Good day, and welcome to the Autolus Therapeutics EHA Investor Call. At This time, all participants are in listen only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you will need to press Star then one on your touchtone telephone. If anyone should require assistance during the call, please press Star then zero to reach an operator. As a reminder, this call is being recorded. I would now like to turn the call over to CEO, Christian Itin. You may begin. Thank you, Michelle, and good morning or good afternoon, everyone, and thank you for joining us to take part in today's call to discuss the data presented at the European Hematology Association Congress that has recently been held in Vienna. Joining us today, we're extremely pleased to welcome Dr. Steven Horwitz from the Department of Medicine, Lymphoma Service at Memorial Sloan Kettering Cancer Center, and a professor of medicine at Weill Cornell Medicine, Cornell University. Dr. Kate Cwynarski, chair of the U.K. T-Cell Lymphoma Group and consultant hematologist, University College London Hospitals NHS Foundation Trust. Dr. Martin Pule, our chief scientific officer, and Dr. Edgar Braendle, our chief development officer, will also participate in this call. Before we begin, I would like to remind you that during today's call, our discussion will contain forward-looking statements. Please make sure you're familiar with our disclaimer on slide number two. On slide number 3, you will see the agenda for today, which is as follows. Dr. Horwitz, who is also chair of the NCCN T-cell and Cutaneous Lymphoma Guidelines Committee, will provide an overview on T-cell lymphoma and will describe the unmet need and cover the current treatment options. Martin will then introduce our AUTO4/5 program, with Dr. Cwynarski summarizing the AUTO4 data she presented in an oral presentation at EHA. Martin will then round up with the next steps for AUTO4. We'll then switch gears with Martin introducing obe-cel, and we'll cover the AUTO1/22 data in pediatric ALL patients that we presented in a second oral presentation at EHA, and also cover the updated obe-cel data in NHL and primary CNS lymphoma patients. We'll finish today's call with a Q&A. Now I would like to turn over the call to Dr. Horwitz. Horwitz. Thank you. I hope everyone can hear me okay. It's a pleasure to join you today. So what I was gonna do is just go over a little bit of the landscape in T-cell lymphomas, how we treat those patients standardly, what the area of unmet need is, and then some of the newer therapies setting up. I think what you'll hear is very exciting data with the cell therapy program. So next slide, I think, with my disclosures. I'm following along. I'm seeing slide four. If you can go to slide five. Then you can jump to slide six, which is just a bullet point of what I'm talking about. I apologize. On the webinar, I'm still seeing slide. Oh, there we go. Maybe there's a delay as we are across the Atlantic. If you advance to slide six. What I'll just do is a little bit of background. I know this is a sophisticated audience, but maybe not a completely lymphoma-focused audience. Then talk about upfront approaches, dose intensification, patient selection, some of the new therapies, and then relapse again. The next slide, please. You know, I think we think of T-cell lymphomas as an uncommon non-Hodgkin's lymphoma. Slide seven is what I'll be on. We have incidence data in the U.S. that if we look at all lymphoid neoplasms, there's about 80,000 or so new diagnoses a year. We think somewhere between 7%-10% of those are T-cell or NK-cell neoplasms, which we tend to lump together. Next slide. I think there is a bit of a delay. I'll just keep going and you guys try to keep up. I'm on slide eight. You know, we think of T-cell lymphomas as you know, overall heterogeneous and somewhat of a poor prognosis. Out of those 6 or 7 thousand cases a year, there's 29 or 30 different subtypes. There's a lot of individualization in terms of clinical presentation. Some present primarily in the blood, the leukemic. Some present primarily in the skin, those are the cutaneous. Then there's the most common subtypes are sort of the nodal and extranodal, and I have them color-coded there based on what's most common and what's less common. I think one of the things that maybe we'll set up the later talk is that, when we're looking at new therapies, we're often targeting things, specific features of the tumor. That could be surface features, that could be genetic features. You get the heterogeneity. When you're thinking about a surface target as something as fundamental as a T-cell receptor, you do have the opportunity to really cross subtypes in terms of your efficacy. Next slide nine. I'll just go over the prognosis then with standard therapies. For the systemic T-cell lymphomas, standard therapies are really still combination chemotherapies, often with a dose intensification. If you can go to slide 10 on my deck, which shows survival curves from a large national registry from Sweden, looking at over 700 patients with newly diagnosed T-cell lymphoma. These really represent the most common systemic types of T-cell lymphoma, which are the most common T-cell lymphomas. You'll see the blue curve at the top is one less common subtype. That's about the fourth or fifth most common subtype, ALK-positive anaplastic large cell lymphoma. That develops primarily in children or young adults. With combination chemotherapy, the results are not spectacular, but the majority of people are cured, and you see that there with long-term remission on the progression-free survival curve. When you look at the other subtypes, and again, this is basically with combination chemotherapy regimens, CHOP or CHOP-like regimens, which are four and five drug chemotherapy regimens. You see the majority of patients either don't respond, and that's the very steep drop of the curve in the first six months, or relapse after initial therapy, and then that's where those curves slope down kind of between year one and four. Really a minority of patients have long-term remission from initial therapy, and depending on the subtype, that may be as high as 25 or 30% for ALK-negative ALCL, and probably below 10-20% for some of the more aggressive T-cell lymphomas. Next slide. This next slide just shows a way I think of conceptually thinking about that heterogeneous group of diseases in terms of how we approach them. I have them grouped in the middle. I'm on slide 11 now. In the middle are those where combination chemotherapy is reasonable, if you see those in the light blue. Those are the more common nodal types, and the reason we think combination chemotherapy is reasonable is that there is a cure rate, albeit that cure rate may be between 20% and 30% for most of those subtypes. On the left, there's a group of diseases where CHOP-based chemotherapy is not recommended, and some of those are aggressive T-cell lymphomas where CHOP therapy or chemotherapy like that is really ineffective. Some of those are more indolent or chronic diseases where combination chemotherapy may work, but the remissions are