Adaptimmune Therapeutics plc (ADAPY) Earnings Call Transcript & Summary

Welcome, everyone, to day 2 of Citi's Immuno-Oncology Summit. I am Yigal Nochomovitz, one of the biotech analysts here at Citi. Most of you know me. [Operator Instructions] So with that, it's my great pleasure to welcome the management team from Adaptimmune. We have Gavin Wood, CFO; Elliot Norry, CMO; and Juli Miller, VP IR. So welcome, everyone. Thank you so much for taking the time. Maybe just to start out, Gavin, if you would like to summarize the overall strategy for Adaptimmune for those listeners that are less familiar with the story?

It's Ad Rawcliffe, CEO. I'll just touch on areas of focus for this year. Adaptimmune is a late-stage, integrated cell therapy company, focused on the TCR T-cell space for solid tumors. We have a strategy that we laid out a couple of years ago. It's unashamedly a product-oriented strategy as we're leading in late-stage clinical trials and approaching our first BLA. That strategy, which we effectively refer to as 2-2-5-2, you can find in our deck. And the starting point for that is having 2 products on the market over that 5-year period, which began about a year and a bit ago. The focus, therefore, for 2022 is outlined on this slide, a BLA filing for afami-cel. Afami-cel is our first-generation T-cell-targeting MAGE-A4, and we've developed that for synovial sarcoma. And the SPEARHEAD-1 trial, which read out last year, showed a -- the data at that time is a 36% response rate in this very difficult-to-treat patient population. And we confirmed that the trial has met its primary end points. And that data will be the basis of the BLA file, which we anticipate in the second half of this year. The next area is focused on MAGE-A4 as a franchise. MAGE-A4 is a validated T-cell target across a broad range of solid tumors. And in addition to afami-cel, our lead product, we have a second-generation product, which has been developed in a family of trials called the SURPASS trials. We presented data last year across a broad range of tumor types, showing a 36% response rate in the patients at ESMO last year, including complete response in ovarian cancer and partial responses in ovarian, bladder, head and neck and synovial sarcoma and gastroesophageal junction cancers. We are developing that asset in 2 late-stage clinical trials, branching off from SURPASS-1. Those are called SURPASS-2 and SURPASS-3. SURPASS-2 is in esophageal and gastroesophageal junction cancer. And SURPASS-3 will initiate this year in ovarian cancer. And so we are building out that franchise in this, what we believe, is a very important solid tumor target. Just for reference, approximately a little less than 100,000 people die each year with high MAGE-A4-expressing tumors in the U.S. and in Europe. We have been investing in our manufacturing for the last 7 years. And for the last 5 years, we've had in-house cell manufacturing. And the last 2 years, we've had in-house vector manufacturing. And we believe that the CMC capabilities of a cell therapy company are critical, not just from a product delivery perspective, but also from an innovation perspective. We are now invested in scaling up our manufacturing capabilities to support the first commercial product and the late-stage trials. Also to enable the delivery of a fourth priority here, our allogeneic platform with an allogeneic manufacturing facility in the U.K. currently under construction. And that last focus area is an area of differentiation for us. We are, we believe, the only cell therapy company with advanced autologous clinical programs and a robust leading allogeneic platform as well. Our allogeneic platform is based on stem cells and deriving T-cells from stem cells, which we've shown we are able to do successfully. And that those T-cells will serially kill target-presenting cancer cells. The -- our first IND, again targeting MAGE-A4, will occur next year out of that platform. And in addition to our in-house programs, we have 2 collaborations on that. Well, first with Astellas with a mesothelin program that will go into the clinic after our in-house MAGE-A4 program. And then the second, the recently announced deal with Genentech, that will enable us to develop not only combined targets, but also a personalized allogeneic therapy platform over the long term. So all of that is why we are the leaders in the TCR T-cell space, and we're quite excited about 2022.

Okay. Excellent introduction. And just to clarify, it's Adrian Rawcliffe, the CEO, who just spoke. And Gavin Wood, the CFO, the CMO, is not present on the call. So maybe you mentioned TCR T-cells. It would be great if you could just give us a little bit more color on how you see TCR T-cells as differentiated. And why you believe that in solid tumors, they could be potentially much more effective than CAR-Ts? Where, as you know, the CAR-Ts haven't really produced much in solid tumors.

