Okay, well, good morning everybody, and thanks once again for joining us for the 44th annual TD Cowen Healthcare Conference. I'm Yaron Werber from the Biotech team, and it's a great pleasure to moderate this panel with Phil Nadeau and Tara Bancroft as well from the team. So we have a great list of panelists. We're going to be covering both I&I and Heme/Onc, just so you know, so it's going to be different people are going to get different questions. The I&I companies are going to get the oncology questions. The oncology companies are going to get the I&I questions. So we have with us from Allogene Therapeutics and David Chang, President, CEO, and Co-Founder, from Atara, Pascal Touchon, who's the CEO, from Cargo Therapeutics, Gina Chapman, President and CEO, from Fate Therapeutics, Scott Wolchko, President and CEO, from Nkarta, David Shook, who's the Chief Medical Officer, and from TScan Therapeutics, Deb Chattopadhyay, who is the SVP and Head of Translational Medicine. Gentlemen, thanks so much for coming. We're going to start with manufacturing. I know it's a question we've been asking every year. David, maybe we'll start with you. You're pretty late stage. What's the latest on getting production up and running early, getting enough vector, and even getting potentially third-party contract manufacturers to really have enough inventory and really slots to produce? Yeah, and great question. I mean, as many of you know, the manufacturing of the cell therapy requires many different critical reagents, and it has to be done under the GMP conditions. I think it's really critical to get a handle on manufacturing early on, and that starts with the process development and analytic assay development, as well as securing the vendors. That has to be done. I think there are two options: one company doing it internally or leveraging the external CMOs. At Allogene, we believe strongly that this is so essential for advancing the cell therapy that we have taken this in-house from the beginning, not just the process development, but also developing and building the manufacturing facility. Pascal, I mean, you're at this stage, you're in commercial, so. Yeah, I think we have a product launch in Europe right now. It's the first-ever allogeneic T-cell therapy launch in the world, and it's doing very well. But we decided initially we had some in-house manufacturing, but we decided to avoid the overhead of allogeneic manufacturing because we know that we can make inventory for our product, and we have inventory to launch the product, not in Europe as being launched now, but for next year in the U.S. So we decided to externalize manufacturing, keep the process development and process science in-house at Atara, but externalize the last step of manufacturing in selling or manufacturing units to Fujifilm Diosynth Biotechnologies, the CDMO. So they are manufacturing for us. We don't pay the overhead. We just have a 10-year agreement to access the capacity we need when we need it, so that's good for us. And then we have inventory for our product to launch commercially, as I said, doing very well for the European launch right now and to be launched in the U.S. early next year. And then, Gina, you have a CD19 CAR-T. Can you talk about your manufacturing? So we have a CD22. CD22. CAR-T cell therapy, and it's an autologous CD22. We are investing in a manufacturing strategy that ensures that we've got a commercially ready product. So we're doing that pre-pivotal so that we can quickly scale and not make changes post-pivotal, which we've learned from the CD19 CARs is really important to do. I think we have an advantage in coming after the CD19 CARs to be able to hire really talented people with best practices and learnings from that experience and then incorporate that into our strategy. We've done the process and method improvements at Cargo, but we are working with CDMOs on manufacturing. We think that the CDMOs today, as compared to when CD19 CARs are at a point now where they've got the expertise to be able to do this really well and are great partners to us. We're really excited about the future of our company with this initial asset, CD22 CAR. You have data in CD19 refractory. We have impressive data in CD19 relapse refractory patients and large B-cell lymphoma. So normally we ask all the panelists all the same questions, but we've got so much to get through. I think we're just going to ask each one of you three different, and then we'll move to the next question. So I'll move to Phil. Actually, Tara's going to go next. Okay. So can you discuss what progress has been made in understanding and addressing mechanisms of resistance? So what's the most promising technology that can address this and potentially prolong duration of response? Can we start with Scott on this from Fate? Terms of resistance for antigen escape specifically? Yeah. Increasing persistence too can be another. Sure. I think as we think about the heterogeneity that exists, especially in oncology, and acknowledging the fact that CD19 and CD20 are used early and often in treating patients, there certainly is the unfortunate opportunity for antigen escape. And so at Fate Therapeutics, we've always been advocates of you should try and build cell therapies or mechanisms of attack where you can go after more than one antigen. And so one area that we've looked at, for instance, is with NK cells. NK cells are terrific cell types that can synergize well with monoclonal antibody therapy. For instance, building CARs into cells, as an example, against CD19, as well as combining with monoclonal antibodies that are used today early and often in treating cancer patients, for instance, like rituximab to target CD20, I think is a terrific way to think about treating patients late line that may be subject to escape. How about you, David? Yeah. So I think when it comes to resistance, much like cytotoxics, it's likely to be multifactorial. I think there are some traditional mechanisms like lines of therapy, disease status, genetics, etc., that will be inescapable. But in some newer things that we're understanding now in terms of surface expression and ways to engineer around that, I think what we're certainly finding is you see a variety of modalities here that resistance to one may not be resistance to the other. And I don't think it should be considered cell therapy resistance to cell therapy resistance. I think present company excluded. I think there's some the repeat dosing of T cells has not been super effective. Trying to understand mechanisms that trigger different immune cell subsets, I think you're right that from our perspective, natural killer cells certainly use a variety of different mechanisms and aren't beholden to specific antigens. I think understanding not only the resistance on the product side, but on the patient side is important. How about you, Sri? So we have two different strategies in hematologic malignancies versus solid tumors. We call it get the cancer load down versus ganging up against the cancer. So for hematologic malignancies, we treat soon after transplantation when the disease burden is really low, and that avoids the risk of resistant clones emerging because there's a small population of malignant cells to eliminate. In solid tumors, we gang up against the cancers. So similar to what's been brought up before, we think that multiplexing on multiple antigens on different HLA types is a real solution to solid tumor heterogeneity. That's our primary approach in solid tumors. But in addition, we build in these enhancements of these cell therapy products. We add the CD8 alpha beta co-receptors so that CD4 cells can recognize tumors