generally short-lived, and those are patients that may have a better long-term prognosis where they need continuous therapy. In that case, therapies without accumulations of side effects, unless they're curative, are preferred. On the right, there's a handful of aggressive diseases, with very little data or too little data to make a recommendation. Next slide or slide 12. Historically, when we've looked at new therapies or others have looked at new therapies for T-cell lymphomas, it's really been more of the same. If chemotherapy works for some, does more chemotherapy work for more? What you can see in slide 12 is sort of summary data from a series of studies done primarily in Germany. This is really before rituximab changed the fundamental treatment for B-cell lymphomas, where all aggressive lymphomas were treated with combination chemotherapy and not chemoimmunotherapy. If you look at this accumulation of data, this is adding etoposide to CHOP. This is giving some people an every two week versus an every three week regimen, so dose intensification with more chemotherapy, increased dose density with shorter treatment intervals. You can see that in some patients, we may do a little better in terms of progression-free survival. The caveat here is that this data is limited to younger patients under age 60, and most of these patients had lower risk scores. That was based on some of the clinical trial data done at that time. If you look in terms of the cytotoxicity cost on the right, when we do dose intensify, there is a consequence in terms of hematologic toxicities. In younger patients, aged 18-60, we can usually get away with it with more heme tox, but patients clinically do okay. Once you get over age 60, you see clinical consequences which can either be life-threatening or blunt any attempts to increase dose or intensify dose of chemotherapy, and the net increase in toxicity kind of washes out any net increase in efficacy. If you go to the next slide, which is slide 13, it's sort of the maximalist chemotherapy approach that we and others practice for appropriate patients. This is just some phase 2 data from a Nordic study where patients got CHOP plus etoposide as an induction, so that's their initial chemotherapy. Again, this is slide 13. And then that was followed by high-dose therapy and autologous stem cell transplant. Truly maximal chemotherapy. These patients are a bit selected because they enrolled on a clinical trial that involved very intensive therapy. Most of these patients are under 60 and have good performance status. What you can see, I think, if you just look at the numbers in the boxes on the left and right with overall progression-free survival, and I'll focus on the progression-free survival because that's really the readout from the benefits of therapy, is that if we really give as much chemotherapy as a human can tolerate, we can push those progression-free survival rates up to about 40%, for many subtypes, maybe into the 40%-50% for anaplastic and higher for ALK-negative anaplastic large cell lymphoma. That's sort of the most we can do with maximizing chemotherapy. Next slide. Other attempts have been made to add to it. If we sort of follow a paradigm where we have another active drug that's not just chemotherapy, can we do better? Slide 14 just introduces the topic of adding alternate therapies, non-chemotherapeutic approaches to a CHOP backbone. If you just jump ahead to slide 15, this is really the one success we have. There's been a bunch without success, but the one main success we have has been the ECHELON-2 study where we added brentuximab vedotin, which as you know is an antibody drug conjugate targeting CD30 and treated specifically patients with CD30 expressing T-cell lymphomas. These are patients who were treated in the upfront setting, and they received either brentuximab plus a CHOP-based regimen with placebo vincristine, concerns about overlapping neurotoxicity if we added vincristine or CHOP plus placebo brentuximab. I think one of the keys from this study when we're looking at the data is, the majority of patients on the study had anaplastic large cell lymphoma, which is a universally CD30 expressing lymphoma. Other subtypes where CD30 is more variable, patients had to have at least, 10% CD30 expression on their tumor cells. If you go to the next slide 16, that just shows the five-year update from, for progression-free and overall survival. What you can see is that there was an incremental benefit adding brentuximab vedotin to CHOP, both in terms of progression-free survival, this again will be slide 16, and overall survival. The, those curves stay separate even with long-term follow-up. You see the median progression-free survival was almost three times, as high with brentuximab vedotin plus CHP in the green curve. The overall survival, the median overall survival was not met with either arm, but a significant improvement from BV-CHP. You can see the delta there. While the relative improvement was vast, the overall improvement was between 15%-20% absolute difference. Next slide. Slide 17 looks at the subtypes outside of anaplastic large cell lymphoma. The majority of patients, again, in the study, about 70% had anaplastic large cell lymphoma, that one subtype, and that's where we see the greatest benefit. On Slide 17, we went and looked at the other subtypes of T-cell lymphoma. This was not a pre-planned analysis. These patients were not stratified. What you can see is that the benefits of brentuximab plus CHP in the green curves are a little less distinct for peripheral T-cell lymphoma not otherwise specified, and in angioimmunoblastic T-cell lymphoma, sort of unclear that the brentuximab added. As a caveat to the AITL curves, those curves, the blue curves with CHOP, are really higher than anything we have in the literature, so that may reflect some patient selection or CD30 expression on AITL or just the randomness of small numbers. Next slide is slide 18. Other attempts have been done to sort of recapitulate this. Can we add other active agents to chemotherapy and better for all? The next slide is a primarily French study adding romidepsin to CHOP and randomizing that against CHOP for untreated patients with peripheral T-cell lymphoma. Again, Romidepsin is a histone deacetylase inhibitor that, at least in the U.S., is approved for cutaneous T-cell lymphoma and until recently was approved for peripheral T-cell lymphoma. You see here this was a negative study with really no benefit in the blue-green curve adding Romidepsin to CHOP in terms of progression-free or overall survival. Next slide. Part of the explanation for that, if you look at slide 19, may be that Romidepsin did add significant toxicity. On slide 19, there's a table on the left that shows that patients getting Romidepsin had higher rates of dose reductions and dose interruptions due to toxicity. Then if you see the forest plot on the right, and this would be slide 19, I'm still seeing slide 18. The forest plot on the right, you see that the other issue may be that this was an all-comer study or no selection based on who enrolled in