Yes. I don't think we should be dismissive of the CAR-Ts though. Because if you look at this landscape slide, which shows the breadth of cell therapy development, the vast majority of approaches at the moment or the majority of approaches at the moment are CAR-T-based. And as you say, they have proven to be remarkably efficacious in the hematological space. I think the challenges that we face moving from -- into a solid tumor space with CAR-Ts -- and these are not challenges that we don't think will be overcome, but they are nonetheless the challenges that the CAR-Ts will have to overcome, are sort of twofold. One is a target-based challenge. It is a perfectly effective strategy if you want to target a B-cell malignancy to select a target that is on all B-cells and eliminate cells that express that target. You will, by default, get rid of your B-cell malignancy. And therefore, CD19 makes absolute sense as a target. That is not an effective target strategy with something like lung cancer or bladder cancer, where eliminating the lung tissue will not be an effective strategy to eliminate your lung cancer. You need a selective target. And there are very few cell surface proteins, which are CAR targets, which are the subject of CAR attack, which are truly selective for cancer. And as such, that the availability of targets in the solid tumor space that are amenable to CAR attack is limited. It's not 0, but it's limited. The second issue is that a lot of effort went into CARs to ensure that the signaling for the CAR is able to trigger T-cell attack when you put a non-T-cell receptor targeting more -- antibodies targeting more, there are CAR targeting more on it. And the challenge with that is that ultimately, you're dealing with a set of cells that are not behaving in exactly the same way as a normal T-cell response. So enter a T-cell receptor. T-cell receptors are the natural targeting moiety of a T-cell. They are what the T-cells use every day of the week to eliminate things that the immune system doesn't like, including the vast majority of precancerous cells. They don't recognize cancer for a variety of reasons normally, but we can engineer them to do so. They reflect -- they represent -- they attack different targets. So they detect cell-surface proteins. They attack these peptides in the context of HLA. And there are many more of those that are very cancer-specific, starting with the family that has been the focus of most of the activity here, which are cancer testis antigens, like MAGE-A4, NY-ESO, et cetera. And so -- and they also -- because they're a natural targeting moiety of the T-cell, they operate through normal T-cell signaling, including all of the natural co-stimulatory approaches that you have in a T-cell. And what you see when you use an engineered T-cell receptor is a very natural T-cell response, with full engagement of the T-cells, engagement of the rest of the immune system through the T-cell population, and in particular the CD4 population, and then an evolution of the population of the T-cells and the development of different phenotypes of T-cells that very much mimics a natural T-cell response. And that's the overall objective for us, is to recapitulate the natural immune response against these tumors. And that's why T-cells are the chosen approach to do it, these TCR T-cells.

Okay. Very helpful. So if we could dig in a little bit on the MAGE-A4 programs. So starting with the lead program, afami-cel, you had some data at the CTOS conference late last year from the SPEARHEAD-1 trial. About a 35% overall response rate in synovial sarcoma and myxoid/round cell liposarcoma. Just curious, how does that benchmark, that 35%, compare to the standard of care in those settings.

Thanks. So the slide that I've displayed at the moment is the data that we put out at CTOS last year by independent review and investigator review, and shows a remarkably similar waterfall with a mid-30s response, roughly 30% response rate by both assessments actually. The thing -- I think starting point to understand is that these patients are -- have very few options beyond first-line systemic chemotherapy in the metastatic setting. And they are -- however, it's a very interesting patient group because they are typically younger than many other cancer indications. And so although it's a small indication, the actual mortality and morbidity is very significant for these patients. And there have been very few treatments that have been developed recently. And those treatments that are used in the second-plus line setting are not very effective, unfortunately. The discussions that we had with the agency when we were setting the historic control benchmark, we settled on 18% as a response rate as a -- as what historic -- what other therapies' standard of care would deliver. I think it is fair to say from our perspective that, that is generous to those other therapies. So many of them have single-digit response rates. So this represents a significant step change in the opportunity to treat these patients. And I think the commentary from treating physicians around the results of this trial has been that it is a -- it's a step change. It's a -- it's something that has not been seen in their careers in terms of the opportunity for this patient group. So we're very excited about this. Yes, the majority of the patients, the vast majority of the patients achieved tumor regression. And in roughly 1/3 of the patients, those are bona fide a deep and, in many cases, durable responses, and that's a fantastic opportunity for these patients.