and produce cytokines and prolong persistence of the engineered T cells. And then we add genes that make these T cells resistant to TGF-beta, which is particularly problematic in solid tumor microenvironment. So by all of these strategies, we believe that we should be able to overcome these resistance mechanisms. Great. David and Pascal, next questions for you. It's on commercialization. Commercializing cell therapy seems to have opportunities and challenges. Opportunities are you're often treating diseases that had had no prior therapy. The challenges are manufacturing is difficult, and these tend to be expensive. You both have experience in commercializing therapy, so we want to hear your thoughts on both those opportunities and challenges. David, maybe we'll. Yeah. I think when you think about and how the question is phrased, I mean, the challenges, I mean, whenever something new is happening, it comes across as a challenge, but we see it as an opportunity. And time after time, it has shown that when you take this kind of challenges and address those issues, that's where the innovation occurs and that's where the opportunity gets created. So we have been developing allogeneic CAR-T, and much of our early days was spending on demonstrating the allogeneic platform. And recently, we have taken a little bit different tack. And this is rather than just following what the autologous CD19 CAR-T has been doing in a non-Hodgkin lymphoma in the third-line setting. And actually, we were doing a study. We pivoted into the front line. What enabled us to do that was, one, we knew that we had highly effective treatment, that cema-cel, our ALLO-501A program, that has shown the response rate, complete response rate, as well as a duration of response in the third-line setting. Matching that together with a new approach of being able to select the patients based on the MRD assay. Now we are about to start a front-line study that we call ALPHA3 or the front-line consolidation. The objective of the study is really to increase the cure rate in patients who are not sufficiently addressed with the current chemoimmunotherapy, R-CHOP, or Pola-R-CHP. Essentially, we allow the patient to undergo front-line treatment. At the end of the front-line treatment, these patients will just go into the observation. Unfortunately, about 1/3 of those patients will recur. Working together with our diagnostic partner, we are using an MRD assay that will identify those patients who are likely to progress and then randomizing those patients to what would be a standard care, which is observation versus CAR-T. So this is really a very innovative approach of moving the therapy to the earlier line as quickly as possible and also trying to capture as many patients. So I think this kind of innovation, rather than viewing as a challenge, is what's really going to create the market. And if we look at the market opportunities that we can potentially create by advancing the CAR-T to the front line, this far surpasses. I mean, it's probably too early to talk about the estimate of a market opportunity, but the number of patients that we can capture with the front-line consolidation far exceeds the number of patients in either second or the third line. So I think when advancing a new modality, I mean, it's always looking for differentiation and innovation. I think that's going to be the key. And then obviously, when the commercial time comes, the differentiation is going to be another key feature. Yeah. And I agree with that. I think back seven years ago, when the first CAR-T were being launched and I was part of that journey, there were three key issues. One was pricing because it was a one-off therapy and many pricing systems were not used to one-off therapy. The second one was the fact that you needed to certify and train the site. So there were a limited number of sites that could treat patients. And the third one was manufacturing. The third one is still a major issue today. The first two have been addressed in different ways. Now, the development of allogeneic T-cell therapy allows to answer the three of them. Pricing is fine. In Europe now, we have even a better rating than the autologous CAR-T in terms of pricing because the systems are being used to this type of one-off therapy. In terms of the site, we have with our allogeneic T-cell, with Ebvalo and the new product we are developing, there is no need to train and certify the sites. Patients can be treated in outpatient clinic. That changed a lot the ability to access more patient population there. I see that as a possibility also with our allogeneic CD19 CAR-T, and I'll come back to that in a minute. Manufacturing has been the key issue and still is the key issue when you hear from J&J, from Novartis, from Yescarta. They still have some challenges in addressing the need of the patient because of their manufacturing constraint. That's where allogeneic is making a huge difference because you have inventory available. So we don't have any problem to treat patients. We can ship within 3 days the product to the site, and within 3 days, the patient is being treated. So that makes a big difference. And that's the only way, I believe, for cell therapy to go to autoimmune disease where the number of patients to be treated is going to be very, very significant. And here we have the possibility to have inventory ready for use at the time of the need. I was going to maybe shift to an I&I question, and I think it's probably relevant right now to Fate and Nkarta. I'm not sure if, as far as I know, you haven't announced plans to go into I&I as far as. No, we discovered. You have. So please chime in. Please chime in as well. What do you think is going to be the single most important driver of durability? And when we look at some of the data from bone marrow transplants, admittedly, right, not from engineered cells, the role of consolidation makes a big or myeloablation initially makes a big difference long term. So can you address both points? We can start with you, Dave. When it comes to I&I specifically? For I&I, yeah. Yeah. So the bone marrow transplant experience, I'll start with that. I think that's what I'm most familiar with. I still have the privilege of doing that as a second job. And I think historically, what we've seen for at least in autoimmune diseases is that the intensity of myeloablation or conditioning regimen hasn't necessarily correlated with better outcomes. And, spoken in a different way, you can actually get to cures with less intense chemotherapy up front. And it varies across diseases, it's for sure. And some diseases are more amenable to transplant than others. And I think in terms of drivers of durability of response and consolidation, I think one of the most exciting things that has occurred for us is really the breaking down of this long-held narrative that cell persistence is the same as durable response and that somehow you need long-term persistence for durable response. I think the Erlangen data in autoimmune disease, so the CD19 CAR-T effectiveness in autoimmune disease, particularly lupus nephritis, and to lesser extent, systemic sclerosis, has really shown that persistence really isn't necessary. You can see that autologous CAR-T in autoimmune disease is not the same as CAR-T in oncology. Instead of 18 months of persistence, you have a few weeks of persistence. And instead of 18 months of B-cell aplasia, you have a couple of months of B-cell aplasia. And for us, that was most informative because the response data was compelling, for sure. But the lost in that is the PK of those. And I think that if there has been a historical knock-on in NK