to determine when we have cells that are ready for the clinic. In summary, our first allogeneic program has a differentiation process that's compatible with GMP manufacture and makes T-cells that show potent killing. All the cells in the product contain the same genetic modifications as they were derived from a single clone. And I'd like to bring you back to the innovation cycle that John was mentioning earlier. So we have [Technical Difficulty] that we are pushing towards manufacturing for the clinic. We're putting significant effort into scale up right now so that we can do this as soon as possible. Access to an allogeneic product will be game-changing for patients. And this will be a vital part of making cell therapies mainstream. We also know from our past experience how important it is to have full control of manufacturing when developing a complex product. Our integrated company approach gives us control of tech transfer and manufacturing scheduling, things that we will need to deliver off-the-shelf products for people with cancer. We're making the most of all that we've learned in developing our autologous therapies, using the best of that knowledge to get the first stem cell-derived engineered TCR T-cell product for people with cancer by 2024. That's it for me. And I'll hand back to Bill for some more Q&A.

Thank you very much, Jo. We are in the home stretch. I just want to remind everyone if you have questions, please use the box that is in your screen in front of you. And we have several that have been submitted, so I will get to those in 1 second. But again, just a quick sort of recap. I think it was another very interesting session that we had just now. We've gone through the second 2 of our four 5-year value drivers, including bringing 5 autologous products to the clinic, exciting information about the TIL program we are working on with CCIT, exciting developments in our HLA-independent programs and then Jo's summary of where we are from an allogeneic program. So let me run through the rest of the questions for the next 10 or 15 minutes or so. And after we do that, I will turn to Adrian for some closing comments. So this first question, let me direct this to Dennis. Dennis, can you discuss the importance of MAGE-A4 expression levels and homogeneity in determining whether a patient responds and whether the response is durable?

Thank you for the question. So I think as you may have saw in the CTOS presentation yesterday, we do see some preliminary evidence that MAGE-A4 expression, meaning those that have a higher expression, tend to have greater reductions in their tumor size. The caveat to that limitations is a limited data set for 16 patients. So I think the analyses that we are conducting are still ongoing. And when we have the larger data set from our SPEARHEAD-1 trial, we'll be able to further interrogate some of the questions about A4 expression and its effect on response and duration of response.

Thank you, Dennis. I'm going to direct the question to Helen first, and then I have another follow-up question for Karen after that. So -- but Helen, in SURPASS and the AFP trials, have we generated translational insights about why some patients respond better or deeper than others?

Thanks, Bill. We could spend a week talking about that, but we can't today. So I think we have generated some insights. We saw some of that with some of the data that Karen showed you on the single cell analysis, which relates to the patient product that we're making. There's obviously a whole raft of tumor analysis that we're doing as well. And both of those things together are the things that we're absolutely mining to look for links between response and effective product. So stay tuned on that. I think there's going to be an awful lot more to come. We wanted to give you a snippet of it today. But in both cases, I think we are starting to get some insights, but it is very early days, a very small data set, as Dennis was alluding to just now.

Great. Thank you, Helen. Karen, this is a question for you based on our HLA-independent program. Why would we use a HiT rather than an antibody-based CAR to target an extracellular protein like mesothelin?

Thanks for the question. It's early days, of course, but I think we've got good reason to believe that the HiT molecules will have distinct advantages over CAR-Ts. The first thing is that our HiTs have natural TCR signaling, unlike CAR-Ts which tend to have tonic signaling. And this, as you are probably aware, has been directly linked with more severe CRS and neurotoxicity from CAR molecules. CAR-Ts tend to bind with very, very high affinity, whereas our HiTs bind with normal affinity giving better engagement and better signaling, better control of the immune response. And there's also some indication that this tight binding actually prevents the access of T-cells bearing CAR-Ts into the tumor because the binding is so tight. So I think that [Technical Difficulty] mechanisms to try and understand a little bit more about any potential further advantages we may have over CAR-T.

Perfect. And Karen, you could probably just stay at the podium for 1 second. For each new HLA, isn't this a completely new TCR? What will be the development time there? Or do we have a lot of them waiting to use?

Okay. Another good question. Yes, we do have to do some work in research when we're looking to identify TCRs expressed with additional HLAs. However, we have, of course, already derisked the 2 targets, MAGE-A4 and AFP. So that will reduce the amount of preclinical safety testing that we will need to carry out. I can tell you that we have identified some very good peptides on these additional HLAs from patient tumors. And we've been able to identify TCRs to those additional HLA peptides. So we are well on the way to discover it.

Adrian, this next question is for you. How will you build a commercial organization at Adaptimmune? And when does that start?