this study. We now know, and some of this knowledge is since the study was designed, that patients with angioimmunoblastic T-cell lymphoma, if any, have the greatest chance of response to Romidepsin. When you look at those hazard ratios, there's a sense that maybe if you confine the study to that group and expand it a little bit, you might find significant benefit. Nonetheless, this was a negative study. If we go to slide 20, you'll just see a list of attempts at adding new therapies to chemotherapy backbones, and you'll see that most of them have been negative studies either due to lack of efficacy or in some cases like Alemtuzumab increased toxicity. Slide 20. If you want, that's sort of a number of negative studies. If you want to move to slide 21, I think one of the issues that comes across when we're trying to use new targeted therapies is that there's a tremendous heterogeneity as we're understanding more about the biology in terms of the genetics, the molecular pathogenesis. You can just see over on the left there that there's a number of pathways that are deregulated, and these may have different targets when we're thinking about targeted therapies either at signaling pathways or epigenetics. Next slide. You'll see on slide 22 that maybe one of the reasons that some of the genetically targeted therapies have been less successful in T-cell lymphoma is that there's extreme heterogeneity. This is a series of 133 cases, again on slide 22, looking at mutations. What you'll see is that there's a vast array of mutations. Outside of things like TET2 and TP53 most of the mutations are in less than 5% of cases. There's a lot of heterogeneity that isn't well addressed by genetically targeted therapies. Next slide 23. I think when we think about adding to combination chemotherapy, at least with a targeted agent, we know that for anaplastic large cell lymphoma or with a very powerful drug like brentuximab vedotin, if we target the universally CD30-expressing T-cell lymphomas, we can add benefit. I think when you look at other subtypes of T-cell lymphoma, sort of in the, that middle bullet there, PTCL, NOS, AITL, and this goes for a number of other subtypes, we really can't draw a definitive conclusion by adding a single drug, and some of that is due to the heterogeneity of the diseases we're treating. I think as we're trying to go forward adding to new therapies for T-cell lymphoma, I think we need to be able to enrich for those most likely to benefit. If it's a targeted therapy, that target should be broadly expressed and also not add significant toxicity. I'll just give a few slides on relapse T-cell lymphoma with what we do standardly now and then turn it over to Martin. Slide 24 just transitions to relapse T-cell lymphoma. Slide 25 shows data with allogeneic stem cell transplant in the relapse setting. We know that in patients with relapse T-cell lymphoma, they can sometimes be cured with allogeneic stem cell transplant. Again, this is on slide 25 now, if you can catch up. That cure rate is about 40%, and most of the cures are in patients who have a complete remission. When we're thinking about treatments in the relapsed setting, we're either thinking about in a younger, healthier patients getting a complete response to bridge them to allo, or in a patient where allo transplant is not feasible due to, you know, all the reasons allo transplant is not the right treatment for everyone. We're looking at drugs that can maintain remission. Right now, for our current agents, that usually means on continuous therapy. If you go to slide 26, this shows some of the standard drugs that are FDA approved in the U.S. or that we have available here for routine use in T-cell lymphomas. What you'll see in this table, again, slide 26, is that most of these drugs have response rates between 25%-30%. If you look at the two histone deacetylase inhibitors, you have belinostat at the top and romidepsin at the bottom. Their pivotal studies had response rates between 25%-30%, with only about 10%-15% of patients having complete responses. We think a complete response would be important to bridge to transplant. When you look at the durations of remissions of those drugs, you do see that patients can be on those drugs long term with continuous therapy to try to maintain remission. Very similar data with pralatrexate, which is an antifolate. Overall response rate just under 30% and a complete response rate of 10%. In that subset of responders, you can sometimes maintain remission. Of course, the outlier in the middle is brentuximab vedotin for anaplastic large cell lymphoma, with a very high response rate in that subtype. If you go to slide 27, you see the progression-free survival curves, you know, to sort of graphically display what we, what we achieve and what we don't achieve with drugs in the relapsed setting. On slide 27, you'll just see the PFS curves from the pivotal studies of these drugs, showing that the majority of patients either don't respond initially or relapse after brief responses. There's a subset of patients, you know, more in the 10%-15% range that really have long-term benefit. There's a tremendous unmet need in T-cell lymphoma that a therapy that is both effective and if it had the potential of creating durable remissions, would be incredibly valuable. One could think of many ways that could be applied to improve treatment for our patients. If you just go to the next slide, 28, I just list some other emerging therapies in T-cell lymphoma. A number of drugs are being studied, inhibitors of the JAK-STAT pathway, inhibitors of the PI3K pathway, EZH1/2 inhibitors. These drugs all fit sort of the what we've seen before, which is they are probably targeting vulnerable subsets, and they don't cause durable remissions off of therapy. At least for the top three bullets, you would need to maintain patients on therapy to get durable remission. Very early days for immune therapy, which I think we'll talk about more in terms of some cell therapy studies being explored, some checkpoint inhibitor studies, and some anti-CD47 strategies. Most of these studies are in their phase 1 experience. Just to conclude on slide 29, peripheral T-cell lymphoma, if we think of first-line treatment and then where we go from that, peripheral T-cell lymphoma remains heterogeneous and poor prognosis for too many of our patients. Again, slide 29 is my conclusion. We do have cures for some patients with combination chemotherapy, and that's probably about 20-25% overall, maybe as high as 45% for those that can endure most intensive therapy. Some improvement for those, particularly with anaplastic large cell lymphoma, where we see adding brentuximab really provides significant benefit. Overall, in the universe of T-cell lymphoma, there remains a high unmet need. Most of the attempts to date to improve therapy have been adding active agents to upfront therapy. I showed you that we have had some success there, but also a lot of failures in being able to do that, both due to our inability to enrich populations and our inability to minimize toxicity. Then I listed for you some of the