cells, it's been, well, how can you have a durable response if you don't have persistent cells, right? What we can do is now look at the data and say now, not just in the initial Erlangen set, but in the follow-up set presented at ASH, really nobody has long-term persistence. And the idea that you can get in to get a deep immune reset without long-term immune suppression, without interruption of long-term vaccine immunity, disease immunity that is helpful, right? I think the adding on of additional targets, etc., may add deeper reset, but so far you're looking at 100% response, near total response with long durability with a short-term immune reset. So what's going to drive that durability? One, it's not going to be persistence. I think it's going to we're going to have to make sure that we're going to get adequate depth. And I don't think anybody's defined what that depth is going to be. I would agree with the points here in terms of differentiation and learning from the bone marrow transplant literature. More chemo is not the answer. In terms of accessibility, what's going to really drive these kinds of cell therapies? The next generation get into clinics, get into the outpatient setting. It's going to be less chemotherapy. It's going to be making this more accessible. As the diseases become less morbid and we say, "Yeah, this is going to cure autoimmune disease," well, it's different than saying chemotherapy with cyclophosphamide and fludarabine sort of typical approach is fine if you're weighing that against dialysis or life-threatening diseases. As you expand into other diseases, that's going to become a far less compelling narrative. We're really interested in disease-tailored lymphodepletion and how we can deliver safe and accessible cell therapies in I&I. So durability yet to come, but it's clear it's going to be driven by immune reset and not sort of long-term persistence, at least in I&I. Yeah. Scott, what do you think? I think I agree with all that. I think it was well-stated. I think if you think about what's been done today so far and the results have been remarkable in small numbers of patients in autoimmunity, the patients today, for the most part, have been treated like oncology patients. I mean, we've taken patients that have severe autoimmune diseases, without a doubt, but undergo leukapheresis, undergo Cy/Flu conditioning, hospitalize patients. The vast majority of autoimmunity patients cannot be treated that way. We can't treat oncology patients that way today in the way that those patients deserve to be treated. I mean, there's some real logistical challenges here with trying to treat an autoimmune patient like an oncology patient. So from my perspective, I totally agree. We have to figure out how to reach autoimmune patients where they live and breathe. It's not an academic medical center. It's not with Cy/Flu conditioning. I think the real important trigger here is going to be, can you reach those patients? Can you reach those patients with friendlier regimens? And can you deliver an immune reset in a large number of those patients? I think what's been shown to date that may be differentiated with cell therapies as opposed to the monoclonal antibodies is the cell therapies up here, at least CAR-T cells today have been shown to be able to access bad-acting cells, B cells that are sort of hiding or sitting in secondary tertiary tissues. And I think that's what's been unique, the unique observation about those cell therapies, is they've been able to reach those bad-acting cells that are not sitting in the blood and that that has contributed to the immune reset. Yeah. We have experience with that. I fully agree with what you say because we have treated already more than 600 patients in different settings with our two allogeneic EBV-T cell product, including 130 with progressive MS. We've been able to treat these patients without lymphodepletion in outpatient clinic, treated by neurologists. It's very similar to what we now want to do in other types of autoimmune disease. We are bringing our allogeneic EBV-CD19 CAR-T to the clinic. We just cleared the IND for lupus recently. We know that we have the possibility of that type of product to allow patients to be treated in outpatient clinic, hopefully without lymphodepletion in the future because that will be the possibility to really address the need in a more adapted way to the way the patients are being presenting themselves in these types of settings. Having all that clinical and safety experience because the chassis, if I may say, for allogeneic CAR-T is these allogeneic EBV-T cells. We have treated all of these patients. We know how to treat them safely. And with repeat administration for some of them, all that is going to be very helpful to address the need in autoimmunity. Maybe I can just add a quick word that we haven't talked publicly about our plans in autoimmune diseases, but what we have talked about is expansion opportunities from the products that we are testing in heme malignancies. And that's where I would just add that I think what's very clear is the unmet need in autoimmunities being chemo-free, being able to get rid of these myeloablative conditionings. And our TCRT products have the ability to achieve that because they target all hematologic cells, whether they are stem cells, B cells, T cells, or myeloid cells. And so it can create that reset by essentially enabling myeloablation without the use of chemotherapy and allowing that immune reset to occur. So that's the expansion opportunity. All right. I think we're going to switch to company-specific questions now. We have a lot of you guys to get through with lots of exciting things. So I guess we could start on the end with David. So you already mentioned your recent pivot to the frontline strategy, which is a really interesting approach, especially at this juncture. So if you want to add anything to what you already previously said on that, but I think it would also be good to set some context with if there's any precedent for treating MRD-negative patients after CHOP. Are there any other trials we can learn from, like ZUMA-12, for instance? Yeah. I mean, in the hematologic malignancies, the concept of MRD positivity is pretty well embedded. So in leukemia, in other settings, the concept of consolidation based on MRD positivity has been used. And frankly, Blincyto, CD19 bispecific antibodies, are proof for the MRD positive indication. What is sort of still a growing advancement in the non-Hodgkin format was such MRD testing was not readily available. Now, for you to use the MRD as a basis to make a treatment decision, it has to come with the assay sensitivity and the specificity. So in fact, at Allogene, we've been looking for opportunity to move to the earlier line, whether it was a second line or even the front line for quite some time. And also, as we were doing that, this is a quite challenging situation as the field was getting very crowded. Autologous CAR-T products were getting approved in the second line setting. So what really enabled us to make this pivot is the progress that was being made in the MRD space. Our head of R&D, Zach Roberts, who was sitting in the audience when C joined, he really spearheaded our effort to advance the concept of MRD into the frontline setting. Essentially, this is a very elegant concept because at the end, what you can achieve is providing the CAR-T therapy with the intent of improving the cure rate only in patients who need the treatment. R-CHOP or Pola-R-CHP is very effective. If he was simply trying to improve above that by adding onto it or trying to replace it, that's almost insurmountable. What