It's so great to see so many of you in the room in person. It has been long overdue. Welcome and thank you for joining us today in our R&D showcase. As I said, many of you are here in this room, but there are a lot more who are joining us online. My name is David Chang, President and CEO and Co-founder of Allogene. Many of us have been immersed in cell therapy and sometimes forget to realize that we are in the early days of creating a new modality that is unlike any before it. A single infusion that can induce deep and durable responses, where we now talk about the possibility of cure, even in the advanced and refractory disease setting. CD19 CAR T trial had a humble beginning as an investigator-sponsored academic trial in 2019, quickly gained the momentum as early reports of complete remission were published a few years later. That brought the attention of many in biotech, leading to approval of the first autologous CAR T directed therapies at CD19 in 2017, Yescarta and Kymriah. That momentum continued, by the end of 2021, we now have five FDA-approved CAR T therapies in non-Hodgkin's and multiple myeloma that are expected to generate over $2.5 billion in revenue this year. This is birth of industry we are witnessing. I would say that most of you in this room have played a role. CAR T market is expected to grow at a record pace, projected to reach $10 billion in revenue by 2030. Even with this significant growth, it only represents a small percent of patients, drastically underserving many patients in need. What is needed in this field is to transform CAR-T therapies into off-the-shelf, on-demand CAR-T products that can democratize CAR-T field and meet the growing patient demand. The reason CAR-T therapy market is in crisis and falling behind patient demand is the access challenge. This slide covers a recent survey. 82% of hematologists physicians agree that CAR-T therapies have changed how they manage aggressive cancers. However, only 50% of eligible patients can wait for the manufacturing of CAR-T and receive the therapy. The majority of those patients have to wait 3 to 6 months before they can receive the CAR-T therapy. These are only some of the reasons why access has become a real issue with autologous CAR-T. Allogene was created with one singular mission of creating and leading the next revolution in cancer therapy by delivering to patients first allogeneic CAR-T products for blood cancers and solid tumors, because no patient should have to wait or worse, miss a potentially life-saving therapy. Since the founding of Allogene in 2018, we have made significant advances. Five foundational platform technologies to fuel our innovation. Over 175 patients treated across our CD19, BCMA, and CD70 programs, which by my account, represents as many patients treated as our key competitors combined. Over 300 full-time employees believing in and working relentlessly to achieve our mission. All that leads to what Allogene is about, focused on developing allogeneic CAR-T products. How we operate and how we fuel our innovation and how we continue to execute for growth is depicted in the slide. Leadership experience, clinical execution, manufacturing integration, and research and translational insights. We will cover each of these areas today. Over the last three years, we have been carefully and stepwise assembling key to unlock the potential of allogeneic CAR-T. First, we showed the safety and feasibility. We follow that, as we will do today, by demonstrating durability. We are also working towards scalability, reliably manufacturing all our CAR-T products at our own state-of-the-art manufacturing facility while we focus on execution of clinical programs with the goal of unlocking addressability issue. Our work will continue as we have extensive pipeline in hematologic indications. ALLO-501A, we have initiated industry's first potentially pivotal phase II study, which we project to complete enrollment in the first half of 2024. We are preparing to move to earlier lines with ALLO-501A, and we have identified a next generation developing candidate for CD19. ALLO-715, this is the only allogeneic CAR T therapy that has shown proof of concept in multiple myeloma indication. We will cover our progress in this presentation as we prepare for potential pivotal phase II trial in multiple myeloma. Can we go back one slide? Please go back one slide. Sorry, I advanced too fast. Next slide covers our work on solid tumor indications. Solid tumor is an area of immense interest to us and to me personally as a trained oncologist. Here we have ALLO-316, currently being studied in renal cell carcinoma in phase I dose escalation study. ALLO-213 is targeting DLL3 for small cell lung cancer. ALLO-182, which we are adding to the pipeline, is directed at CLDN18.2 for gastric and pancreatic cancer indications. We have early programs covering additional 7 targets. Today, we will cover updates to our CD19 program, specifically demonstrating that ALLO-501A can achieve deep durable responses and has best-in-class pote ntial. BCMA program, as we prepare for the potential pivotal phase II study in multiple myeloma. Our CD70 program targeting solid tumor, where for the first time, we will present initial proof of concept data for ALLO-316 in renal cell carcinoma. Along with the AGRA technology, an innovative technology based on CD70 biology. Before I go into the agenda, I wanna say something about the durability of allogeneic CAR T, which has been the number one question many of you have asked, because it addresses whether or not allogeneic CAR T products can compete or be an alternative to autologous CAR T therapies. Shown here is the survival plot of 14 patients we presented last year at ASH. At the time, 10 out of 14 patients were in complete remission, with 7 having complete remission at month 6. All of them continued to be in CR after that landmark time point. The same survival plot now a year later. Remarkably, 9 of the 14 patients continue to be in CR, some beyond 2 years. I personally have been in CAR T therapy, CAR T field for some time, and the durability seen in this survival plot and the stability of CR after 6 months is very reminiscent of, and I would say, mirror what autologous CAR T therapies have shown. I would argue such durability is clinically significant and meaningful, and move the field from the possibility to a reality. Next 2 slide covers today's agenda, which is available on our website to be downloaded. In addition to the presentation, we have 2 panel discussions. One on non-Hodgkin's lymphoma and multiple myeloma titled Investigator Insight, where Dr. Eradat, Locke, Munshi, and Rossi, the luminaries in the CAR T field, and more importantly, experts in non-Hodgkin's lymphoma and multiple myeloma who take care of these patients on a daily basis will participate. On the solid tumor panel titled AlloCAR T for renal cell carcinoma, my boss and my mentor, Dr. Arie Belldegrun, the person who had his hands on the creation of the CAR T field, will be part of this panel. Before all that and foremost, he is a practicing urologist with immense experience in the management of renal cell carcinoma. We also have Dr. Malcolm Brenner, Dr. Ritesh Kotecha, and Dr. Robert Motzer for this panel. With that, now let me introduce the next speaker, Dr. Rafael Amado, who is Executive Vice President and Head of R&D at Allogene. Thank you, David. Before I pass the floor to Dr. Locke and Dr. Rossi, to present the updated data in large B-cell lymphoma and multiple myeloma, I just wanna make some remarks about the current state of the programs and future directions. It is important to understand that the science of allogeneic cell therapy differs immunologically from that of autologous, as the patients and products are not HLA matched. Therefore, we had to work from the beginning to mitigate the risk of GvHD and rejection and optimize clinical outcomes. This has required extensive investigation across programs, and we have done this by introducing five products in the clinic, executing seven clinical drug trials, multiple centers to ensure the reproducibility of the findings. We've treated over 175 patients across four different malignancies. Multiple regulatory interactions have taken place, we've obtained Regenerative Medicine Advanced Therapy designation for our two leading candidates in heme malignancies. This slide depicts the evolution of the CD19 program in large B-cell lymphoma. We treated 78 patients between ALLO-501 and ALLO-501A, our two products in non-Hodgkin's lymphoma. In October, after extensive discussions with both FDA and EMA, we initiated the first pivotal trial in large B-cell lymphoma with an allogeneic product in non-Hodgkin's lymphoma. After relapse, refractory large B-cell lymphoma, we'll advance the product to early lines of therapy, starting with second line, we will move into other histologies. This was a process that I wanna emphasize through methodical study. We established proof of concept with the ALPHA trial by showing that TCR gene disruption eliminates GvHD and established proof of concept in NCH 2001 that we validated the platform with this use of the anti-CD52 antibody ALLO-647 and we've determined the randomized phase II dose with this product. We have also optimized the manufacturing process and demonstrated not just the activity, but the durability of complete responses, as David has shown and Dr. Locke will also show in his presentation. Therefore, we're now poised to execute