newer approaches that are underway. I will conclude there, and thank you. Thank you very much. It's a wonderful presentation. If we now move to slide 31. As Dr. Horwitz has shown you, T-cell lymphomas represent an area of significant unmet clinical need with a majority of patients being either refractory or relapsing after initial treatment. Standard of care is variable and often based on intensive treatments, but despite this, the median overall survival at 5 years is about one-third of patients. For patients with relapsed or refractory disease, their prognosis is even worse with a median overall survival of less than 6 months. In terms of immunotherapy, brentuximab can be useful to patients who are CD30-positive, but this is mostly the patients with an ALCL subtype of T-cell lymphoma. I think it's fair to say that generally, T-cell lymphoma has not benefited from immunotherapy the same way the B-cell lymphomas have. If we go to the next slide, the reason why, of course, is that when targeting B-cell malignancies, we target pan-B-cell antigens and pan-B-cell depletion is reasonably well-tolerated. Doing the same thing in targeting a pan-T-cell antigen would result in unacceptable immunosuppression. If we put that aside for one moment, and we were to pick the perfect antigen to target in these diseases, it would be the T-cell receptor CD3 complex expressed at high level on most subtypes and in nearly all cases. The way the biology of this receptor actually gives us a therapeutic strategy that can stop us from having profound pan-T-cell depletion by targeting it. Most people know that the alpha and beta chains of the T-cell receptor rearrange during T-cell development, but quite a few people have forgotten that actually during this rearrangement, the T-cell has to pick what beta constant region gene it takes. Either a T-cell becomes a TRBC1 T-cell expressing the TRBC1 beta constant region or a TRBC2 T-cell. In our peripheral blood, there's a mixture of these two cell types. T-cell lymphoma is obviously clonal, so it's going to be entirely one or the other. This then gives us a therapeutic strategy when, for instance, if you have a patient with a TRBC1-positive lymphoma, it should be all TRBC1 positive, and if you target it, you should be able to target all of the lymphoma cells but only about a half of the normal T-cell compartment. That's the therapeutic strategy. If we go on to slide 33, I think this shows you how useful a target the CD3 TCR complex is. It's expressed on 95% of T-cell lymphoma subtypes, and the exception really are these extremely rare lymphomas that come from NK cells or gamma delta T-cells. All the other alpha/beta-derived T-cell lymphoma subtypes will express the CD3 TCR complex. There are other potential T-cell lymphoma targets. These either have problems one way or the other. Either they express the normal T-cells as well or T-cells when they become activated, or else they're only expressed on a proportion of the entire set of T-cell malignancies. If we go onto slide 34, I said that this fact about TRBC1 or TRBC2 gene selection is often forgotten. I think if you look on the left of the alignment, you'll see why this is often forgotten because the two chains are really almost identical. There's only a 2 amino acid inversion of the amino terminus of the constant region that is really targetable. Remarkably, we've identified an antibody that's exquisitely selective for TRBC1, and we've flipped the selectivity of this antibody from TRBC1 to TRBC2. Now we have two antibodies, one that binds TRBC1 and one that binds the TRBC2. I think the nicest illustration is that scatter plot at the bottom middle of slide 34, where you can see the normal person's peripheral blood, and you can see two nice populations of either TRBC1 or TRBC2-positive T-cells. If we go onto slide 35, we've converted these two antibodies into chimeric antigen receptors. On the top right, you can see some very simple killing data with Jurkat that are natively TRBC1 positive or Jurkat that have been genomically engineered to be TRBC2 positive or Jurkat that are TCR negative. You can see a nice selectivity of our TRBC1 and TRBC2 CARs with the CD19 CAR as a negative control. We can reproduce the same findings in an in vivo model in grafting TRBC1 or TRBC2 T-cell lines and treating with either TRBC1 or TRBC2 CAR T-cells. If we move on then to slide 36. The Autolus strategy for T-cell lymphoma is a companion diagnostic initially to identify what patient with relapse refractory T-cell lymphoma has either TRBC1 or TRBC2, and then TRBC1-positive patients are treated on the currently open AUTO4 study, and in future, we'll open a TRBC2 study targeting TRBC2. Julia, if you go to slide 37, just a very quick word about companion diagnostics. You can actually figure out if a patient is TRBC1 or TRBC2 with relatively straightforward NGS-type assays that looks at VDJ recombination. That's something that's fairly standard you can do in genomic DNA. We've also developed antibodies that work in fixed tissue. You can do it by FFPE if you want to. We can use the same antibodies by flow if you do lymphoma diagnosis by flow, which is amenable for some subtypes. I think having introduced the concept, I will hand over to my colleague Kate Cwynarski, who's gonna just run you through what she's presented at EHA. Kate Cwynarski, over to you. Thanks very much. I presented this data in Vienna at the European Hematology meeting on Saturday. I presented the initial data from our phase 1 study of AUTO4 in patients with relapsed refractory TRBC1-positive peripheral T-cell lymphoma. Next slide, please. A two-part consent. We have seen patients to screen for their tumor. We can use archived tissue to assess whether it's TRBC1 positive or not, using next-generation sequencing as outlined by Martin. Those that have TRBC1-positive tumors then can be screened in part B. We do allow bridging therapy, and you can see here that from leukapheresis to QP release, there's a median of 20 days, and the efficacy and safety follow-up with first disease assessment at day 28. Next slide, please. To date, we've treated 10 patients, a median age of 55 and median prior lines of therapy of 3. Advanced stage in the majority, so 80% have stage 3-4 disease, and half of them peripheral T-cell lymphoma NOS. 4 patients with angioimmunoblastic T-cell lymphoma and just 1 with ALK-negative ALCL. A third of the patients had a prior autograft, 70% ECOG 1, and bridging therapy was used in 70%. Next slide, please. To date, as I've mentioned, we have treated in 4 different cohorts with increasing dose escalation from 25 million cells up to 450 million cells. You can see here there've been no limiting toxicities and only mild cytopenias likely to be because of the FC condition, the fludarabine and cyclophosphamide, as this was seen at low dose cohorts. In terms of any grade CRS, you can see we just have one grade 3 CRS and no grade ICANS at all. Generally, really well-tolerated. In terms of data, this is certainly encouraging, although this is very early phase 1 data. If you look at the two highest doses, we've used