the assay allows us to do is identify those patients, and we are just targeting those patients. The goal is already about 60% of the patients with the non-Hodgkin lymphoma, large B-cell lymphoma, can be cured with R-CHOP. With our consolidation approach, we are trying to improve this even further. Okay. Thanks. Pascal, we'll go to you next. Atara has announced a number of IND filings for the CD19 CAR-T program. For those less familiar, can you provide a background on how your CD19 CAR-T could be differentiated and what your strategy is for development, both in oncology as well as in I&I? Yeah, certainly. I mean, we have a very unique and differentiated allogeneic CD19 CAR-T in the sense that we use, as I call, the chassis like a car. The chassis is the allogeneic EBV-T cells. That is really the backbone of our platform where we know how to make that. We know how to get that full regulatory process as we have the first product approved, Ebvalo, which is an allogeneic EBV-T cells for PTLD. Now, we use that chassis, and then we insert a car. But we do that in a very unique and differentiated way in a sense that we are doing three things. We keep the TCR, the endogenous TCR, and the MHC, which we believe and has been proven by a number of clinical studies is enabling more persistence of the cells. You have more of a signaling for persistence there, and you keep the natural biology of the T-cells. The second thing is that we use a new co-stimulatory domain called 1XX because there are two mutations in CD3 zeta. And that co-stimulatory domain that was invented by Michel Sadelain, MSKCC, is enabling a more physiological type of stimulation. So you have less T-cell exhaustion. You have more persistence of the cells, and you have less stimulation of cytokine. And that's much better. And that's been proven in a clinic by a study done by MSKCC on an autologous CAR-T to lead to a lot of efficacy with just 25 million cells per patient, so 10 x less than the typical autologous CAR-T. So that's the co-stimulatory domain we're using in our product. And then third, we are also manufacturing this allogeneic CAR-T in a way that preserves a very non-differentiated phenotype, especially central memory cells and memory cells that allows to have also more persistent, better expansion, and potentially better safety as well. So these three features, maintaining the TCR, having this co-stimulatory domain, and having a memory phenotype, are really the key features of differentiation of our product. And each of these features have been used independently in a clinic by other teams, leading to better results than autologous CAR-T, CD19 CAR-T. Here, we are putting the three in one product. That's why we believe it could really create a best-in-class type of approach. We have already cleared last year the IND for lymphoma, and we are enrolling patients as we speak. And then we have just cleared the IND for lupus. We're going to start the study over the next few months. We're very excited to see in a clinic the type of differentiation that we've seen already with some of these features being used independently. Can you remind us when we could see the first data from the two programs or the two trials? For lymphoma, it will be in the next few months, in the second part of the year. And for lupus, we expect the first data to be in first half of 2025. All right. Next to Gina. So for those who are less familiar with Cargo, I thought maybe you could start with how Cargo was founded and the specific attributes of your lead program, CRG-022, that led to the frankly very impressive data that you have so far. And why others historically have been unable to successfully target CD22? Okay. Well, thanks for the question about the founding of Cargo because I think it's a fun story. So CD22 antigen was being targeted by NCI with CRG-022. And Dr. Crystal Mackall is one of our founders and just known, I think, worldwide as a real leader and pioneer in this space, was one of the co-inventors of CRG-022 while she was there. And that was being developed for B-ALL. And I think that at that time, the focus in large B-cell lymphoma was on CD19 antigen. And she brought the construct over to Stanford. And there were patients at this point in time who were being treated with CD19 CARs. And I think she foresaw that there was going to be a growing population of patients with very high unmet need. About 60% of patients are relapsed or refractory to CD19 CARs. The CD19 CARs were being adopted because for some patients, this is potentially curative and very transformative. So she saw that this was going to grow and that this unmet need was going to be quite high and started developing CRG-022 in large B-cell lymphoma. And what we know today, Cargo was founded in February of 2021 based on this, as well as we in-license some platform technologies as well that allow us to basically engineer and develop and deliver more complex CARs to really address multiple mechanisms of resistance, which others spoke about earlier. But with CRG-022, Stanford's data has been impressive. 38 patients have been treated to date. And the overall response rate is 68%. And the complete response rate is 53%. Only 4 out of the 20 patients have relapsed so far, so 16 have not. That's with a median follow-up with our dose that we're taking into phase II of over 27 months. So it is very impressive, especially when you think about the fact that these patients have already received CD19 CAR in earlier line of therapy. The patients in this study at Stanford, the 38 patients, are about a decade older than the patients who were treated in the CD19 CAR initial trials. They also, I think, really interestingly, about 30% of these patients were refractory to all previous lines of therapy. So it's a really high bar for this study to show results. And this is the one that really caught my attention. 84% of patients have high LDH. That's a marker of tumor burden. And in those patients with high LDH, that's a very strong poor prognostic factor for overall response rate and durability. So when you see these responses that look very similar to what you see in CD19 CAR, it's obviously got my attention. It got the attention of a lot of people. And we're now in our potentially pivotal phase II study. We started that last year. Last year was a very big year and busy year for us. We dosed the first patient in September. I announced at JPMorgan that we had 9 patients dosed. And in early January, we had, I think it was 14 sites that were activated and recruiting. And now we're at 20. So I'm also just incredibly proud of how the team is executing last year and this year. So why wasn't CD22 targeted before? There were some assets there, but they were, I think, deprioritized as the CD19s were developed. I can't really answer why that was. I think Crystal, again, was a visionary when she said, "Hey, let's try this in large B-cell lymphoma." I think it had been, in a way, niched as a B-ALL drug by NCI. And so we're just really fortunate that she had that forethought. There's definitely something there, in my opinion. All right. Scott, next. So Fate has been pretty deep in the scientific trenches and developing this next wave of pipeline candidates. So I thought you could highlight some of you have a lot of interesting new edits that you're making. And I thought if you could highlight some of those different edits that you're engineering and where you're at with each of your clinical candidates that are progressing through phase I right now. Sure. I'll try and keep this brief. So a couple different, and you're right. I think one of the unique things about what we do is we edit, not for