our phase II trial, and we'll prepare BLA submission, launch, and commercial activity. In order to arrive to the execution of a phase II study, we had to optimize a numbers of parameters, as I mentioned. With regards to cell dosing, we explore a single dose versus consolidation, and some of you know that, we've treated a number of cohorts across these schedules. We decided to choose single dose based on clinical outcomes and patient convenience. Ultimately, what we've chosen is standard doses of fludarabine and cyclophosphamide with 90 milligrams of ALLO-647 because that afforded the optimal balance. Lastly, we had to optimize manufacturing, and you will hear more from Alison during her section. We tested the Alloy material and determined that it gave robust, consistent performance, and we've chosen this process for phase II. This has all been done in consultation with regulators, and we're now executing the phase II program in large B-cell lymphoma, as I mentioned. I've been telling you that we have been optimizing a number of parameters, and David showed you the swimmer plots of patients who were in response past 6 months, demonstrating that durability of response in the majority of those patients that attain a CR that lasted for at least 6 months. This is one of the key questions in cell therapy and the most frequent questions that we have received over time: Can allogeneic cell therapy deliver durability outcomes that are commensurate with autologous cell therapy? The following Kaplan-Meier curve depicts the published PFS results of the 3 licensed autologous products in relapsed refractory large B-cell lymphoma. You can see that there's a plateau in the curve, approximately, 40%-55% of the patients. Here we have superimposed the curve of our CD19 product at the recommended phase II dose of SCA 90, which we're using in our pivotal trial. The mean PFS is 23.1 months with a plateau that starts early and remains comparable to that of autologous products, with patients followed in response up to two year. The drop at month 24 is due to a single progression event among those patients who were in CR at two years and simply reflects the smaller sample size compared to the autologous trials that are depicted in the plots. I 'm personally very proud of all the work that has led to the optimization of our CD19 program and has resulted in PFS comparable to that of autologous therapies while treating patients without delay. How have we been able to accomplish this? Here I want to introduce our proprietary technology of ALLO-647. Immune rejection of allogeneic cells is largely mediated by alloreactive T-cells in the host to mismatch HLA antigens of the donor, and therefore reason that effecting a longer window of lymphodepletion with an anti-CD52 antibody could delay rejection and optimize clinical outcome. This graph demonstrates a response relationship between concentrations of the antibody, ALLO-647, and the probability of attaining a response. SCA 90, shown in the box plot at the bottom, leads to higher concentrations and therefore clinical outcomes that are superior. The role of ALLO-647 will be tested formally in the EXPAND trial that I'll explain in a minute. Development program of ALLO-501A in relapsed refractory large B-cell lymphoma is composed of 2 clinical trials. The first utilizes FCA90 and 120 million CAR T-cells in a single arm design that follows a classical design used for registration of autologous CAR Ts. The key endpoints are overall response rate, complete response, with a key endpoint also durability of response. This study will enroll approximately 100 patients. As I stated, the EXPAND study will study the contribution of ALLO-647 to standard fludarabine and cyclophosphamide doses in a 1-to-1 randomization of 70 patients to FC alone versus FC plus ALLO-647. The primary endpoint of this study is progression-free survival, this is the most efficient endpoint that allows us to measure differences in durability between conditioning with C and conditioning with CA. The trial is relatively small as the treatment effect is expected to be large based on the existing data that I just showed you. We're targeting completing the enrollment of these two trials in the first half of 2024. I want to spend a few minutes talking about the evolution of our multiple myeloma program. This is clearly a fast-moving field. We'll talk about it, and we are very proud to have the first allogeneic product that has demonstrated robust activity in this disease. We reported the first allogeneic data back at ASH 2021, where we established the safety and efficacy of ALLO-715, including the data obtained with the optimized cell dose regimen of 320 million cells and optimizing for depletion. Importantly, in contrast with the existing autologous cell products, we can treat the majority of patients and have been able to deliver product to our 67 patients in the UNIVERSAL trial wit hout delay. This product meets specification in every single patient, and we've never used bridging therapy for any of our patients. We have continued to test this dose in an expansion cohort of a standard FC with either 39 mg or 60 mg of ALLO-647, and we have continued to see the durability of the responses. Dr. Rossi will slice the updated data. We're planning regulatory discussions prior to initiating the phase II study and continue to optimize the process for clinical and for commercial manufacturing. We see in 19 allogeneic CAR, the key questions surrounding the field of allogeneic cell therapies, whether durable responses can be achieved. To illustrate the durability of response, this is the swimmer plot shown by Dr. Sham Mailankody from Memorial Sloan Kettering Cancer Center at ASH 2021 for those patients that have remained in response. There were 9 ongoing responses at that time. Of those 9 ongoing responses at ASH 2021, 5 remain in response 10 months later, with some in response for up to 24 months and continuing. We have continued to optimize lymphodepletion, and we'll continue to follow patients to ascertain the optimal response rate and the durability. What is the plan for ALLO-715? We believe we have a competitive benefit risk profile and that this product can play an important role in the treatment of myeloma, given its activity, ability to be administered to all patients without delay, and lack of bridging therapy. We have finalized a lymphodepletion regimen, we have scheduled regulatory discussions under our RMAT designation to discuss a potentially registrational trial, we continue to optimize manufacturing and expect to source material for the clinical program and commercial launch to be manufactured from our CellForge One facility. In conclusion, we have created the most active and durable platform of allogeneic cell therapy products in both CD19 and BCMA programs. ALLO-501A can show deep, durable responses, ALLO-647 is fundamental to the improvement of clinical outcomes. The phase II ALPHA study with ALLO-501A is already ongoing. We believe that ALLO-715 demonstrates activity that's on par with approved BCMA-directed therapies while overcoming some of the drawbacks of these products. Plans are underway for a potential pivotal phase II trial. Having established proof of principle of activity and safety comparable to autologous therapy in most patients enrolled on an immediate treatment basis, our hematological franchise is now poised to undergo late-stage development and become important options for patients. Now it is my pleasure to pass the floor to Dr. Freddie Locke, who will join us remotely from Moffitt to walk us through the latest results in the CD19 program. Subsequent to that, Dr. Adriana Rossi from Mount Sinai Hospital, who's here with us today, will present the updated results in the expansion cohort of ALLO-715 in multiple myeloma. Dr. Locke, you have the floor. Thank you so much, Rafael and David. Thank you so much. I'm sorry I couldn't be there in person with you all. It is good that we're getting back to in-person meetings, but I'm here in Tampa with my family and with my patients. I'm really pleased to be presenting today, the data from the ALPHA studies. See if I can control the slide here. Can you advance the slide, please? Okay, great. Really there's two pillars of any allogeneic CAR T strategy. The first is we need to prevent graft versus host disease, and that's done here with TALEN-mediated TRAC knockout, which prevents the allogeneic CAR T cells from expressing the native T cell receptor, which could activate these T cells against normal host cells. TALEN-mediated knockout of the TRAC locus prevents graft ve rsus host disease. The second pillar that's important in allogeneic cell therapy is protecting the allogeneic CAR T cells from being prematurely rejected by that patient's own immune system. This is achieved here by TALEN-mediated CD52 knockout. This allows the use of ALLO-647 for lymphodepletion, which targets against CD52, which of course is knocked out of the allogeneic CAR T cells. This is really a unique and differentiated approach that has worked well for ALLO-501 and ALLO-501A. ALLO-501 has really shown promising activity in relapse refractory large B-cell lymphoma and has established a proof of concept, and studies have transitioned with the Allogene team to ALLO-501A, which is identical to ALLO-501, except it lacks the rituximab kill switch. ALLO-501 had a rituximab binding region which when you give rituximab could kill the CAR T cells. We now know that that's not