Can you talk a little bit about the characteristics of the patients that responded versus didn't respond in terms of prior therapies and things of that nature?

Yes. So actually, the -- we've got quite a range of patient characteristics where we've seen benefit and responses in these patients. And it's difficult to sort of identify a one thing that really moves the needle. I think this is a multifactoral discussion. And actually, we are planning on -- at the data that we put out at ASCO this year, we plan on delving into elements of that. If I could paraphrase more generally without being absolutely specific about these patients, they -- if you said what would have really -- what would I want to see in a patient that I would have a high degree of confidence would have a really good outcome from this, I think there are a number of characteristics. I -- we've not shown that actually MAGE-A4 expression is strongly correlated with response, but I would want to see a reasonably high level of MAGE-A4 expression. We've not shown that cell dose is particularly correlated with response, but I would want to see that the patient cells grew well in our manufacturing facility and, therefore, that they had a reasonable cell dose and reasonable cell doses, several billion plus cells. I would want to see that the patient is healthy. These therapies take 8, 12 weeks to embed and graft and really start to get at the tumor. And so this -- and you can see this in the waterfall and the slopes of these curves. And so patients need to be able to have good status, good functional status and be able to tolerate and survive for long enough to get the really meaningful benefits from these therapies. And then lastly, I do think that this might be linked to the stage of the disease. But we've had a lot of success with very deep, very durable responses with patients with lower levels of tumor burden. Now patients with high levels of tumor burden, we've seen remarkable regressions in individual patients. But the starting point there is often with very large tumor masses, whereas I think some of these some of these deep, durable, complete or near complete responses have been seen with patients with a lower tumor mass, still significant, but at the lower end of our range. So those are the spectrum of things that we would want to see.

What can you tell us about the durability or the persistence of the transduced cells? Have you measured that? How long do these cells exist in the patients?

So we have measured that. And yes, we've been at this for quite a while. And actually, the field has measured these. And I think the key thing to realize about a transduced T-cell is it's really a T-cell transplant. We take the patient's own cells, we engineer a new T-cell receptor into that. But there's not that much else that changes in that cell. And as such, the -- there is no really good reason why that cell would ever be rejected. Now T-cells go up and down on the basis of when they see antigen. And so you do see as the T-cells go into a patient and you see significant expansion of the cells as they see antigen over time, and then as they stop seeing antigen, either because they have eaten up the tumor or for another reason, then they drop off. But they're still present out months. And in many cases, we can follow them out for years after the patient was infused with the cells. And this replicates the work, going back to when people were looking at TCR T-cells targeting HIV in [ Belgium ] where they were able to demonstrate that 15 years after transfusion, they were still able to see T-cells -- engineered T cells in the patients. And I think this is just a function of giving a very -- it's actually a T-cell transplant, a natural T-cell transplant.

I see. Very, very helpful. So you're guiding to a BLA for afami-cel later this year. Just curious to know what are the gating factors to get that BLA filed in terms of patient follow-up and CMC requirements. As you know, we've seen some other cell therapy companies encounter delays in the BLA submission process due to manufacturing CMC. So would be curious to know where you stand on that front.