instance, an NK cell or a T cell, but we edit an induced pluripotent stem cell, fully characterize that, and use that essentially as a master cell bank to create an NK cell or a T cell. And so we are able to do multiplexed engineering. We do it at an iPSC level. It gives us an opportunity to test a lot of different edits and fully characterize those engineering events. I think as we think about the spaces like hematologic malignancies and autoimmunity, some of the edits that we are focused on are, for instance, as the panel has discussed, how do you begin to move away from conditioning chemotherapy? And so we have an NK cell program called 522. That program is CD19 targeted. It has five edits. One of the important edits in that is actually a second CAR that targets 4-1BB. So we have a second CAR. And 4-1BB is often expressed on, for instance, patient immune cells. And so the idea is you can give 522, as an example, in the background of a fully functional, competent immune system. No need to give Cy/Flu conditioning. And ideally, you wouldn't want to give Cy/Flu conditioning to patients if you wanted to treat them, for instance, in early line, whether it be oncology or autoimmunity. And so in targeting 4-1BB with a CAR construct, we've actually found preclinically that 522 actually now synergizes with the patient's background immune system. It can cause an NK cell to continue to proliferate, extend its persistence, and bring just greater potency to the NK cell by being activated through a second CAR. We think that's really important, especially as we think about the world of autoimmunity. How do you continue to bring cell therapies to patients outside of an academic medical center and move away from Cy/Flu conditioning? So we should have first initial data on FT522 without conditioning chemotherapy in the second half of this year. As we look at solid tumors, solid tumors is now a whole new world of challenges that exist. You're talking about, for instance, a really sort of aggressive tumor-suppressive microenvironment. You're talking about T cells or NK cells needing to find their target that are not sitting in the blood. You need to figure out how you can infiltrate that tumor. And so on the solid tumor side, we have focused to date mostly on T cells. We've engineered in multiple different novel mechanisms to address some of these challenges, specifically in solid tumors like homing. So for instance, we have a synthetic CXCR2 receptor, which will allow the cell to home better to the tumor. We've also engineered in, which essentially is a TGF-beta redirector receptor. So it takes actually an immunosuppressive signal in the microenvironment and turns it into an activating signal, which can cause the cell in the microenvironment to ratchet up its potency and infiltration potential. That's been a product that we've been developing for years preclinically with Ono called FT825. And we're now starting to generate clinical data with FT825 in the solid tumor setting. I think lastly, I think what we're excited about as we think about the world of solid tumors, and you've touched on this, is how do you overcome resistance mechanisms, especially in solid tumors, and target more than one antigen? So with FT825 as an example, we've also added a piece of what you might consider innate NK cell biology, a CD16 receptor, and now added that into a T cell backbone. So we have a CAR T cell that has these interesting mechanisms to specifically address solid tumors, but have also added a CD16 receptor so that this cell could potentially be delivered with a monoclonal antibody and target more than one antigen. Thanks. David, let's maybe pick up on some of your earlier comments. I think the IND is cleared now for the autoimmune disease study. The first patient is going to get enrolled. I believe it's going to be Lupus Nephritis, right, in the first half of this year. As you think about the protocol, what are the key biomarkers that you're going to be watching for in terms of long-term durability, long-term response? And then secondly, can you talk a little bit about what is the conditioning that you're going to be using? Yeah. And I think they go together. And I think we're excited about delivering patients treatments now effectively, accessibly. And I think we're the only ones that are going out in a cyclophosphamide-only conditioning right away in lupus nephritis. And we do that by exploiting NK cell biology. We know that the PK, as I mentioned before, is vastly different than T cells, where it's a delayed expansion, sort of confuses up therapeutic dose, weight expansion. NK cells come in active, never more active than they are on day zero. And so the lymphodepletion window that we have to create is much smaller and allows us to spare fludarabine in those patients that don't need it. We've sort of pioneered this disease-tailored lymphodepletion that really exploits NK cell biology. And we think gives us a real advantage not only for safety, accessibility, but also regulatory advantage as well. This is an ATA therapy, ATA dose that's used in the rheumatology field so that we know we have historical controls that we can use and we think have read-through as we don't feel like we'll have to necessarily tease out contribution of effect quite as much. And so we'll be leading with that. I think fludarabine is active in NHL. We have it as part of our NHL platform. It's active in AML. We have it as part of our AML platform. In autoimmune disease, as we mentioned, as those diseases get less morbid, as we've talked let's talk about expanding to other indications, and we certainly will. The idea of exposing patients to genotoxic medicines like fludarabine is just, I think, becomes insurmountable. And fludarabine really provides some benefits that NK cells don't need. The long-term immune suppression I mentioned, the elimination of cytokine sink, the proliferation of T cells, all of Nkarta cells are cytokine-independent. They come pre-engineered with membrane-bound IL-15. And they're a healthy donor source. They are sort of ready to be delivered. And I think we think in a regulatory-friendly way. In terms of biomarkers, as you mentioned, we announced that we'll have first patient in the first half of this year. And we're well on track for that. I think some of the advantages that I spoke of are really aiding our site activation and enthusiasm among investigators. And it's likely that the data that follows will be somewhat iterative. I think everybody's excited to see the kind of PK that we can generate with cyclophosphamide-only conditioning. We are certainly enthusiastic to share those data. And the subsequent B-cell suppression, as I mentioned, the characteristics of what adequate B-cell suppression looks like in autoimmune disease is likely to be far less than is historically seen in NHL. I think this is, again, having to avoid the square peg round hole oncology, autoimmune disease. So the data will come in iteratively. We'll look at PK/PD. We'll look at B-cell suppression, autoantibody suppression, and then subsequent clinical findings as well, like renal function, disease status. And then obviously, where we all want to get to is to drug-free remissions. The dosing scheme would learn from the AML and NHL experience in general? It's going to be a totally different dosing scheme with even lower doses? No. So the advantage of this not being a first-in-human product is we've used this for dozens of patients in NHL. And so in our conversations with the agency, we were able to start at a therapeutic dose right away. And so we are excited to come out dosing at a level that we've seen consistent responses in NHL and