necessary. These CAR T cells can be given safely with expected toxicities. The ALLO-501A is identical, it just lacks that rituximab kill switch, and this really enables rapid treatment in large B-cell lymphoma patients, many of whom have already received rituximab. Importantly, with this allogeneic CAR T approach, no HLA matching is needed, and it allows for a true off-the-shelf CAR T cell product. Next slide, please. This slide shows the study design for the ALPHA trials. These trials tested out, you know, ALLO-501 and ALLO-501A in patients with relapse or refractory large B-cell lymphoma who'd had at least two or more prior lines of therapy, had had a prior anthracycline and an anti-CD20 monoclonal antibody, and patients who had a relatively good performance status with an ECOG performance status of zero or one. Importantly, the ALPHA2 study excluded patients with prior autologous CAR-T cell therapy. The primary endpoints are safety, dose-limiting toxicity of the ALLO-647 fludarabine cyclophosphamide regimen, followed by ALLO-501 or ALLO-501A. The overall response rate was by investigator review. You can see here the study schema, enrollment, giving lymphodepleting chemotherapy, including ALLO-647, and then infusion of ALLO-501 or ALLO-501A. There were some arms where consolidation with additional ALLO-501 or ALLO-501A was given, and then follow-up and long-term follow-up. Secondary endpoints include the expansion kinetics of the CAR T cells, the durability of response in ALLO-647, PK studies. Oh, I think we went too far there. Oh, I actually have control if you wanna let me control it here. Thank you. All right. This slide shows the graphics for autologous CAR T-naive large B-cell lymphoma patients. 48 patients with large B-cell lymphoma were treated on the ALPHA and ALPHA2 studies. Of those 48, 33 received the Alloy manufacturing process for their allogeneic CAR T cells. Of those 33 patients, six received a single dose of CAR T cells but had less than 90 milligrams of the ALLO-647. 15 patients received additional consolidation therapy with more CAR T cells, that leaves 12 patients that got a single dose of the CAR T-cell therapy with fludarabine cyclophosphamide and ALLO-647 at 90 mg. It's this dosing regimen that's gonna go forward in the pivotal phase II portion. Importantly, across all large B-cell lymphoma patients, these patients really had advanced disease. About a quarter had an IPI score of 4. 58% had stage four disease. These are heavily pretreated patients with a median of three prior lines of therapy. 17% had a prior autologous stem cell transplant. Really these are advanced, heavily pretreated patients who are going on to get allogeneic CAR T-cell therapy on ALPHA and ALPHA2. The safety profile of, on the ALPHA and ALPHA2 studies is such that the CAR T-cell therapy and the lymphodepleting chemotherapy was manageable entirely by the investigators. There was no Graft-versus-host disease seen, no immune cell-associated neurotoxicity syndrome. 33% of patients who were treated on the single dose FCA90 regimen did have a cytokine release syndrome. However, these were all on the low end, mild, less than grade 3 cytokine release syndrome. There were neurotoxicities seen in a third of patients, but these were generally tremor, muscle weakness, not the ICANS-like confusion syndrome that we typically see with autologous CAR T-cell therapies. 67% of patients had some infection and prolonged cytopenias were seen in 17% of patients. This safety profile compares very favorably to what we see with autologous CAR T cells. Prolonged cytopenias are very common with autologous CAR T cells. Cytokine release syndrome is seen in at least this percentage of patients and more, quite frankly, in large B-cell lymphoma patients, up to 90% of patients with some of the products. Neurotoxicity is generally seen in more patients. I think although we're looking at the numbers of the 12 single-dose FCA90 patients, this is consistent with the other doses of ALLO-501 and ALLO-501A across the study. I think this is generally what we can expect as we move forward in the pivotal clinical trial. This slide shows the outcomes on the ALPHA and ALPHA2 studies. I think what we can see is that the single dose of CAR T-cell therapy with FCA90 really provides optimal responses. You can see the overall response rate, 67%, the complete response rate, 58% respectively, and this is with a median duration of response of 23.1 months. Patients that received a single dose of FC, FCA90 and who had the opportunity to be followed for 6 or 12 months had 6 or 12 months CR rate of 50%. Again, half the patients who've had opportunity were treated at least 12 months ago are in complete response 12 months later. 92% of enrolled patients that were enrolled with the Alloy manufacturing process received the product with that 8% having some ineligibility criteria popping up. Really 100% of infused product manufacturer was manufactured and released per product specifications because this is pre-manufactured CAR T-cell therapy unlike autologous, where it's a bespoke made for the patient product. Here we've got it truly off the shelf. Treatment was initiated within two days of enrollment. I cannot stress how important this is in this field. When we have a patient in front of us, we have to wait to collect their leukapheresis to make an autologous CAR T-cell product, sometimes many weeks to get a manufacturing slot. We have to wait, at the least 3 weeks, and in some cases 6 weeks or longer for that manufacturing process to occur. Many things can happen, and patients can progress. They can require bridging therapy. New toxicities can happen. Frankly, having this product truly off the shelf will make a difference for our patients. David showed us earlier the Dr. Chang showed us earlier the swimmer's plots and the durability responses we're seeing with these allogeneic CAR T-cells. Another way of looking at this is by looking at a progression-free survival curve. The 12 patients treated with a single dose of CAR T-cells at the FCA90 lymphodepleting regimen. You can see here the Kaplan-Meier curve for progression-free survival. It plateaus, it flattens out. Really, this is very encouraging. We need to treat more patients on the pivotal trial. If we can get these kind of results in patients with allogeneic off-the-shelf CAR T-cells that are ready to go, it's really comparable to the results that we have with autologous CAR T-cell products for large B-cell lymphoma. Not only that, we're gonna be able to treat more patients and treat patients more quickly because of the availability of this product. I'm certainly very excited to launch the pivotal portion of the trial and hopefully see these results with a larger group of patients. In conclusion, the ALPHA studies demonstrated the access, feasibility, and durability with AlloCAR T-cell therapy. A single infusion of ALLO-501 or ALLO-501A, manufactured with the Alloy process, produced deep and durable responses in patients with relapse refractory large B-cell lymphoma. Again, these are heavily pre-treated patients, who have relapse and refractory disease, prior to approvals of CAR T-cell therapy really didn't have good treatment options at all. The objective response rate was 67%, with a CR rate of 58% with the single-cell dosing. 50% of patients who were treated at least 6 months before in an ongoing complete response. 50% of patients treated at least 12 months earlier, in ongoing complete response, with the longest CR ongoing at 26 months. There are no dose-limiting toxicities, no immune cell-associated neurotoxicity syndrome, no graft versus host disease. FCA90 was generally well-tolerated with grade 3 or higher CRS or neurotoxicity, and the safety was aligned with a CAR autologous CAR T-cell therapy. In fact, comparing favorably to the CAR T-cell therapies that are on the market now for treatment of large B-cell lymphoma. 92% of enrolled patients received the product, and 100% of infused product was manufactured and released per the product specifications. Treatment was initiated within two days of enrollment. Again, can't stress how important that is for our patients to be able to get them the therapy rapidly. The FDA has granted the RMAT designation to ALLO-501A for relapse refractory large B-cell lymphoma, and this data establishes a strong foundation for the ongoing ALPHA2 study, and hopefully, I believe the industry's first potentially pivotal phase II trial leading to an approval of an allogeneic CAR T-cell therapy for patients with large B-cell lymphoma. I thank you for your attention and I wanna thank all the investigators and the Allogene team for putting this trial together and this day to highlight the exciting results that we have. Thank you very much. I get to do it in person. So I'm Adriana Rossi. I'm with the myeloma program at Mount Sinai, and I co-lead the CAR T-cell therapy program. Do we have the myeloma slides? Perfect. Thank you so much. I think Dr. Locke really set the stage and did a lot of the work for me. Very similarly, the ALLO-715 is a construct, this time targeting BCMA, so in multiple myeloma, it's a separate disease state. Using very similar thinking in that we are using the TALEN technology again to remove the TRAC, as he's already mentioned. That has really provided us with zero graft-versus-host in our patients as well. This knockout of CD52 allowing us to use a monoclonal antibody to then eliminate the patient's own T cells, so the new guys don't