Yes. So we have made the decision really when we started as a public company that one of the key areas of investment for a cell therapy company is in the CMC space. And I want to point out that was done, not just because of the ability to deliver cells for patients and not just because of the ability to execute on things like a BLA, but also because of the importance of the manufacturing process in defining the potency of the cell product itself. And I've said before that we think that there's just as much value to be gained from epigenetic programming of the cells during manufacturing as there is biogenetic programming of the cells in the research space as anything. So this is a core competency for us, and we've been investing for over 7 years now with that in-house cell therapy, cell manufacturing for about 5 years. And we've had in-house vector manufacturing for 2 years now. And so our focus is really bearing out as we go towards this BLA. We've got this slide, which show what we've completed, which is largely clinical and preclinical, and what has yet to be completed, which is largely on the CMC side. The submission process, which we anticipate in Q4 this year will be preceded by the steps here above that, the ones that are in progress, starting with vector and T-cell product characterization, the method validation for the potency assays and other lot release assays, et cetera. There's a couple of things that we have going for us. This is not a well-trodden path. But I think our process and our -- the details of the process are more to the CAR-T manufacturer than they do to other cell therapy forms. So in terms of potency assay, we have a canonical target. We can use a cytotoxicity assay with MAGE-A4 expressing cells. For our process itself, the origins of it are not dissimilar to, for example, the Novartis' process with KYMRIAH, although there's been substantial development in both of those since then. And so there are routes that have been trodden before. The other advantage that we have is that because we've been invested in CMC for so long, every single product, every single patient in the SPEARHEAD-1 trial was manufactured in this facility that I'm sitting in at the moment. And this is the facility from which we will launch the afami-cel when it is ultimately commercialized. And so I think we're not in the situation where we have to either change process or change our facility in order to continue that -- delivering cells for patients in the commercial setting. So I feel, at the same time, this is a lot of work, and it is our first BLA. I've got a team around who have years of experience and many BLAs under their belt individually at other places. But this is Adaptimmune's first BLA. And at the moment, there are only 5 people who have proceeded with cell therapy -- successful cell therapy BLAs. And so this is, obviously, an area of critical focus for us for the remainder of this year.

And where do things stand with respect to inspection of the facility by the FDA? Has that happened yet? Or is that still pending?

That has not happened yet. That is still pending.

Okay. And then just one more sort of general question on MAGE-A4. Just curious how confident are you with respect to expression levels of MAGE-A4 across various tumors given that, as you know, for NY-ESO, the recruitment was slowed because of the prevalence being lower than it was initially envisaged.

So I think we've had experience over the last, I think, decade with the public information about expression levels being inconsistent with actual clinical experience. And so we have done quite a lot of work, including with our partner, MD Anderson Cancer Center, to try to understand the real prevalence of MAGE-A4, in particular, in real cancers, real patients with real cancer samples. And so the data that's shown on this slide, the MAGE-A4 expression data by tumor type on the -- in sort of middle of this slide, you see these percentages here ranging from 67% for synovial sarcoma, down into the high teens for others. There are other indications that are -- that will also have MAGE-A4 expression at lower levels, and there may be some others that have it at these sorts of levels. But this is what we will try to identify at this point. That expression is based off our screening experience. And so therefore, we have a lot of confidence that at the centers that we are currently enrolled out, which is a mix of North American and European centers, these are reflective of MAGE-A4 expression in these relatively late-stage patients in those centers, which is probably closely linked to our target patient population from a clinical and commercial perspective in the short term. However, it is limited by that assessment. And if we expand more broadly, it may change. This will be a Western Hemisphere-biased patient group. And we are, therefore, working on other HLAs for MAGE-A4 as we look to go out beyond Western Europe and to expand the population as a whole in order to get to this total of something like 95,000 patients that die with MAGE-A4 expression on a -- in the U.S. and Europe.

Okay. Let's talk a little bit about the next-generation MAGE-A4 program, which is the ADP-A2M4CD8. Hope I got that right.

Yes.

Can you put that initial Phase I data into context for us? I believe that you had about -- again, about a 35% ORR across a range of solid tumors. And then it seems like you've selected esophageal and ovarian to move forward. Just help us understand why you've chosen those 2.