It's a great question. So we're 2 years out from the first launch of our product. And as Dennis outlined, the starting point for the commercial insight and then the commercial build-out and expansion has already begun with the understanding of the patient journey and the research into payers, et cetera. Now looking forward, I think we'll look forward to expanding that as we go forward, taking advantage of the learnings from other companies who have been here before. So there's 2 cell therapy products in the market, and there's a nice template for how one actually approaches launching and commercializing these types of therapies, and we'll take full advantage of those. And the objective of those, given the pipeline that's coming behind the synovial sarcoma launch, is to build a focused but scalable commercial presence in U.S. and in Europe to enable us to deliver this first therapy to patients who, as you heard, desperately need it, but then also to be able to expand into other indications as they come through from our value drivers.

Thank you, Adrian. This is a question for Jo Brewer. I recognize the need for beta 2M edits but can you discuss further the need for the HLA-E knock-in? What would persistence be with the HLA-E knock-in, obviously, related to the allogeneic program?

Yes. So when you use the beta 2M knock-out, you get rid of all that Class I HLA on the surface, which is great from a T-cell point of view. But then you become a real target for NK cells, the lack of Class I HLA makes you a big target for NK cells, which the patients, obviously, will have. As they recover from their lymphodepletion, their NK cells will come back, and they'll get rid of the allogeneic cells. So HLA-E is one of several different receptors that you can use basically to give the signal to the NK cells to leave the cells alone. So that's why we're using HLA-E specifically to address the NK cell attack from the patient.

Thank you, Jo, and maybe if you could stay at the podium for 1 second. Another question on our allo program. We just find it here. Why do you think your allogeneic cells are better killers?

So I think there's lots of different hypotheses as to why we see that faster killing. And to be honest, as far as the patients are concerned, as long as they kill, that's all that matters. The fact that they don't look exactly like the peripheral blood T-cells that I was showing you earlier, the autologous product. Partly, that could be because they're younger. They have longer telomeres because they're from a stem cell source. There may be a slightly more innate phenotype, maybe slightly more fetal, and that's why we're not concerned about them being identical. They are probably quite different, and we want to see whether that's actually an advantage in the clinic for patients. So that's something that we're going to pay close attention to as we get clinical data and the translational data that we get from these cells is going to be vital in understanding what makes the best product overall. So they have several characteristics that look younger and less tired in effect. I mean by the time you isolate certain cells from patients who've been through multiple rounds of treatment, of all different sorts of treatment, they're older in age generally and they've been through an awful lot. So the stem cells haven't been through any of those things and really trying to understand the biology is a long-term aim for us. It's not going to be a quick answer. But it's something that we're setting up to be able to get the right [ answer ] so we can answer those questions over the coming years.

Brilliant, thank you, Jo. This next question is for Dennis. Dennis, the FDA has approved cystic fibrosis drugs for rare mutations based upon clinical activity and more common mutations, percent IIb in vitro activity in the rare mutation. Can this be applied to development of MAGE-A4 products for rarer HLAs?

Thank you for the question. I think the short answer is that option may be on the table. And in fact, it's certainly done in oncology as well. There have been examples where drugs that are NTRK fusion inhibitors, very targeted therapies approved, very rare cancers. I think the FDA is willing as the European Medicines Agency is willing to work with sponsors if there is compelling data, these rare cancers and the move, expeditious way to develop those. So I think when you have an effective therapy that works in a rare disease, there are options to have interactions with agencies to expedite and think of the most optimized development program.

Thank you, Dennis. This next question will go to Karen, I believe. So Karen, can you talk about the ease of expanding the binders outside of HLA-A2? Is it a simple plug and play or how many changes are required as we look to develop our products in different HLAs?

This just fits into our standard platform. We obviously have a very good mass spectrometry setup to be able to identify peptides expressed on many different HLAs. Once we've identified those in tumor samples that we're interested in, we get a good idea of what the best peptides are and then we, of course, will generate TCRs to those products. So it's just part of our normal pipeline.

Great. Thank you. Helen, I have a couple of questions for you. I'll ask them both since they are partnership related. The first is, what is the status of the PRAME program? And the second is, what is the status of our Astellas program? And how do you feel that is going?

Thanks, Bill. So GSK has been a partner with us for a long time. And PRAME has been nominated. It's actually target 3 in the GSK collaboration. It was also a target 2, but we moved to a second version, a second TCR and a second program with them. So it's a preclinical stage program. It's been moving very well. Key thing about PRAME is there are lots of peptides. Actually, as Karen was just mentioning, and actually homing in on the right one has been very important in that program, but it's moving forward very positively now. So the other question around Astellas, different collaboration entirely focused on our allogeneic platform, started out with our collaboration with Universal Cells, which was acquired by Astellas. On the gene editing side, the HLA edits that Jo was just talking about. But as our company has evolved -- as Astellas's interest is evolved in cell therapy and immunology, it's been a great synergistic fit to come together and focus on co-developing and co-commercializing products going forward. And that's the nature of that collaboration, 3 targets of that will be -- form part of it. The first one, as we've revealed today, is a mesothelin-targeted HiT and HLA-independent TCR. So that's also going very well. Collaboration was announced in January, where we've already got the first target TCRs moving forward. So we're very pleased with that.