have to fight with anyone. Again, there's no HLA matching required, and I get to present an update on just the expansion protocol of patients with 715. Here again, a very similar study design. We have patients coming for screening therapy. These are patients with relapsed myeloma who are refractory to their last line of therapy. These are what we consider patients with an unmet need. They've had all of our standard therapies. As you see in the diagram, we have patients come in for enrollment. They undergo the lymphodepletion, which again, were different combinations evaluated using Cytoxan, fludarabine, and the ALLO-647 combinations. We've now gone through 54 patients, the expansion protocol is specifically looking at the FCA30 and FCA60 cohorts. Patients receive their therapy, then they are with us for two weeks in the hospital, followed by two months of close observation. They expand out to the follow-up phase and ultimately go into long-term follow-up. Very similar design. Here we show patient demographics. Again, fairly small numbers of the 54 patients who've been treated to date. 28 of them are in the expansion cohort. They were then divided into the two different lymphodepletion protocols, all of them receiving the 320 million dose level 3, ALLO-715. Very impressively, again, most of our patients getting autologous products require a month to get their apheresis state and then another one or two months until the prod uct is ready. When we see medium time between enrollment and cells being five days, this is absolutely a completely different experience for our patients who usually, after being relapsed in so many lines of therapy, don't have a lot of time and very challenging to control disease. 92% of those patients received the ALLO-715, again, with 100% manufacturing meeting specifications. This is specifically important given that our commercially available are really kind of hitting a 50% meeting specifications, so adding delays to patients who are waiting for the autologous products. We had 86% of patients being penta-exposed, meaning they've had the 5 other good therapies that we have, and a quarter of them being penta-refractory. Again, fairly small numbers, but most clinical trials will exclude patients with extramedullary disease. Here we had 25% of the patients having extramedullary disease. This is myeloma that has learned to grow where it doesn't belong and really provide very challenging clinical cases for us. As far as safety profile, again, the very construct since we are removing the TRAC with the TALEN technology, we have seen no Graft-versus-host, which I think was our biggest concern theoretically with an allogeneic product. Similarly, the CRS really on par with what we see with the autologous product that we have, about 60%-65% CRS. Here, all but one patient with grade one and two, which is easier to manage. Grade three is when we start to pay attention, we've just had that one patient. Similarly with infections, these are patients who have all their white count depleted sometimes for a prolonged period of time, most infections being grade one and two, so the more manageable. Notably, ICANS, which is the neurotoxicity driven by these immune effector cells, only seen in one patient. The neurotoxicity listed in 17, really very broadly defined. I think we had a very low threshold to label patients as such. No DLTs were seen, so really a very favorable and encouraging data to date. Deep and durable responses. Here's the table with the overall response rates. Very much on par with what we have with the autologous, given a product that we have ready off the shelf. The VGPR are very good partial responses, and all patients who had... Were able to achieve either a complete remission or the very good partial remission were found to have MRD negative responses. We do have a lag, just given the biology of how we measure proteins in the blood. They have a half-life, so they may not match that MRD negativity which we seek and have documented in the marrow, which I think is a more reliable, response. The swimmer's plot, which I really think are easier to conceive than the tables, show that in both cohorts, we have patients getting into CRs and VGPRs. Those that do, again, having been treated long enough and having had the chance to show us, are now lasting up to 24 months. Very impressive, very long-lasting remissions in these patients who are recognized as very high risk with very resistant, disease to date. Responses really, at least on par with the autologous, with much low toxicity. In conclusion, the UNIVERSAL really demonstrates significant durable responses with manageable safety toxicity. We don't have large numbers yet, but it's a very promising start. The ALLO-715 with the different lymphodepletion cohorts, I think the dose level 3 of 320 million of the ALLO-715 with the FCA60 cohort would probably be the adequate expansion for the phase II as we look forward to starting that one up. Thank you. We wanted to introduce the speakers, Dr. Rossi, that you just heard from, and Dr. Locke. Then we will have Dr. Munshi, who will join us from Dana-Farber, as well as Dr. Eradat, who is a hematologist, a malignant hematology expert from UCLA. Before we do that, I just wanted to spend a couple of minutes juxtaposing the results that you just saw for both large B-cell lymphoma, as well as the results coming from our ALPHA and ALPHA2 programs. Here in this charts, we've plotted all the data coming from the label of the products that are approved. We've also plotted both the Alloy products, as well as the 12 patients treated with FCA90, also with Alloy. I just wanted to remark on what Dr. Locke really mentioned before. Remarkably, we see a very low level of neurotoxicity and CRS, particularly the grade 3, in all 45 patients. This compares really very favorable with these approved products. This is something that we hear from investigators pretty often. These numbers are actually not small for a safety assessment, so it really affords us really good confidence that at least for these two class effects, the products are actually mild with regards to serious adverse events. The rate of response, the complete response, at 6 months are very similar across Alloy, resulting in a recommended phase II dose. That is the FCA90 that you saw. Importantly, we look at durability, particularly the CR rate at six months. Across these products, you can see ranges between 31%-50%. And those for Kymriah, Yescarta, and Breyanzi range from 29%-40%+. Therefore, across a very large number of patients, our CD19 program leads to results that are comparable with those of autologous therapies, with the majority of the patients receiving the product as intended. You can see that, the attrition rate in these patients compared with autologous product is much lower. If we now look at the multiple myeloma data, here we are displaying, you know, what Dr. Rossi just showed you, 67% response rate with FCA60, VGPR rate, of 42% with all the patients in VGPR plus having, negative minimal residual disease. This is also associated with very low level of neurotoxicity. We don't see any movement disorders, and low levels of CRS as well. The important thing to note is the patients are treated within five days of enrollment, and we've been able to treat every patient with product on spec, as you would expect from an allogeneic product. We have a greater pool of patients that can gain access to this pre-treatment. We think that this data actually can compare well to the established products when we take into account particularly the percent of patients that don't receive the cell product as intended, which is listed in the chart. These are patients that actually are not in the denominator. That number of patients, which is in the 20s, is very different from the number that we see in our UNIVERSAL study. Therefore, we believe that ALLO-715 really can play an important role in the treatment of multiple myeloma. It clearly can reach more patients. When that is taken into account, the product, you know, would have value for patients at large. As has been mentioned as well, this product also has RMAT designation, and we're in the midst of regulatory discussions to potentially move forward with a pivotal trial. With that, I wanted to start a panel discussion and ask a few questions. Some of our speakers are online, so hopefully technology will help us. I wanted to start with Dr. Rossi, who's here, and Dr. Locke, you know, you both were instrumental in the development of autologous products, and you use them routinely in your practice. I would just want to, you know, ask you to characterize the data that has been presented with Dr. Locke. You know, how would you view that in the context of existing therapies? Right. Yeah. Yeah. Sorry, Dr. Rossi. The lymphoma side to you. Certainly in myeloma, you know, we had a lot of envy because of all the CD19 products that were approved for the lymphomas. Really didn't show any kind of enthusiasm in the myeloma cells. Mostly because these are later cells that don't express the CD19. When BCMA came along, I think there was great enthusiasm. Again, really the field has completely changed since we first started. The autologous, there was great success. These are usually patients who, again, had not a lot of other options. In the autologous side of things, as I mentioned, did still require we're using their tired T cells trying to generate a product that is of benefit and despite the