Yes. So this is a Phase I trial, SURPASS. The Phase I trial, this is the waterfall block, the 22-page that we presented at ESMO. These are enrolling. I think it would be best to characterize them as very late stage, very heavily pretreated patients across a broad range of tumor types. So originally, all of the tumors on that slide that you saw previously. Subsequently, we've been focusing on lung, bladder, gastroesophageal, head and neck and ovarian cancers. And looking forward, the majority of the patients will be in those 5 focus indications. The interesting thing I think about these data is that we see responses across a broad range of tumors. But again, like with synovial sarcoma with the first generation, something like over 2/3 of the patients show reductions in their target lesions, so significant antitumor activity from the T-cells. And in something more than 1/3 of the patients, that translates into responses. That's across all of the tumor types that we have sufficient patients to really understand that in. And in some cases, those responses are deep responses. And in one case, we had a complete response in ovarian cancer patient that went out to 6 months. And so we are -- most of the patients enrolling in this trial have run out of other credible treatment options. So it's difficult because of the pan-tumor nature of this to give real specifics. But I think an informed listener will understand that the options for platinum-ineligible ovarian patients in the post-PARP setting are relatively few, and they're not associated with the outcomes that we've seen here. The 2 indications we decided to go forward in, gastroesophageal and ovarian, so far are different in the esophageal and EGJ cancers. We saw 5 out of 7 patients with tumor reductions. These were particularly sick patients, with 3 of these patients not surviving past 8 weeks. And so the results here are really significant for this patient group. Most of these patients are -- these patients were third, fourth or fifth line therapies. And this is a very aggressive and rapidly progressing tumor type. So we are targeting a Phase II trial, and we put the trial design out in at ASCO GI. We are seeking to take advantage of the fact that chemotherapy plus checkpoint is now first-line indicated for these patients as opposed to them getting that serially over a longer period of time. And so we're seeking basically to come behind what are the 2 effective therapies that have shown reasonable response and reasonable benefit in this setting that are now being given in combination with first line. So we anticipate enrolling a combination of second and third-line patients into the Phase II trial. And there are -- there's such a paucity of options for these patients that we've designed this trial, which we hope will be a registration-directed trial with response as an end point versus and comparison with historical controls. Ovarian is slightly different. The signal here is, I think, stronger and includes 3 patients with confirmed RECIST responses, including 1 complete response, again, out of the 7 patients that were dosed at the time of the ESMO cut. Here, we are initiating that trial or we will be initiating that trial this year, and the study design is being finalized. I think it's fair to say that this is a more competitive space with more options available for patients, although very few of them are associated with this level of activity. But we are keen to develop that in a more sophisticated fashion and probably with more sophisticated end points as well.

Okay. So it sounds like you're saying from your comments that the bar in esophageal is quite a bit lower than that in ovarian in terms of response rate that you might need for an approval. If you could, perhaps, give a little bit of context in terms of quantitative numbers on what the bar would be in esophageal as well as ovarian.

Yes. So I think what our trial -- point you to the trial design from ASCO GI as to exactly what we're trying to separate. The only thing I would say is that in the first-line setting, the combination of chemo and checkpoints in that first-line setting produced a duration of response of something like 8 months. And that's in a first-line setting in a minority of patients. And so I think that it is correct to say that the options available for EGJ patients and the benefit for those patients of existing therapies is lower. However, I'm not backing away at this point from the idea that I think cell therapy should deliver robust responses. And the overall gestalt that we've been guiding towards consistently, and I think that would be similar for that -- is similar for esophagogastric junction, is that the response rate measured in something like 3 out of 10, so 30% of patients. And something like 6 months of durability would be very robust in these late-stage patients. With respect to ovarian cancer, here, I'm going to slightly diverge a little bit and say, yes, I think response rate is important in ovarian cancer. But I also think that response rate is only ever a surrogate for other patient benefits. And I'll point you to the -- and we believe that our cell therapies will deliver, in addition to the response rate, significant benefits downstream. And I think we need to demonstrate that if we are to actually establish cell therapies as a broad modality of indications across a range of tumors. And so I'd point you to what the work that Immunocore did with a TCR bispecific recently, where against a relatively modest response rate and a very modest progression for survival benefit, they nonetheless showed a profound overall survival benefit in uveal melanoma. And so that -- I think, our focus for the development of SURPASS in some of these indications will need to move away from rank response rate and towards other, more substantial measures of benefit. Now I don't think that, that necessarily means that this becomes massively more expensive or massively more prolonged simply because the survival status and history of these patients is not great. But I do think that we've got to start to address where the real benefits will come from this therapy, which in addition to response rate, should be in prolongation of progression-free survival and overall survival.

Okay. Cool. Let's switch gears a bit and talk about manufacturing. It would be great to get a better sense as to what your current capacity is as well as what the current turnaround time, needle-to-needle, is for patients in your current process. And how are you continuing to optimize or improve the turnaround time as well as enhance the capacity?