in a similar dosing scheme. Now, we have always done sort of a 3-dose regimen of once weekly for 07 and 14 or 3 doses in 2 weeks. And the NHL side, we've moved that into a single week to try and optimize that PK window. I think that has an opportunity to be a platform modification. But yeah. Right now, what we'll be doing is leveraging the safety experience from our initial study in the same drug that, again, has allowed us to have very open and effective conversations with the agency about what we hope to do with this drug and have to be able to use a safety database that is now several years old. All right. Sri, we'll go to you next. So TScan takes a unique approach relative to traditional TCR. So I was hoping you could tell us more about the TargetScan and ReceptorScan platforms, what's special about them, and how do you adapt to different HLA subtypes? Great. Yeah. Thank you. So we have two technologies, as you mentioned. It's called TargetScan and ReceptorScan. But the purpose of both those technologies is to find therapeutic T-cell receptors that are anti-tumor, potent, and selective. But we do it with two different approaches. For TargetScan, we start with T cells that have known anti-tumor activity, but we don't know what antigens they recognize. So we take T cells from checkpoint immunotherapy responders, and then we run them across a genome-wide screen where there are more than 1 million possible peptides. And we fish out the exact antigen that that particular T cell recognizes. And so that was the foundational technology of TScan. And that was the basis of the first two therapeutic TCRs that we filed INDs on in the solid-tumor program. Both of them recognized cancer-testis antigens called MAGE-A1 but on two new HLA types. So that was TScan. And then for known antigens, when the antigen is well established and validated, we start with the antigen. And then we discover the right T-cell receptors for those antigens. And that's where we use Receptor Scan by screening billions of healthy donor-derived T cells to find those rare, naturally occurring T-cell receptors that have high affinity, high selectivity for those target antigens. So that's what we did with PRAME and with HPV16. And that's how we filed INDs on those. The key advantage of our approaches is that we use naturally occurring T-cell receptors. We don't need to mutate those T-cell receptors to make them even more potent for their targets. And they're post-thymically selected. So they're naturally very selective. But we also run them across the genome-wide screen. So we know that they're very selective. And because they're naturally occurring, the time for discovery to IND filing is really short. And so we've been, in the last 2.5 years, able to successfully clear 6 TCR-Ts in the solid tumor program and 2 TCR-Ts in the heme malignancy program for a total of about 8. We're on track to adding 2-3 more by the end of this year. So we're really accelerating the pace of therapeutic T cell receptor discovery using these two approaches. And we believe that that would be required to overcome the heterogeneity of cancer. Okay. We have time for everyone to go again, but we're going to switch it up and go this way. So we're going to stick with you. Can you remind the room that the data that TScan presented last week and looking ahead as we think about potential durability, you referenced this ACROBAT trial. And how would you say that that increases your confidence in long-term durability? And really, the question is, how long or how durable do you think it potentially can be, TSC-100 and TSC-101? Yeah. So thanks for that. So we're really excited about our initial phase I data on the heme malignancy program. Now, just for the rest of the panel, we're addressing AML, MDS, and ALL, where CAR Ts have really not proven much benefit because of the difficulty finding antigens that are highly expressed in these myeloid malignancies that spare normal myeloid cells like neutrophils, for example. And so there, these cancers are treated with an allogeneic hematopoietic cell transplant. But the big unmet need post-transplant is relapse after transplant, where there's a 90% mortality if they relapse after transplant. So this is where we exploit these antigenic differences between patient blood cells and donor blood cells so that you can selectively target all patient-derived blood cells, whether they're malignant, premalignant, or benign, and spare all healthy donor-derived blood cells, whether they're myeloid or otherwise. A key biomarker that can be used post-transplant to measure success of the transplant is called chimerism. That's where we saw the greatest differences in our initial study. Chimerism measures any residual recipient blood cells or patient-derived blood cells. We use a very high-sensitivity next-gen sequencing assay that's developed by a company called CareDx. Using that assay, and it's a lot like MRD for lymphoid malignancies, we found that all 14 patients that were enrolled in our study had mixed chimerism post-transplant. We are using a type of transplant called reduced-intensity conditioning, which does not fully eliminate patient blood cells. So this was not unexpected. There was a big difference between 6 patients in the control arm and 8 patients in the treatment arms. In the treatment arms, all 8 treated patients achieved complete donor chimerism in all blood cell subsets that lasted for up to a year post-transplant for the longest follow-up. In the control arm, only 2 patients achieved complete donor chimerism out of 6. And out of those 4 that had mixed donor chimerism, 3 ran into trouble. 2 had a frank clinical relapse post-transplant. One of them, unfortunately, passed away 9 months after transplant. And a third control arm patient required a clinical intervention because of worsening mixed chimerism that was concerning for impending relapse. None of this happened on the treatment arms. So the big question that we were faced with is, what is the prognostic significance of having complete donor chimerism? So that's where we collaborated with this company, CareDx, that's developing the high-sensitivity chimerism assay. They have a separate prospective clinical trial called the ACROBAT study that they fully enrolled 307 patients and are studying chimerism post-transplant across all kinds of different transplants. They released their initial data last month with us at the Tandem meeting. In the first 139 evaluable patients, they found that of the 50 patients who had achieved complete donor chimerism just spontaneously through transplantation, there was only one relapse after median follow-up of about a year. So that really solidifies the prognostic significance of achieving a complete donor chimerism and maintaining complete donor chimerism, which all eight of our treatment arm patients have achieved. So we're really encouraged by that. We believe that based on this, the patients who are treated with TSC-100 and TSC-101 are likely to have a large effect size in comparison to the control arm. That's where we plan to have regulatory discussions. David, I want to ask about immune reset. What's really known biologically as to what's happening? After the initial depletion of B cells, is that the pathogenic clone or subpopulation doesn't repopulate? Or is it that the relationship between the B cell and the rest of the immune system changes? Then I have a follow-up on double-stranded DNA antibodies or antibodies. Bringing that heat? Yeah. Well, I think when it comes to immune reset, I think what the field has largely done is look at therapeutic outcomes, look at the associated dataset, and sort of reverse engineer