it at 225 and 450. All four of those patients were in complete metabolic remission at month 1, and 3 out of 4 at 3 months to ongoing remission. This is in the early phase study, really encouraging. Next slide. Sorry, I think we have to. Sorry, I didn't mention next slide. If you go back to the next slide. I'll wait for that to be seen. I'll just mention that here you can see the highest dose is mentioned at the top, and the green line represents complete remission. You can see at the 1-month and 3-month intervals, really encouraging responses, with 2 of those patients still in remission, really encouraging for phase 1. This is a PET scan from one of our patients I've treated. They've had 4 lines of therapy. They've never achieved complete remission. They were in complete metabolic remission at day 28, and at 3 months, still in complete metabolic remission and remains in clinical remission at month 5, awaiting the 6-month scan. Next slide, please. You see that, the PET scan, there you go, complete remission at day 28 and 3 months. The next slide, please. We've detected CAR T-cells in a lymph node biopsy for one of our patients who achieved complete remission. To date, we haven't identified CAR T expansion either by PCR or flow in the peripheral blood. Next slide, please. I'll hand over to Martin Pule, and unfortunately, I have a clinic that's just starting, and after the Jubilee weekend of being away at EHA, I can't miss this one. Thank you very much. No, thank you so much, Kate. Thank you. Really appreciate it. Exciting study. Julia, if you can go on to slide 46. To summarize, AUTO4 is generally well-tolerated. The early efficacy is encouraging, particularly looking at the higher dose levels. We've detected CAR T cells in lymph nodes, but we haven't seen expansion in peripheral blood at this point. The study is ongoing. We are also optimizing our manufacturing process, and the plan is to enroll further patients and try and define the recommended phase 2 dose in preparation for a pivotal study. With that then I'm gonna change track, and if we go to slide 48, Juliet, I'm going to talk about obe-cel now. And many of you know about obe-cel. To remind you, this is a CD19 CAR with a fast off-rate binder. The idea here is to reduce the amount of inflammation per target cell encounter, which in turn will reduce the amount of immunotoxicity in the patients, reduce exhaustion in the CAR T-cell, and improve engraftment and overall persistence. Those of you not familiar, I refer you to our paper by Sarah Ghorashian in Nature Medicine in 2019. If we go on to slide 49, again, many of you will know that obe-cel is currently being tested in a phase 2 study of adult relapsed refractory B-ALL. What we presented at EHA was some ongoing work with obe-cel in NHL, primary CNS lymphoma, and also a 21/19 variant of obe-cel in pediatric ALL. These are the areas I will quickly touch on next. If we go onto slide 50, the ALLCAR19 study is currently a basket study where we're testing obe-cel in a variety of different B-cell malignancies, and we presented an update as a poster. If we go through this data very quickly, our follicular lymphoma cohort, and we've treated 7 so far. Sadly, we lost 1 patient to COVID, but all other patients remain alive and well in complete remission. We've treated 7 patients with diffuse large B-cell lymphoma, and 6 remain in complete metabolic remission. If you look at the median follow-up of the follicular and diffuse large B cells, they're 9.2 months and up to 19.1 months. That data continues to accumulate. We've treated three mantle cell lymphoma patients. One relapsed at six months actually with a skin relapse that was salvaged with radiotherapy and allograft, but the other patients remain in a metabolic remission. We've also started treating some CLL patients, and from the three patients that have reached the initial evaluation, two have gone into a molecular CR under bone marrow, but have some residual lymphadenopathy on CT scan. Just to remind you that the CLL patients don't tend to get PET CT scans, so this is just a regular CT scan. What we have in these patients is some lymph nodes that are larger than the one centimeter. The significance of these lymph nodes at this point is still undefined. Those two patients remain well. That's really our update with ALLCAR19. If we move on to the next slide 51. We're also exploring obe-cel in primary CNS lymphoma. Primary CNS lymphoma is a type of diffuse large B-cell lymphoma, but because of its anatomical location, it has a particularly poor prognosis. Initial treatment is often intensive, and performance status of these patients tends to be poor. We've tried obe-cel in these patients, and actually we haven't seen any CRS, any significant CRS, so any grade 3 or 4 CRS. We have seen some ICANS. We haven't seen any grade 3 or 4 ICANS in ALLCAR19, for example. In these patients, we did see two. I think one of them may well have been due to progressive disease at the time, and the other patient had a pontine lesion, which is quite a difficult anatomical location. If we go on to slide 52, we put the slide here to show you that despite these patients having no disease outside of the CNS and having had lots of rituximab treatment, we still see really nice expansion of obe-cel in peripheral blood. If we go on to slide 53, just to give you a sense of results, I mean, I think the first thing to look at is the MRI scans on the right. You can see quite a large parenchymal lesion in the top left that has completely resolved. I think this is. I put this here to show you that obe-cel can result in remissions in patients with quite large parenchymal lesions, which, you know, is interesting. The other thing is to remind me to tell you that actually you can't do PET CT easily for these patients because the brain takes up glucose. I think when you see residual abnormalities on an MRI, it is difficult to know exactly what that means. With that in mind, if we look at our outcome, our overall response rate was 4 out of 6. We have seen some patients converting from, for example, stable disease to a completely normal MRI. Again, you know, this is still very early data. Kinda looking where we are with sort of this sort of franchise for obe-cel, we can see a favorable and consistent safety profile across all indications. While patients are valuable for efficacy across mantle, diffuse large B-cell lymphoma, follicular and CLL, the overall response rate was 90%, and the BNHL cohorts, the complete response rate was 94%. The CLL cohort is interesting, and we have to see what that sort of low volume residual lymphadenopathy on CT means. I think as well as having a good CR rate and a good and excellent safety, I think as more and more time goes on, you can see that these responses are durable. I mean, the next steps for this is really to try and treat 10 patients of all those different indications on the ALLCAR19 study and to continue finishing our primary CNS lymphoma study, which we aim to recruit to 10 patients in total. That's obe-cel. Now if we go on to slide 55, let's take another step forward to AUTO1/22. We