Yes. So our current facility, above me here, can deal with clinical trial output -- level of output. We've previously characterized it as being able to get to 20 to 30 batches a month out of this facility in its current form. As I said earlier, we are investing in building out this facility, into space that we've had fallow for the last few years, whilst we've been occupying it. And then we are hoping to double or triple that capacity in order to be able to launch commercially. And then also potentially launch, at least launch the next indication or the next product commercially, too, and conduct the clinical trials. I think if we want to get to 5,000, 10,000 patients, we will need, obviously, a commercial manufacturing facility such as that, that's been put in place by those players who are slightly more advanced than us in the CAR-T space and, of course, are advanced in the tumor space. The turnaround time for patients with the current process, we feel there's a lot of smoke and mirrors associated with this. People talk about different parts of the process as their turnaround time. In building for us, so from the time that we start manufacture to the time that we finish manufacture, is either about 25 days for afami-cel or high teens, 18, 19 days for the CD8 product. That's our manufacturing process. Everything on the outside of that depends on the hospital, apheresis, availability, patient availability and has a lot more variation on it. So you can add days or weeks to the front end of that, depending on the site resources and capabilities. And then on the back end, of course, we can ship to the site very rapidly, within a day, but then the site has to schedule the patient coming in. And then the patient has to get -- and give the patient chemotherapy the week before. So there's usually a week at the back end. And so the overall process can easily be sort of 4, 6 weeks in total for any given patient. And the extent to which that is a challenge depends very much on that patient's status. We have taken a lot of steps to optimize the process ourselves in-house. So the difference in time from afami-cel to the SURPASS program represents some of the evolution of that. But also, the focus on, actually, the product release and cutting down the time frame on that through use of technologies, for example, on sterility to reduce the testing time for that and on investment in the processes, electronic batch records, et cetera, to streamline the quality processes for product release. Those are all important elements. And just to underline, this is why I think, I believe that the CMC aspects of this are so critical. And having those in-house and being able to adapt those is really important.

Got it. Now are you leveraging some of these third-party, closed systems for cell transactions, such as from Miltenyi Biotec, there is something called the CliniMACS Prodigy platform. Or are you -- do you have your own technology to do the transduction for autologous?

So there's -- I think ultimately, when the processes that we are using as an industry are reduced to transparent practices, and when the level of innovation in the process, both from a time perspective and from a cell phenotype perspective has been reduced to -- out of sort of art and into hard science that can be replicated time and time again by anybody, then I think the opportunity to use automated approaches will be really real. Up to that point, almost all of the practitioners in this space are adapting their process for both scientific and patient delivery reasons. And so our view is that we are still moving around the modules of the process and adapting and changing those modules. Obviously, not in our late stage in commercial processes, but as we do -- as we iterate the process for our earlier-stage trials. And therefore, there's more value to us in having that flexible than having it in any one given automation platform. So I think automation has an important role to play, but its real place is probably as we go forward and the processes are more robust and more standardized between products and across the industry.

Okay. And then to your point about being modular and adaptive with respect to your earlier-stage programs. So for the next-gen SPEAR T-cell program, I'm just curious to understand what's the thinking behind exposing the cells to the AKT inhibition. What is the goal there?

So one of the things that I mentioned previously was that the phenotype of the cells, defined through the manufacturing process, probably has as much to do with the success of the therapy as the genetic engineering of the cells through research and through the lentiviral insertion and any other editing techniques that you might want to make. And so we've had an ongoing program, of which the AKTi is one example, to define steps that we could take in manufacturing that would produce a different and potentially better phenotype of cells. And I think there's a number actually I -- there's a bit of research in the space. There are a number of hypotheses about the role of AKTi and exactly what that does. Our data and information suggests the most likely mechanism by which this works is that it decouples -- it effectively decouples the expansion of the cells and the growth in number from the differentiation towards a sort of terminal effector phenotype. And as such, the -- we end up with the right -- with a cell dose with sufficient numbers in, but those cells are less differentiated. And we've shown that -- a couple of consequences of this. One, we get more in vivo expansion in patients over more prolonged period of time with the product with AKT inhibitor than we do with the product without AKT inhibitor, indicating that the cells are less -- slightly less mature. And as we showed at SITC last year as well, in addition to that expansion taking longer -- and you can see that in -- when patients develop cytokine release syndrome and the growth of the cells over time. We also have a slightly different phenotype of cells as we go through the process. And in particular, there's been a lot of focus recently on the role of the -- a small subset of the cells, the stem, central memory phenotype, and more broadly, memory phenotypes. And it's our belief that the -- based on the data that we're seeing out of patients, that the AKT inhibitor, that the slightly less mature nature of the cells also results in a larger, a more persistent stem/central memory cohort of the cells in patients.