delays, really, very encouraging responses in our most advanced patients with their own T cells. I think many of the areas that we're excited to expand to is to bring that earlier in the disease course, having the option of an allogeneic that is, again, 5 days instead of, in some of our patients, 2-3 months away from getting them that kind of therapy, and of course, looking at different targets. Hoping to get lucky again. Dr. Locke, any further comments on that point? Yeah. Yeah, I would agree with all those comments by Dr. Rossi. I mean, really, what these allogeneic CAR T-cell therapies will hopefully bring to the table is rapidly getting CAR T-cells to patients, okay. We have amazing results with autologous CAR T-cells. We've tested them in a randomized fashion as a second-line therapy, and we see that they can improve outcomes for patients. We still have to wait to get those cells. I mean, we... They're made out of the patient's own T cells. Even in a second-line setting, patients have exhausted T cells that hang out within the tumor, that are exposed to the tumor microenvironment and the systemic inflammation associated with lymphoma or myeloma. We can circumvent that, we believe, by using these allogeneic off-the-shelf products. You, Rafael, you showed the slide. It was very clear. When you see side by side, we've got a small number of patients from ALPHA2 with the doses of conditioning we know we need and the single dose of CAR T-cells. It's very, very promising and a lot of excitement about testing this out in the pivotal trial. I wanted to ask Dr. Eradat if this product, in particularly large B-cell lymphoma, was approved, how would you use it? How would you make the decision to use this versus an alternative? Yeah. Thanks so much. Actually, if I may make a comment regarding kind of recognize this is the first time that I'm aware of that we are actually able to expand allogeneic CAR T-cells. Just the technology itself is quite impressive. I mean, you know, the, we were obviously very impressed with the data efficacy and safety, but the fact that you can actually have allogeneic CAR T-cells that you can put in and the T cells expand and are functional, that in itself is really pretty remarkable to me, separate from the remarkable safety and efficacy. In regards to its use, honestly, you know, part of the difficulty that we have for majority of patients that have relapsed large B-cell lymphoma is the wait times for these sorts of cellular therapies if you're using autologous products, and that's not a minor thing. You know, cumulatively between getting insurance approvals and then getting a cell product collected all the way to infusion of the cells, at its best, at a large center like mine, it can take on as much as 5 weeks. That for a disease that is really galloping away is a very long time to wait for an autologous product. Most... Quite often, I would imagine, if the, that really in the future, what would end up happening is this would probably largely replace autologous cells, really for the majority of the patients that have galloping disease. For the patients that have a sort of a disease that can actually wait and perhaps they can. The disease is controllable to some extent with interim therapy. You know, certainly there's room for autologous products there as well. The other aspect, actually, and I think, is the issue of what happens. Unfortunately, majority of the time, unfortunately, whether it's an autologous product or an allogeneic product that, you know, they may not achieve a durable remission. Here, the data looks impressive. I mean, you're seeing really pretty similar data to what we do in autologous patients. My point in bringing that up is really that what I've seen actually personally and what you have actually enumerated here, a lot of these patients actually after completing the therapy, really don't have protracted side effects. Obviously not only during this course of therapy, but also after the course of therapy. They don't have prolonged cytopenias that limit subsequent lines of therapy. This platform in and of itself actually lends itself to combining with other strategies. Also, you know, you haven't limited the patient's options by giving them cellular therapy, which is one of the concerns with an autologous product at this point. Thank you so much. I wanted to ask a question to Dr. Munshi because I know that his time is short. But he was instrumental in the development of Abecma and has obviously been involved in the development of Carvykti and some other therapies. I wanted to ask you, do you envision that CAR T therapies will be broadly adopted really, and fundamentally change the treatment of multiple myeloma? What are the barriers to really get there? I think, first it's really good to be here, virtually at least. You have brought up a issue that has been reasonably established in our myeloma community that CAR T-cell therapy is here to stay. The depth of response we see, the frequency of response we see in a very late stage patient, six lines and beyond, has been amazing. That's number one. Number two, any therapy we do, and one of the standard therapy in myeloma has been the high-dose chemotherapy with transplant, our aim is to get MRD negativity. What we observe with cellular therapy, is that that's probably the most effective treatment to achieve MRD negativity, not only at one time point, but even sustained over a period of time. With that, the very effective at a very late stage of the disease, ability to achieve a deep response and the response that even at a late stage is sustained over a period of time, has made CAR T a reasonably assured place in myeloma therapy. We are beginning to use it early. It's being compared with transplant, but there is a very high chance that it'll win over transplant as well. There's a really changing field of treatment in myeloma and not just because I'm involved in CAR T-based treatments. They all feel that it will have a very important central role in sustained remissions in multiple myeloma patients. The second question you were asking about was, if I remember right, is any hurdles to treatment, right? Can you hear me? Yes. Yes. Yes. Yeah, yeah. Are there any obstacle to treatment? I think currently, the main obstacle to treatment, CAR T-cell treatment is the production time. The reason we are discussing this is that there's at least 4 to 6 weeks time required currently to produce it. The stage in which patients are getting this is a time when there is reasonable urgency. In one of the study, in the KarMMa study, for example, 88% patients required therapy during the time the CAR T-cells are being produced. Almost all patients require treatment if we have to wait for 4 to 6 weeks. I think that is the hurdle that changes its need. We need to use standard treatment, et cetera. I think that would be number one argument for something that is expeditious and something that can be applied to patients very quickly. Myeloma normally is considered an indolent disease in old days, in earlier stages, in smoldering disease, et cetera. In relapse myeloma patients, there is always an urgency to do the next line of treatment. Since you have the floor, I just wanted to follow up with, you know, the armamentarium is expanding with autologous cell therapies, bispecific, potentially in the future allogeneic cell therapies. How will you make decisions as to how to treat patients based on this wealth of new agents that are coming to, you know, your disposal? I think if you are looking at comparison of what you mentioned, the CAR T cells, bispecifics and then whether it is autologous or allogeneic origin CAR T cells, I think the critically important decision is going to be the access to treatment and one which we can use it for a longer period of time or its effects are observed for a longer period of time. As far as the bispecifics are concerned, which of course are off the shelf and from the bottle, the way the current thinking is that, yes, it is very helpful to give it to patient when we cannot wait, but it also is being evaluated very actively as more as an additional treatment. It is not either/or. I think what we all see it is that the CAR T-cell would be the initial cytoreduction that will lead to MRD negativity or close to it, and then we may continue the immune-based treatment with bispecific. That's not the right word, but you could call maintenance or consolidation treatment that can go on for three, six, 12 months. together, a cellular therapy plus bispecific would achieve the maximal response. I think this algorithm is beginning to be established, beginning to be studied in number of centers and number of situations. I think that's gonna be our algorithm, where cellular therapy followed by bispecific therapy. There'll still be role for some induction therapy if we are bringing it upfront. In the earlier stages, there will be four drug regimen induction followed by CAR T-cell is what we envision. But at a later stage, it would be CAR T followed by bispecifics would be an algorithm that I envision happening in a reasonably near future. Fred, I have the same question for you. You know, how would you use all these therapies in your practice? Well, I think the... We have to do the trial with more patients, the hope is that these could be just as effective as autologous CAR T-cells. frankly, that we are able to get the same level of durable remissions in patients with refractory, relapse refractory disease