have tested obe-cel in children with relapsed refractory B-ALL, and we, you know, we see the same as we see in adults. However, in pediatric leukemia, since children are better able to tolerate toxicity isn't really a major issue. But what is a major issue is antigen-negative relapse, so CD19 loss. The obvious solution to this is to target a second early pan B-cell antigen, and the one antigen or other antigen you can go for is CD22. CD22 is actually a much more challenging antigen than CD19, being bulky and expressed at lower density. We have a lot of experience from previous programs in targeting CD22, and we've developed a very, very sensitive CD22 CAR that's sensitive to very low antigen density. AUTO1/22 is a co-transduction, so there are cells, so the obe-cel component of it is left as unchanged as possible. We've tested this in a phase 1 study in children with relapsed refractory B-ALL. If we go to slide 56. The main thing to note here is that Kymriah's standard of care in the U.K. where these patients are treated. These patients were Kymriah ineligible at the point of recruitment to the study. The other thing to point out is actually 4 patients had received Kymriah, and 3 had CD19 negative disease, coming into the study. If we go on to slide 57, manufacturing led to, I think Sarah Ghorashian presented this, a nice product profile with a balance of CD19, CD22, and double CAR positive T-cells. We saw a nice expansion and engraftment in patients. Whenever you take a new CAR to clinic, there's always questions about what its safety profile would be. Actually we didn't, I think, have a penalty, a safety penalty here for co-targeting CD22 in these patients. There was one patient who did have a severe neurotoxicity, but we went and extensively investigated this patient, including a brain biopsy, and our conclusion is that this was most likely due to Fludarabine, although obviously, CAR-T related neurotoxicity can't be excluded. Apart from that one patient, the AUTO1/22 was really very well tolerated. If we go on to slide 58, you can get a sense of where these patients are. Nine patients were in molecular remission at day 28. We've had two patients who've had a frank relapse. Neither of these two patients had any antigen loss, and we've had one patient that became MRD positive at 12 months. The other thing to point out is that three of the patients who were CD19 negative going into the study went into molecular remission. We go on to slide 59. Where are we with this study? We show that we can make the products, that the products expand and persist, and there's a favorable safety profile. We can see that the 22 CARs working from those patients who've gone into remission with CD19 negative disease. Given this patient's cohort, we're pleased with the response rate and the ongoing remission rate. To date, albeit with limited follow-up, we have not observed any antigen negative relapse. I think with that, I can hand back over to Christian to close up. Thanks for your attention. Thanks, Martin. Obviously, when we look at where we are with the company, obviously there's an enormous focus on delivering the pivotal study for obe-cel, the FELIX study. This is clearly where the primary focus obviously of our activities are. Obviously, what was exciting about EHA for us this year is to provide not only an update on the continued progression of obe-cel in additional exploration and additional indications, but also start to see very interesting profiles for AUTO1/22 in pediatric ALL and in particular for AUTO4 in T-cell lymphoma, which is obviously a new set of targets that we're going after there, as well as obviously a completely new clinical experience that we have with the approach that we're taking. We're also in the process of transitioning again in our collaboration that we're running with UCL, and you've seen obviously some of the output of that collaboration in today's call. The AUTO8 program in multiple myeloma and also the AUTO6NG program later this year in neuroblastoma. With that, I would first of all like to thank all the presenters for excellent presentations. Thank you very much for taking the time today. At this point, I actually would like to open up the presentation for Q&A. As a reminder, if you'd like to ask a question, please press Star then one. If your question has been answered and you'd like to remove yourself from the queue, press the pound key. Our first question comes from Matt Phipps with William Blair. Your line is open. Hi, everybody. Thank you for taking my questions and nice updates at EHA over the weekend. I'm gonna ask some AUTO4 questions. What do you think is the reason why you're not seeing or detecting the CAR T-cells in the periphery, and only find them in the lymph nodes? Is that something that you think is just from the small patient numbers or is that just how this therapy is going to work, I guess? Yeah, it's Martin. I mean, I can try and answer that. You know, I think this is a new target, new set of diseases, so we don't really know what to expect. I guess from the B-cell experience, you would expect some peripheral expansion and persistence, but I guess this is something new for us, so we don't really know. I mean, I think the one thing that will be interesting to see is when we treat patients with CAR T-cells that have been made with an improved and shortened process, because those cells may have a higher capacity to expand and persist. That'll be an interesting next step with this. Okay. Have you been able to look at just the presence of TRBC1/2 cells in the periphery to see if you're getting kind of aplasia of that specific compartment? We have looked and at this stage in the peripheral blood at least we haven't seen a selective aplasia. Okay. Interesting. I guess what you mentioned, you know, some improved process. I guess, is it just shortening the process? Again, trying to get more of a naive, you know, cell type. And then also, what is the timeline, do you think getting the IHC or other diagnosis? Because it does seem like the NGS screening is taking a while and not really making enrollment as easy as it could be. Yeah. I mean, I think in terms of the NGS, or in terms of the companion diagnostic, I think we've, you know, shown that it's possible to do by those three methodologies. I think that's something that, you know, which is obviously, you know, really big for a step because it's quite tricky. But I can't give you any particular timeline when we can, you know, formalize those companion diagnostics. Okay, one last question. Timelines for getting AUTO5 into the clinic? With regards to AUTO5, Yeah, thank you. With it, first of all, you had a question related to the process. One of the things that we're doing obviously is we're taking a lot of the experience that we gained on obe-cel, and we're applying that also to the AUTO4 process. The goal, as you pointed out, is to shorten the manufacturing process and also with that create a product that actually has a less differentiated phenotype. That's clearly one of the areas we're going into and which we'll explore during the later part of this