Thank you, Helen. Just looking through to see what we still have in the queue here. Maybe one more question for Jo, and then I have a follow-up question for Adrian that we'll use probably to close the session. So Jo, what is different from what we are doing with our allogeneic program compared to Fate, Allogene and other companies?

Right. So that's a great question. I think there are several differences. We're focused on solid tumors from the very outset. A lot of the competitors are starting out in the hemo-oncology space. So there I know many of them are moving towards solid tumors as they go. When it comes to stem cell-derived platform, I think Fate are obviously -- they're there with their NK cell platform. They have a T-cell platform. They announced the IND this year. So we're following up in a very similar vein to Fate. They're using CARs. We're using TCRs. So a lot of the biology will be different between our programs. And how those cells perform, I think we'll see some different parallels. In the same way as we do with the autologous platform, differences between CARs and TCR therapies, different set of targets. When it comes to Allogene and the other healthy donor platforms, I think I've spent a long time talking about those things. Healthy donor platforms have a whole variety of different variabilities in terms of the supply of donors, but they also are that much closer to autologous platforms and that they're made with mature T-cells. So I think you have the different questions with those, and I certainly see it comes down to what doses do you need and how many patients you can manufacture in one batch. And that can be quite different for CARs and TCRs, bearing in mind the amount of cells needed at effective doses at the moment in time. So Allogene and other companies working like Precision is working on the healthy donor approach, again, very much focused on heme CARs at this moment in time. And we'll see how the whole field develops more in solid tumors as things progress. But always with the TCR platform that we're using, we'll have a range -- we have access to a different range of targets, whether it be HLA restricted or the HiTs that Karen was describing.

Great. Thank you very much, Jo. So Adrian, one final question for you. As the CEO, you get the joy of getting some of the real tough questions. So I will present this one to you. And then I think you will go into your closing after that. But despite all the work that is being done at Adaptimmune, why has the share value been diving down continuously?

That's a good question, although probably better addressed to those people who are buying and selling the stock. I mean, our focus, as we've outlined in this discussion, isn't around short-term value creation in this regard. It's around how we're going to create long-term value for patients and thereby for our company and for shareholders. And I think it's really important to recognize in this space -- in biotech, it is a truism. All value is created by benefiting patients. And a patient doesn't benefit actually long-term until they're actually getting treated commercially with the product. Until that point, everything prior to that is really a surrogate for the proximity and the probability of those final events happening. So what we've done today is we've laid out a path to get to those real value-creating events, cell therapies on the market, treating patients in dire need. And that's what's going to create value for us, as it's done for every other truly successful biotech company out there. And I think what you've got at Adaptimmune is a set of people who are wholly committed to that and that's what's going to ensure that long term the value creation is real and durable for both patients and for investors. So with that, I just want to perhaps wrap up with a couple of remarks and in doing so, I want to go back to the mission and vision for the company. I want to do this because this is where I started when I took over as CEO last year. And it's what's guided us for the last year. And it's what's going to guide us for the next 5 years as we deliver the value drivers that we've spent all this time outlining today. So we're a cell therapy company. We believe that our leadership in cell therapy in developing cells as medicines results in these unique capabilities that can be leveraged within the field, and we've shown you how we're doing that. We harness these cells against cancer, we're a cancer company. To this end, we've built a set of oncology-specific translational capabilities and in the relationships with the network of experts and leading centers of excellence, and this enables us to execute on what is very challenging R&D. Our objective is transformational, as we've outlined today, not incremental. The responses across patients with 6 different solid tumors confirm the potential of our products to transform the lives of patients. But beyond this, we are focused on further developing the platform to make medicines that are both curative and mainstream. So the value of Adaptimmune is as an oncology cell therapy company, integrated from research to commercial, with the capabilities and the speed necessary to design, develop and deliver transformative cell therapies for people with cancer. And this is the company that over the next 5 years is going to deliver the 2 marketed products, 1 in sarcoma, 1 in gastroesophageal cancers, 2 additional BLAs in other solid tumor types, 5 autologous and 2 allogeneic products into the clinic, all supported by our integrated capabilities as a ground-up cell therapy company. And with that, I'd like to thank you all very much for your time, the 175 people who have stuck with it for the 2.5 hours and we are -- look forward to updating you on the progress against those value drivers as we go forward. And with that, we'll wrap up the conference. Thank you.