as we get with autologous CAR T-cells. We essentially start using these off-the-shelf products for all those patients that we'd give autologous CAR T-cell therapy. I think that's possible if the safety profile is what we think it is, and the durable remissions, the remissions are durable and the degree that we've seen in the small number of patients that I've presented. You know, clearly these have activity. I, you know, the bispecifics, they're not quite as, you know, forefront in large B-cell lymphoma as they are in multiple myeloma and follicular lymphoma. Having an off-the-shelf CAR T-cell product that clearly works well and works as well as bispecifics, I think is gonna also be a product that people would use because it can be given quickly. You know, you've got a patient in front of you who's got rapidly progressing disease, you can get them this therapy very rapidly. I think that that's gonna be most desirable. I'm really encouraged that the results are pretty impressive with this small number of patients, and we obviously have to do it for more patients. How it will be used? You know, I... It depends on what. You know, on the trial, I'm gonna enroll patients who would be eligible and, because we're excited about this therapy, and they can get it quickly and rapidly. If it becomes a product, we'll have to see what the label shows. You know, this is definitely something that our patients could benefit from, so I'm excited. If I- Yeah. If I may add that one more point to Dr. Locke's point. In myeloma, that is very true that we need a good immune system for bispecifics to work. The T-cell fitness is important. On the other hand, for CAR T-cell and cellular therapy, because the cells are generated externally, we would be giving healthy cell. In that regards, the allogeneic product has an even leg up over the autologous product, where the T-cell fitness is much superior to what an autologous product would be. There is general clear sense that cellular therapy achieves deeper response and maybe then bispecific can be given later on. Keeping in mind the cellular fitness or the T-cell fitness is an important consideration in deciding one versus another in myeloma setting, and I presume same thing would be in the lymphoma setti ng as well. I couldn't agree more. As we get to later lines of therapy, you know, you have more exhausted T-cells. If you can get this allogeneic product, that's great. If we use a bispecific, we may be exhausting the T-cells too, right? Mm-hmm. Absolutely. Going to an autologous product after a bispecific may not work, but using an allogeneic product, may be helpful. It may be helpful to use it earlier too because you won't cause that exhaustion of the T-cells. You can save those bispecifics for later. I want to ask a question both about lymphoma and myeloma. Maybe Dr. Rossi, I'll start with you in myeloma. You know, what is the setting in which these products should be developed next? I mean, right now they're in the penta-refractory setting, and there are studies across the board looking at, you know, various settings in earlier lines of therapies. Where do you see the, you know, most immediate, you know, subsequent need of? Absolutely. It does make sense. As we were saying, you know, as the patient's T-cells get more and more tired, that is the most unmet need. The other thing, and also in a comparison to bispecifics require the patients continue to come back for repeat dosing. The CAR T-cells, once they get through the acute recovery, they could potentially have years without having to come in and without dealing with the chronic side effects of all the other therapies. I think the sooner we can get CAR T deep remission, long-lasting remission, which with every drug that we use, the earlier in the disease course we use it, the longer the remission is expected. You know, if we have these upfront, as Dr. Munshi was saying, we can get an induction to CAR T and have them in a maintenance-free remission for many years. I think that would be the ideal that we'll work for, at the moment. Thank you. Dr. Munshi, your thoughts on that? Yeah, no. I think Dr. Rossi really mentioned very appropriately that as we develop this therapies and as we apply it to the earlier stages of the patient, we would be able to sequence them appropriately to get maximal response. I think the task for us is to decide what's the maximum response is. In multiple myeloma, it is a little bit becoming clearer with 10 to minus 6 MRD negativity. Looking at the results that was just presented by Dr. Rossi about the MRD negativity observed in all the VGPR patient, it's very encouraging that this may become one of the standards to be utilized to get the deep response we are looking for. The same question for Dr. Eradat and Dr. Locke with regards to large B-cell lymphoma. Obviously there is data and approvals in second line, but, you know, do you think that this cellular therapy should be moved, particularly allogeneic therapy, to earlier lines of therapies? You know, in what setting would you do so? Yeah, I mean, I would echo what was said a little bit earlier in the sense that, you know, part of the concern, for example, with autologous cells, after patients have received a fair amount of cytotoxic therapy, is really some degree of ineffective T cells, whether by exhaustion or depletion of T cells or whatever. In this context, you're at least theoretically able to introduce, basically, T cells that are unaffected by any prior cytotoxic therapy, and they should really. Clearly we know from this data that they are able to expand. I think one of the things that I hope will continue to happen is we will continue to use these sorts of therapies earlier in the, in the relapse setting, and also really potentially even for patients that have high-risk disease, patients that have double hit lymphomas that we know generally, unfortunately, do not have durable remissions with anthracycline-based induction therapies. There is certainly room to try this kind of a strategy with an allogeneic in the front line therapy to perhaps achieve higher response rates and more importantly, durable responses. I think it will largely become the standard, not just because of the durability and the safety, but really just these issues will factor in as well. Yep. I would totally agree. I think- How long do you see these therapies also in the, you know, first, second line? Yeah. Also just a general question. How would you imagine broadening access to CAR T? Yeah. I agree. I think we wanna see it move up into earlier lines. It'd be great to see allogeneic CAR T in the 2nd line setting. In exactly as Dr. Eradat said, you know, in the front-line setting for high-risk patients. I think those are, you know, clinical development questions down the road, I, I see us heading there based upon the current efficacy and safety data. That's really critical too. I, I think CAR T-cell therapy has a very bright future. What was the second part of your question, Rafael? Yeah. How would, you know, would you envision broadening access given that this remains largely confined to tertiary care centers and their, you know, waiting lines and-? Yeah. You know, it becomes an arduous process. I think that this is a critical question. I think the safety is the key piece here, right? If it can be given safely, with low rates of cytokine release syndrome and neurotoxicity, low rates of severe cytopenias or other infectious complications, then you can broaden it out to other tertiary care centers that don't have as much transplant or CAR T experience or even potentially smaller community hospitals. I think it's a safety question, is the main piece there. We need to treat more patients. Just like with autologous CAR T, we got better and better at managing safety profiles. I imagine that will happen with allogeneic CAR T. As far as access and more patients getting it, we already see lineups, especially in our myeloma patients. 100 patients on a waiting list here at Moffitt Cancer Center to get autologous CAR T-cell therapy. They should get CAR T-cell therapy. They may end up getting a bispecific, which I, in my view, is probably not the right sequence, but only because we can't make enough of it. If you've got your product off the shelf and we can give it to our patient, that's what we're gonna do. Yeah. There is I think- Dr. Munshi, do you wanna make one last comment? I just want to make a point that the waiting list, what brought up is so critically important. We need an easy access to it for very, very effective treatment. I think anything that solves an allogeneic example will solve that, is going to play an important role in this disease. Both myeloma, but I would presume lymphoma as well. One, added point is also. Thank you so much, Dr. Munshi. Dr. Dr. Eradat? I was just gonna say, I mean, you know, I could, considering the safety profile here, I could easily envision this being an outpatient therapy in terms of even the glu... I mean, right now we give the lymphodepletion as an outpatient and then meet the patient for cell infusion. Based on the data that has been discussed and presented, it appears to be really quite safe and potentially doable, kind of eliminating the bed situation in a lot of transplant centers and centers that want to deliver this sort of therapy. I think the safety kind of factors in in that context as well. Okay. Well, thank you so much. I think, as I said, we're out of time. Dr. Locke, Dr. Munshi, Dr. Eradat, and