year and into early next year. With regards to the timeline around the AUTO5 program, obviously the focus at this point has been to get the AUTO4 proof of concept done, which I think we're starting to get a good feel for. Obviously, we'd like to see more follow-up on the patients as well. We're obviously in the process of running through the IND-enabling studies in AUTO5. The goal is that we should be in a position during the course of next year to move also with AUTO5 into the clinical development as well. Is Dr. Horwitz still on the line? Yeah, I'm here. If he's available. Oh. Oh, I'm here. Yeah. Just one question for you, if I may. Would you want to move these patients to an allogeneic transplant in a better CR? Do you worry about, you know, missing your chance on, I guess, a transplant? You're saying if they receive investigational therapy like this? Yeah, yeah. Yeah. I mean, our main problem is not getting CRs. There would be few patients who I think that would be a high risk. In some of the CD5 CAR T-cell studies that are, again, in early phases, because of concerns about long-term T-cell aplasia, they do have allo backups, and some of those patients, and there's just a few treated, have gone to allo after CR, or just been observed. My sense is with a treatment like this, at the beginning, if you're seeing CRs, you know, some of these patients, and Martin can comment on how the study's being run, we're not part of the study. Some of these patients could be observed, and you're looking for durable responses. There might be other individual patients who you'd capitalize on the CR and take them to allo at that point if that was part of the plan. You know, allo has a 10% or so treatment-related mortality, so there would be a lot of ways to do better. Yep. Thank you. All right. Thanks, Matt. Our next question comes from Mara Goldstein with Mizuho. Your line is open. Thanks very much for taking my question. I just have a question on the AUTO4 results and the patients that had that long-term PR with an ongoing response. Can you provide us with some, just some, background and details on that patient? Martin, can you take that? Yeah, I can take that. This is a patient that really never went into remission. I think actually interestingly, the patient then relapsed quite a long time later with skin relapse, which was quite interesting. I think, you know, it'll be very interesting for us to present what, you know, what's happened to this patient next. I mean, the patient's actually still remains quite well. I don't know what else I can really say about them. They, you know, they had refractory PTCL. Okay. They went into a metabolic remission, stayed in metabolic remission, and relatively recently relapsed with an isolated skin relapse. On the AUTO1/22 program, for the patients who had prior Kymriah, are you able to isolate out their results relative to the rest of the cohort? Yes. There are four of them. One of them didn't respond at all, that was a patient who didn't engraft Kymriah, didn't engraft, and AUTO1/22 didn't. There were two patients who were CD19 negative and went into remission, and those patients stayed in remission. There was one patient who's very interesting actually, who was 19 negative, and didn't respond. Actually bone marrow day 28 showed double negative disease, which was interesting. Those are the four patients. Okay. Thank you. I appreciate it. Our next question comes from Asthika Goonewardene with Truist. Your line is open. Hey, guys. Thanks for taking my questions. So just to dig back into AUTO4 a little bit more, Mark, you mentioned about the change of the product. You're gonna have maybe a shorter manufacturing period to promote a more naive phenotype. Can you talk to us a little bit about what else you're doing to change the product? Is it just the shorter expansion? Are there any new cytokines being used? And I guess the related question I have here is, if you're changing the manufacturing, how does this not require a new IND? And then I got a quick follow-up after that. Yeah, it's Mark. Yeah, Asthika Goonewardene. So- Please go ahead, Martin. Yeah. It's Martin here. You know, there's two things, you know, the two things you can do to increase the stemness and the naivety of your product. You can shorten it obviously, and then the other thing you can do is you can very simply increase the number of T cells going into the production, because that means you can make the dose for a shorter period of time. Those are the two maneuvers. They sound really simple, but actually they're the two things that really make a big difference. In terms of do you need a new IND? No. I think it's very, very common in CAR T cell studies, you know, that you file an amendment, a major amendment with a modified manufacturing process and you can keep on going. I'm almost embarrassed to say that nearly all of my phase one studies I've ever done, we've changed manufacturing at some point during the study. In my hands at least, it's not uncommon at all. I think it's relatively common. Obviously, if it's a pivotal study, you don't have that flexibility, but for a phase one study, you do. Got it. Okay. Can you just give us a little bit more time to understand the timelines on when you plan on getting this new AUTO4 into the clinic, and how many patients would you need to treat in phase 1 before you can make a go or no-go decision to pivotal with this new AUTO4 product? I think, Edgar Braendle or Christian Itin, you might want to take that. I can take that. The plan is obviously to implement these changes which are in fact being done now, and we expect to treat in the range of about six patients to get a feel for obviously the impact of the modifications that we've done. That will get us into the early part of next year plus follow-up in these patients. It gets us into that first half of next year in terms of actually having data for those patients and an understanding of the performance of the changes. Great. Thanks, guys. A real quick one on AUTO1. We've obviously seen some data from Bristol Myers Squibb, and that's also coming from the Fred Hutchinson Cancer Center about how combination with the CD19 CAR T plus ibrutinib has a synergistic effect there in terms of CAR T cell persistence and long-term durability of response. Just trying to think what's, in light of that, what's your next steps for taking AUTO1 into something like CLL? And maybe we wanna try and look at doing a combo study as well. Yeah. It's Martin Pule here. I think at this point, I think what we're Oh, sorry, Christian. Go on. Yeah. I think at this point, what we're planning to do is really kind of, as Martin pointed out, complete the current cohort and get a proper understanding of the activity of the product on its own. I think the analysis with ibrutinib is interesting. Obviously it's a common background if you have these patients being treated with. It's certainly something we'll be looking at. I think at this point what we really want to understand is the basic activity of obe-cel on its own. I think once we know that information, at that point we'll make decisions