what's happening, right? I don't think necessarily everybody's saying, "We need an immune reset. We generate an immune reset." And the clinical data happens. It's like, "We give this intervention. They get better. And so what's happening?" It's clear that the reset, at least when it comes to the autoantibody-driven immune-mediated diseases like lupus, lupus nephritis, scleroderma, etc., those autoantibody-generating cells, which are generally the CD20-negative, CD19-positive plasmablasts, are being, if not eliminated, certainly reduced, right? I think one thing that we can know from transplant and mixed chimerism and other interventions and even the natural history of lupus is that it's not a disease that sort of takes off and stays up. It kind of waxes and wanes. It's a disease of flares and remissions. And so we know that it's not so much an eradication of B cells. And we see that in the sort of early CAR T for autoimmune data is because the cells are coming back within 45, 50 days. So we're not talking about complete ablation and retention of long-term immune response. So there's a lot of discussions about different targets, whether or not you can add BCMA to knock out the long-term plasma cells, etc. Right now, it appears that at least in autoantibody-driven immune-mediated diseases, CD19 seems to be the right target, right? Whatever that elimination is, whatever that reset is occurring, we know that those cells are coming back with a more non-class switch phenotype, a more naive B cell. That makes sense, right? I think biologically, everybody looks at the totality of the data. Even the Schett-Erlangen data sort of did those as proof that their drug was working, right? It was they gave an intervention. The patients had drug-free remission and said, "What's happening?" Right? So it went back, looked at the translational data. I think that's important. It makes sense that you're sort of taking back to the initial, almost post-transplant phenotype of having naive B cells where you can then it can be reeducated because, again, lupus is a predisposition, but it's not an inherited condition. So you can have identical twins that one have really severe autoimmune disease and the other be totally unaffected. And so somewhere along the line, either infection or cryptic antigen or something, something goes haywire and that B cell is set off. And that ebbs and flows. And I think in the concept of immune reset is at least to drive that inappropriate immune response down adequately to let the rest of the immune system kick in because, as I said, in therapies, it's not as if you have to be on immune suppression all the time. It's when you have these flares, you get to the point where you get the and that appears to be what's happening. So that's a long way of saying targeting the autoantibody-producing cells seems to be appropriate. And even in the short term of driving those down will lead to long-term responses. Okay, Scott. So I imagine you probably get the question a lot of, "When are we going to see multiple myeloma data?" And it is fine if you'd like to answer that. But I do want to focus on the newer pipeline programs because I think those are very, very exciting. And so FT825, you mentioned that in your opening. And I think that one's really interesting. It has those seven synthetic elements. So at a high level, can you talk about where you would expect this to fit in among other HER2-targeting products that are in the market? And now that you say that it's enrolling, when could we see data for that? Sure. So yeah, FT825 is a CAR T cell has 7 different edits in it with lots of different synthetic biology designed to try and overcome some of the unique challenges that exist with solid tumors that, for the most part, cell therapies have not been able to adequately address to date. I think as we look at FT825, I think one of the unique features of it is it's a cell therapy that has a CAR that targets HER2. Most of the HER2-targeting agents that exist today use a binder that is similar to what's used in Herceptin and is the trastuzumab binder. I think what's unique and exciting about this product candidate is the binder that we're utilizing is novel in targeting HER2. So it targets a novel epitope. Can't take credit for developing it. Ono, our collaborator, developed this binder. And what we've seen really that's interesting with this binder developed by Ono and incorporated into the product candidate is really two different features that we're excited about specifically. Number one, given that it targets a novel epitope, we've seen differentiated activity compared to trastuzumab. So for instance, we have much greater activity in targeting tumors that have low HER2 expression. And so we think that provides a whole new world of opportunity to address other solid tumors that have not traditionally been targeted with, for instance, trastuzumab. So you can get well beyond breast cancer and start thinking about other types of solid tumors where HER2 expression is low and there is significant need. Obviously, we also include a CD16 receptor in that. So you can couple that and target a second antigen if you'd like to do so. Additionally, I think what we're excited about also is that because this is a novel binder and one of the development strategies with this binder was there's toxicity associated with HER2. HER2 is expressed on healthy tissue. And so in designing this binder specifically, there was an effort to move away from targeting the healthy tissue and specifically coming up with a cancer-specific way to target HER2. And that's also been incorporated in the binder. So as we think about FT825 and moving into solid tumors where I think there is a real opportunity for cell therapies, especially multiplexed-engineered cell therapies, and we think specifically in targeting HER2, very excited about low expression of HER2 and how the cell therapy can be differentiated in that area and moving away from some of the toxicities that have been seen both with monoclonal antibody as well as historically with some cell therapies that have tried to target HER2. Great. Okay, so Gina, can you give us a status update on enrollment in the potentially pivotal phase II trial for CRG-022? And based on that, if you're able to tell us whether initial data could come in the first or second half of 2025? And from that, do you think that you would be able to file for approval based on that top-line dataset? Or how much durability would you think that you need for that? Yeah. Okay. So thanks for those questions. I think I'll just repeat what I said before about CRG-022 in terms of the enrollment. I announced in early January that we had enrolled nine patients. We started enrolling. Our first patient was dosed in September of last year. And we're excited because we now have 19 sites up and activated to recruit patients. So the momentum is great and the demand has been great for the product. So very excited. That means that I sort of narrowed the time period when I would expect to see top-line results to first half of 2025. We're also excited because we're executing at the same time on CRG-023. And I don't think you've asked me about that, but I'm going to take this opportunity to share some more about that program. That's in IND-enabling studies. What's really interesting there and I think a lot of us talked about this need to engineer more complex CARs, multiplexed CARs, and target multiple antigens to address mechanisms of resistance. That's what our CRG-023 does. This is a tricistronic. We went through nearly two years of a pretty extensive campaign to look for new binders. There's three distinct CARs: CD19, CD20, and CD22. CD19 and CD20 are new binders. Then we've also optimized ordering of these. We did try to find a better binder and construct than CRG-022 and didn't. We're using that same binder in this bicistronic. Then we also have a CD2 co-stimulatory domain, which is another proprietary technology that we have as a platform. That addresses CD58 loss, another mechanism of resistance in large B-cell lymphoma, also other B-cell malignancies, and some solid tumors. We've pulled all that together. We're hoping and looking forward to announcing an IND submission in the future. Pascal, we'll go to you. Despite what the countdown clock says, we do have another six or seven minutes. Pascal, could you give us a brief update on where tab-cel is in the U.S. regulatory process, your alignment with the FDA, and give us Atara's most recent assessment of the market opportunity in both the U.S. and Europe? No, thank you. I think it was great that we reached alignment with the FDA on all the CMC remaining questions. So the field is clear on that front for the BLA filing. We are on track to file the BLA for tab-cel in the U.S. in our first indication, which is second-line PTLD in Q2 of this year. We have a commercial partner that is ready and getting ready to launch. It was just announced a few days ago. And that's Pierre Fabre, the French company that they have hired. A very experienced commercial leader was the GM for Kite in the U.S. And she is now recruiting the team to launch the product. We've done so much work to prepare ourselves for the future commercialization of tab-cel in the U.S. that we know that about 70 sites in the U.S. have already tested the product, have already treated patients. And so the efficacy of the product, we have already worked on pricing. We know that the product is already listed in DRG18, even though it's not yet filed. We also know that the awareness is very high. Most of these physicians know very well the unique features of tab-cel, which we confirmed recently in the new data cut of our pivotal study that we're going to file in Q2, which is 49% objective response rate, and duration of response, and overall safety assessment as well as the median OS that are very consistent with what we've seen in previous studies, which means that this product is really supported by amazing clinical data. Not only do we have the pivotal study, but in total, we have the supportive data that means that we have 260 patients that have been treated with PTLD with the product and successfully. In total, more than 470 that have been treated with tab-cel across indication. It's a unique set of clinical data for an ultra-rare disease that we're bringing to the agency in Q2. So we feel very confident about that. And the beauty of it is also that this is also supported by new data that we presented last December at ESMO IO on potential label expansion once we get the first approval in second-line PTLD where we've shown data in CNS PTLD, which is very, very deadly lymphoma. And in that case, we have a response rate of nearly 78%. And when you look at the overall survival at one year in the responders, so most of the patients, it's about 85% survival at one year. In the non-responders, it's 0%. And they all, unfortunately, passed away. So that tells you how transformative this product could potentially be. And that explains also why we are very high ambitions with our partner in terms of pricing for that product. Now, our partner is getting ready to launch. We are now on track to file. We're very confident about that filing there. This is on the back of very successful experience in Europe about making the product available. Again, this product is very easy to use because you don't need lymphodepletion. It's an allogeneic T-cell therapy, but you don't need to lymphodeplete the patients. It's a 5-10 minutes IV. It's only one or two hours monitoring. You don't need to hospitalize the patients. The patient can go out because the safety is really pristine for that product at this stage, having treated that many patients there. So it's a product that is really to be used like a monoclonal antibody, even though it's an allogeneic cell therapy. That makes a big difference for physicians, a big difference for patients. This is, again, backed by amazing type of clinical data. So we feel very confident about the regulatory process in the U.S. We feel very confident about the future launch of the product in the U.S. And this is, again, supported by a very good launch in Europe where the listed price that they've achieved in Europe so far is about $640,000 per patient. And usually, the price in Europe is about 40% lower than in the U.S. So you can feel the type of price that could be achievable in the U.S. So with just a few hundred patients, we think that with this pleasurable expansion, they can reach our partner more than $500 million peak sales in the US only. So very exciting times. Okay. David, so can you tell us more about the opportunity in terms of how you're thinking about peak sales for the front-line consolidation setting for cema-cel? And especially in the market, how do you think it will exist with current and emerging products? Are autologous products going to be used after you in the second line? Or how do you think about that? Yeah. I mean, I guess I'll be the last one to speak. So before I go into the details of what we're doing at Allogene, as I'm listening to this and I'm just so excited about what's happening in the cell therapy, I mean, not only in hematologic cancers, solid tumors, addressing the tumor escape and things of that nature, but also going into the autoimmune space. So when I sort of think back about how cell therapy was over the last couple of years, I mean, there was a little bit of quiet period. But as I look toward 2024 and 2025, you're talking about all the scientific innovation coming to fruition, novel study designs, as well as not only in malignancies, but also going into other autoimmune indications. I think this will be really the resurgence of cell therapy over the next few years. I'm very excited about that. Also, I think that's also reflecting the market opportunities. I mean, the front line, I mean, you're talking potential market opportunity in excess of $3 billion. Also, we have a program going into the CLL, which is another area of growing medical need. Even second and third-line CLL, you're talking about $2 to $3+ range of market opportunities. I'm not even talking about autoimmune. A lot has been talked about. I fully agree with this concept of immune resetting or clonal depletion or however the terminology that you want to use. I think the emerging data is providing a clear indication that this is real. It's really left to all of us to safely and effectively advance this novel innovation. I would agree with a lot that has been said. I mean, we should not think this as an oncology drug development path. You got to think differently. And also, the concept has evolved quite a bit. You're moving away from persistence, but you're going after deep depletion to enable the resetting of the immune system, thereby providing a complete remission. And we have a program that is pre-IND stage, but they'll be going into the IND that addresses not just the pathogenic B cell component, but also T cell. And that product is really designed with the idea of eliminating the lymphodepletion. So very exciting time and market opportunities growing. And my colleague here, Pascal, will make sure his products are successful. And that's also going to do fantastic more opportunities for cell therapy. And with that, thank you very much. Thank you. Thank you. Thank you.