Dr. Rossi for a fantastic discussion. Thank you. Thank you. Good afternoon, everybody. I'm Alison Moore. I'm the Chief Technical Officer at Allogene. It's a pleasure to be here this afternoon and tell you a little bit about the capability that we've established in Allogene Operations Technology, and to talk about the development of our processes and products. First of all, the Operations Technology organization and the totality of the capability is comprised of four separate components that work together on a daily basis. Process and Analytical Development that develop the processes and characterize our product. The Manufacturing Organization, which has an excellent track record of flawless execution, and also our CellForge One production facility, which was highlighted in the video. Supply chain management expertise is absolutely critical when making these advanced therapies. The raw materials are also complex, and it requires real supply management skill in order to have products available to make our CAR T product available on time. Our quality organization is releasing product on a regular basis and studying the product to characterize it. As you saw in the video, we couldn't be more proud to have built a state-of-the-art manufacturing facility for our AlloCAR T products. The reason why we think this is very important is severalfold. First of all, control of manufacturing execution. What I really mean there relates to success rates. It takes quite a while to manufacture these products and an even longer time to release them, and it's critical to have excellent execution. Secondly, control of manufacturing allows control of schedule. This is a very competitive industry, and securing scheduling slots in third parties is quite challenging. Having control of our own manufacturing capability allows us to have complete control of that. Also, this allows us to control and project costs accurately. We can control current costs to supply the clinic, and we also understand in fairly great detail what the costs look like for projecting cost of goods manufactured. When we built CellForge One, we thought about building a flexible design which we've achieved. We have a philosophy of having in-house quality control so that we can develop those methods ourselves, understand the performance of those methods, and therefore understand our product as well as we possi bly can. Our facility is built within driving distance of headquarters so that there can be that constant back and forth between the development teams and the execution teams. Under the roof of CellForge One, we have end-to-end capabilities where we are processing PBMCs, we are manufacturing CAR T, and we're filling and maintaining inventory. I'd like to talk about kind of our philosophy of development and how we think about developing and improving the development of our processes in my part of the business. We start with a product concept with a molecular design, and then we proceed with a process development. Alongside that process development, we develop the best methods we can to be able to continually interrogate our process and learn about our product. We can execute and actually make product. As we observe product performance, we're constantly learning. We're learning from the in vitro models that we test our product in. We're learning from a very broad array of methods that we're using for product characterization. We're learning from the translational data that's created within Rafael's organization, and obviously, the clinical outcomes also delivered by Rafael's organization. A key element that was established very early on in Allogene was a data architecture that established a data lake so that all of that cross-functional data can be available to be analyzed, sometimes almost real time. That generates insights that feed back into improved molecular design, process design, and method design. I'd like to touch a little bit on the Alloy process that Rafael has mentioned in his presentation. The Alloy process is a production process that includes a series of unit operations, as do most processes. In the Alloy process, we've come to understand that certain components of the process, for example, transduction, electroporation, expansion, and filling, are interdependent and influence the resulting T cell populations. We've understood that through various orthogonal methods that we've used to study the product, and process conditions have been now optimized for performance and reproducibility. Returning to our cycle, we now have significant manufacturing experience across programs. We did deploy multiple processes in our phase I studies, and our data analytics captured the superior performance of the Alloy process for ALLO-501A. Therefore, we are initiating our phase II trial with Alloy material, and we're deploying the Alloy process in Cell Forge 1. This cycle will continue, and we'll continue those learnings for potential optimization and changes for future products. I feel really proud of the Upstack organization, and what we've done to position ourselves, having achieved phase II readiness. All of the things that we've been exploring together, both Rafael's team and my team, we've had many interactions with the agencies. Over those interactions, we were able to understand fairly early on what the expectations would be and have now been drafted in the latest guidelines. We have successfully achieved phase II readiness, with fairly in-depth product characterization, method qualification, and validation, and setting lot release specifications that are suitable for a pivotal trial. We believe that we've created a really strong foundation and that we're ready to do the work required to support a BLA filing. Thank you very much for your attention, and I will now hand over to my colleague, Eric Schmidt, our Chief Financial Officer. Thank you. Alison. Good afternoon, everyone. I'm pretty sure that everyone here in this room today and online with us today as well is here, at least in part because they believe that CAR T therapy with its very gaudy remission rates and durability has the potential to truly transform cancer patient care. Yet one of the central themes that we hope to leave you with today is that no matter how impressive the clinical data, the advent of CAR T therapy is essentially useless, truly irrelevant to those patients who just can't gain access. Alison provided a lot of insight into what it takes to get manufacturing right, and I think her sleek slide deck and her incredible British accent probably made things sound and look a little bit too easy. I can promise you that, you know, Alison does work fairly hard, somewhat hard. Things, you know, from my vantage point are not nearly as straightforward. It takes a lot of time, a lot of money, a lot of resource, a lot of cooperativity to get things right in manufacturing. Fortunately, as this slide illustrates, Allogene is in a favorable position of having a very scalable process, one in which a single run for AlloCAR T-cells can treat many patients. As Alison noted, we're continuing to iterate and refine that process in hopes of increasing our yields. In contrast, if you look over to the left-hand side of the slide in the autologous setting, as you all well know, an individualized therap y has an inherent challenge. A single manufacturing run is required to treat a single patient. I can't imagine how difficult it's going to be for treating thousands, tens of thousands of patients with thousands and tens of thousands of manufacturing runs. It's truly a daunting task to try and pull off. In some ways, you know, the future success of this modality is going to only exacerbate the bottleneck that we're seeing. Certainly, as cell therapies move earlier stage or into larger indications, this problem is not going to go away. From the patient standpoint, the complexities of delivering care are well documented today. You know, even in circumstances where patients are able to access therapy, it could take months from the time a decision to treat is made until the time therapy is delivered. The reported manufacturing times or so-called vein to vein times represent only a portion of this time interval. You know, in many cases, it's the other considerations, the logistics, the coordination between manufacturer, treatment center, patient scheduling, leukapheresis. Follow-up visits, et cetera, that can be quite rate-limiting. Our goal, of course, is to take this very complex individualized cell therapy that you see on top and make it seamless, make it a pharmaceutical product that can be delivered to patients on demand, stored, shipped, delivered anywhere in the world, and done so that's hassle-free and in a matter of days. Today, you've heard the latest data from our two lead candidates, ALLO-501A for lymphoma and ALLO-715 for myeloma. These are truly first of kind off-the-shelf products we think can truly transform patient care. As I think back to the days when I used to be in the audience at these sorts of events, I can imagine that, you know, many of you are kinda keenly focused on the top two rows of this slide, thinking about comparing and contrasting the metrics that are out there, various response rates, durability of response, safety parameters, et cetera. These are no doubt very, very important things to look at and to contemplate, and certainly, we believe we compare very favorably in those product attributes. What's really has changed from my perspective now that I'm