around whether to take the program forward as is, or whether an additional use of ibrutinib might actually be beneficial. Got it, guys. Then just a last quick question and I'll hop back in the queue. What can we expect at ASH in terms of updates from any of these three programs that you presented today at EHA? Thanks. Right. In terms of outlook for ASH, obviously we're gonna have about six months additional data in terms of follow-up. I think that's gonna be very meaningful, particularly on the ALLCAR cohort, follicular cohort, where we've already seen data getting us somewhere between 12 and 18 months of follow-up on that patient group. I think we wanna see the cohorts filled out, and obviously also additional follow-up, and particularly on the DLBCL and mantle cell patients. I think that will start to be a very informative set of information. AUTO1/22, obviously there is a few more patients that you know can be enrolled. Think there's a few more patients that we're gonna add to that study. I think what's gonna be very informative is the performance of the product in the patients that are currently treated, which would give us all the patients beyond kind of a 6 months of follow-up. With that, I think a pretty clear view on whether or not we have the impact that we desired with regards to antigen loss and the frankly eliminating antigen loss in potentially relapsing patients. With that, we should have enough follow-up to actually be clear that indeed we've kinda gotten through that. Then finally on AUTO4, as we indicated, obviously more follow-up on the current patient set, and then obviously the additional patients that we're planning to dose with the modified manufacturing process. Those are kind of the key updates for the end of the year on those programs. Great. Thanks so much guys for taking my questions. Thanks a lot, Asthika. Appreciate it. Our next question comes from Kelly Shi with Jefferies. Your line is open. Thank you for taking my questions. My first question is the expression level of TRBC1 and TRBC2 variable from patient to patient? Do you see a treatment outcome, I mean, the impact of the treatment, outcome due to the different expression level? And also, the second question is, what is the manufacturing success rate, from that first 10 patient data for AUTO4 program? Thank you. Martin. TRBC1 and TRBC2 expression on most T-cell lymphomas is really quite high and quite consistent. I think if you look at Macioccia et al, our original paper in Nature Medicine, I think that's got a nice summary of the expression density. The one exception is HTLV-driven T-cell lymphoma, ATLL, where expression tends to be a little bit lower. Generally expression tends to be higher than the normal T-cells. In terms of this study, we didn't see any correlation between expression level going into the study and outcome. That's that bit of your question. I think in terms of manufacturing, I think we had a high manufacturing success rate, which I think was 100% actually for this study. Great. Thank you. Thanks a lot, Kelly. Our next question comes from [Chad Lu] with Needham & Company. Your line is open. Hi, this is [Chad] for Gil. Thank you for taking our question. We just have a question on AUTO4. It seems the lymphocyte recovery is fairly quick in the patients after AUTO4 treatment. Did you have a chance to say if the T-cells recovered are TRBC1 positive or TRBC2 positive? Thank you. Okay. Martin, do you wanna take that? We looked and we have not seen any skewing of TRBC1 and TRBC2 in recovery. We did not see any selective depletion of one compartment or the other in the peripheral blood. Okay. Thank you. Thanks, Chad. Again, to ask a question, please press star then one. Our next question comes from Eric Joseph with J.P. Morgan. Your line is open. Hi, good morning. Thanks for taking the questions. Just a few on AUTO4 from us. The first is whether there's any clustering of responses by PTCL subtype, you know, whether there's any concentration of responses among those that were either not otherwise specified or the angioimmunoblastic subtype. Secondly, I just wanted to follow up on the question on the point related to detection of protein in peripheral blood. I guess, to what extent is peripheral blood detection going to inform or help define the recommended phase two dose. I have a follow-up from here. Yeah, it's Martin. I can try and answer those. I think the answer to your first question is no. I don't think we can say there's a particular histological subtype. I mean, like, you know, again, because the numbers are so few, you know, even if there was, I don't think it would be meaningful at this stage. I think it's too early to tell. In terms of peripheral blood monitoring and making decisions, because it's a new target and a new disease setting, we don't really know what to expect. You know, I think we'll be primarily guided by, you know, what we see in patients in terms of toxicity and responses. Okay. In the abstract, you comment a little bit on the screen positivity rate, and I guess the implied screen failure rate is about 30%. I'm just trying to get a better sense of what resulted in, I guess, patient screening out and whether that might be reflective of the addressable population, I guess, in the real clinical setting here. As it relates to sort of the adapted manufacturing process going forward, is there the potential, or do you see the potential, I guess, with these optimizations to allow patient re-dosing? If re-dosing is something that you know you might look to explore perhaps in the patient, you know, in situations where a patient undergoes a partial response to their initial response, I guess, to the protocol as currently designed for re-dosing. Thanks. Yes. Your first question, screening. I think. You know, obviously this study is designed in two parts. There's a screening part and a treatment part. One of the problems we encountered with the screening is that we were right in the middle of COVID. You know, things were getting slow, and then patients would progress. The TRBC1 to ratio is 40-60, so that's kind of what you expected with one concentration versus another. I guess we weren't far off. In terms of manufacturing and re-dosing, there has not been very much luck with CAR T re-dosing generally speaking, you know, particularly in the autologous setting. I mean, it's certainly something we could think about trying, but it's not something that's really on my mind at this point in time, you know, generally speaking, because it hasn't been a strategy that's worked particularly well. You know, never say never. Okay. All right. Great. Thanks for taking the questions. Thanks, Eric. As a reminder to ask a question, please press star then one. If there are no further questions, I'd like to turn the call back over to Christian Itin for any closing remarks. Well, thank you very much everybody for joining. Particular thanks to Dr. Horwitz, to Dr. Cwynarski for the presentations, which were fantastic. Obviously, we're looking forward to keeping you updated on the progress of the programs, and wish you a good week. Thanks, everybody.