Let me just squeeze in a few questions on your earlier-stage pipeline. Could you just give us a quick update as to the partnership with GSK? And I believe there's a parent-child Phase I trial that's being run with several versions of your NY-ESO CAR-T?

Yes. So the collaboration with GSK involves NY-ESO, which is in the clinic. It involves also another target, PRAME, which is in preclinical development. And they have the rights to nominate 2 more targets in due course, based on certain circumstances. NY-ESO was, obviously, lead program before MAGE-A4, and GSK is developing both the lead program in sarcoma. But they're also developing the next-generation approaches in a broader range of tumors. And they've picked 2 tumor types, and they're developing separate next-generation programs in those 2 tumor types. And I think it's great for us to have a partner -- a large pharma partner like GSK contributing to the overall development of this space. Obviously, we'll benefit from that in terms of milestones and royalties in due course, I'm sure. But I tend to be of the view that in the cell therapy space at the moment, the rising tide lifts all boats. And so we're pleased that they remain committed to developing those.

And then you have some other next-gen MAGE-A4 programs, I believe, that are close to the clinic, but they're still preclinical. Where do those ones stand?

Yes. So there may -- the most advanced of those MAGE-A4 is shown 2 lines on the top here. It has IL-7 and CCL19 as well as the TCR in the same antiviral set. And that's a construct that we've made in collaboration with Noile-Immune, so originally their genetic construct. And they have worked in the CAR-T space as well, both themselves and with partners. And so there's a reasonable amount of preclinical evidence around this and emerging clinical evidence in due course, I'm sure. The role of this is completely different to the CD8. The CD8 approach can basically be seen as a more potent T-cell. It's a bigger stick. It is a more effective killer. And actually, we believe it's a more effective engager of the rest of the immune system as well. The IL-7/CCL19 construct is designed to get around different challenges. So IL-7 is intended for both growth expansion and persistence of the cells, and CCL19 is designed and certainly so far seems to demonstrate, at least in preclinically, that it promotes trafficking of the cells into the tumor and be able to overcome tumor microenvironment. So the combination of those is a more -- if the CD8 is a more potent cell, this is a tougher and hardier cell that's more likely to be able to persist and get to the tumor. So that's -- the other MAGE-A4 ones that we talk -- that I want to mention on this slide are the other HLAs. Because the objective is not only to develop new approaches, but also to broaden the patient population that we can get to. And at the moment, we are at about 40% to 45% of patients in the U.S. and EU have MAGE -- HLA-A2. With the addition of these 2 HLA types, we can get to about 70% of the global population that express -- these tumors that express MAGE-A4.

And then just one final question. With respect to the allogeneic pipeline -- and I believe you have partnerships with Astellas and Genentech there. Can you just give us a quick status check on those?

So the first program out of that allogeneic program into the clinic will be our MAGE-A4-targeting TCR. It's exactly the same T-cell receptor in afami-cel. This will be in a CD8 T-cell, allogeneic T-cell population, and we anticipate an IND for that next year. Behind that would become the first of our partnered programs, which is the HLA-independent TCR-targeting mesothelin. We haven't touched on HLA-independent TCRs. They're basically TCRs that attack TRuC, the target cell surface proteins, so CAR or TRuC targets. And that will go into the clinic after of the allogeneic MAGE-A4 targeting program. And then behind that is the collaboration with Genentech, which as you say, is just initiated. And that has -- that's off to a great start, and it's a longer-term program targeting some off-the-shelf targets that Genentech is going to provide us with the T-cell receptors for. And then -- but then also interestingly, a personalized cell-therapy platform, where on a patient-by-patient basis, we and Genentech will be able to select targets and TCR to go after and insert them on a patient-by-patient basis into our allogeneic cells that are ready to accept T-cell receptors that are selected on a patient-by-patient basis. So that's very exciting, if a little more long term. And so the focus, I think, from an allogeneic perspective, also is the focus for us as a company on MAGE-A4 over the short and medium term, which is the MAGE-A4 TCR going into the clinic with the IND next year.

Adrian, thank you very, very much for an insightful discussion. We look forward to the updates over the course of the year and the progress with the cell therapy pipeline. Thank you.

Thanks. Thanks. Thanks, everyone. Take care.

Bye.