up in front of you and no longer with you down there is that we have a much greater vantage point into deliverability. I'm a little bit closer to the physicians, the logistics of providing patient care, the patients themselves, and I can better appreciate that we shouldn't be underestimating what's on the bottom half of this slide. Specifically, that is that for these patients to be successful, for us to truly deliver on the promise of the clinical data on the top half, we need an allogeneic product. Right now, the current cell therapies are just not doing the trick. We're often asked about how our AlloCAR T therapy might compare to the profile of autologous therapies that are already in the market or bispecifics, which are beginning to emerge. I think as you heard from the panel today, this is not an either/or proposition. This is a very much a both and give me everything I can get proposition. If we do take this question of how we compare to other modalities to its highest levels, I think what's represented on the slide here is the way I would look at this emerging marketplace. With AlloCAR T positioned in the center of the graph, we have a high-end, high-efficacy product. We have on-demand deliverability, and we have one-time dosing. We don't think any of the other modalities can match that same combination of value to the patient. Importantly, as we take a look at the markets where we aim to position ALLO-501A and ALLO-715, we see that these are very large markets, indications that have been historically very receptive to new innovation and markets that even quite recently are seeing rapid product adoption. Specifically, when you look at non-Hodgkin's lymphoma, this is now a $9 billion market that's projected to grow to $17 billion by 2023 in large part, driven by uptake of autologous CAR T therapies. Those therapies themselves are expected to reach $5 billion in 2023. Multiple myeloma, an even larger market today with sales of $34 billion. While the growth in this market is likely to be somewhat constrained by the entry of some generic competition, CAR T sales are projected to ramp up from about $700 million this year to over $6 billion in 2030. If we drill down a little further into the non-Hodgkin's lymphoma market, we see that despite the success that the autologous CAR T therapies are witnessing today, and despite the fact that they're projected to undergo substantial growth in the future, there's still an enormous greenfield or open market opportunity for these drugs. In fact, the projection for $5 billion in 2023 in 2030 sales can be achieved with market penetration of less than 10%. The funnel diagram on the left illustrates that the adoption of CAR T in third line LBCL, this is of course the indication we're going after and an indication where autologous products have now been approved for about 5 years. Despite having unparalleled efficacy in that space, it's pretty clear that autologous CAR T is still reaching less than half of the addressable population. Reasons for this are multifaceted but certainly include barriers that we can overcome, such as limited product availability and rapid disease progression. Moving to the center, as we see the evolution of autologous CAR T products in this market through label expansions, earlier lines of therapy into other histologies. In aggregate, the total addressable population might be 150,000 patients or more per year. Clearly, there is a ton of opportunity here for us to expand into. We think our product profile will allow us not only to compete with autologous products, but as you've just heard from the panel, potentially really expand this market into including the outpatient setting. Oops, can we go back a slide? The story in multiple myeloma is very similar, $6 billion in projected autologous CAR T sales in 2030. That represents a small fraction of the autologous market. Right now, the approved fifth-line indication for autologous CAR T therapy is dramatically under-penetrated, representing the supply limitations that you're all very familiar with. As we look forward, what really needs to happen in myeloma is not just for these therapies to succeed in earlier lines of therapy, which they are doing, but also for us to be able to supply the market, something that we think our off-the-shelf product is very well-positioned to do. In summary, our commercial vision is focused on turning a complex, individualized procedure into a pharmaceutical product. We have the manufacturing and scale that's required to meet demand. Our product candidates, lead candidates, ALLO-501 and ALLO-715, address large markets, which we think are going to be very well poised for further growth and penetration. Thank you. With that, we're gonna take a quick 10-minute break before welcoming you all back to a discussion of our solid tumor strategy. It's 2:35 P.M., so out of deference to those listening online, we plan to restart right at 2:45 P.M. Thanks very much. On the break, well, we're gonna talk about solid tumors and our first foray into solid tumors in the clinic. I'm Barbra Sasu, and I'm the Chief Scientific Officer. I've been running the preclinical pipeline and the innovation platform since 2014 for this allogeneic CAR T platform, first at Pfizer and then at Allogene. Both I and the research group are very excited that we've taken our first CAR T from preclinical studies into the clinic, and we're very excited to show you that data in a few minutes. Where we've started so far in our clinical programs for NHL and multiple myeloma, we've established that our gene editing platform is safe and effective, and we've shown that our lymphodepletion strategy, including ALLO-647, is able to create a window of engraftment which leads to clinical activity. This is great. We're very excited about this, but we believe it's just the tip of the iceberg, and we really wanna dive deeper into other targets to move into solid tumors. Our strategy to start in solid tumors is to go for the easy-to-reach targets and tumor types, starting with targets with high specificity and starting with tumor types that are IO responsive, i.e., tumor types where T cells can infiltrate into them, and if needed, can be used in combination with checkpoint therapies to activate the cells as long as we have the right T cell recognition present. When we have looked at our first couple of solid tumor types, we are in parallel building the tools to allow us to go into the more difficult solid tumor types. Here's the toolkit that we've been assembling over recent years. We're starting with high-impact targets, today I'll be talking to you about our CD70 program. We've been building technologies to help us boost the potency of our CAR Ts, our TurboCAR platform, which gives us a cytokine signal and a site-specific integration platform. We're looking at various ways to overcome the suppressive environment of the tumor microenvironment, in part in collaboration with Antion to develop microRNAs to knock down genes of interest. Last but not least, we're looking at ways to supplement or grow our platform to avoid immune rejection. We're very proud of the work we've done with ALLO-647, and we think we've established the relationship between effective T cell depletion and activity of an allogeneic CAR T. We're enhancing and growing that platform with two more technologies. One called cloaking, where we make our cells, more invisible to the immune system, and the other one, Dagger technology, that I'm gonna focus on today, where we use our CAR-Ts as weapons to seek out and destroy alloreactive T cells. Starting with CD70 as a target. We believe CD70 is a very good target for renal cell carcinoma since it has high and homogeneous expression on about 80% of clear cell renal cell. It's also expressed in some of the solid tumor indications such as lung and in some heme malignancies. Of interest, at the top right there, we see expression in LBCL, where we see good and elevated expression in about 70% of patients, making CD70 a good dual target with CD19. Now in terms of normal tissue expression, we see CD70 expressed just on a subset of immune cells upon activation conditions. A small subset of dendritic cells, but also on activated lymphocytes. What this means is when we make CAR Ts from CD70, when we activate the CAR Ts, we create a wave of CD70 expression during the culture. What this means is CAR Ts can attack neighboring CAR T cells and kill them, a process which we describe as fratricide. In the process of this, many CARs will also get exhausted. What you end up with is not very much product and not very active product. We spent a long time developing a screening pathway where we could get CARs that did not get exhausted and did not commit fratricide during culture. What we actually did was what we have a diagram at the bottom left to illustrate, and this is that we have a class of CARs that mask CD70 on the cells that express them. This means that these CARs next to each other do not commit fratricide because the CD70 is covered and cannot be accessed. However, other lymphocytes nearby that are activated, as in this diagram that express CD70, do get effectively eliminated. This actually means that during production, our CD70 CAR Ts enrich because they basically destroy all the cells around them that are not CAR T positive. That's one mechanism by which we've really enhanced the potency of our CD70 CARs. The other one on the right was epitope selection. You can see an epitope in red there, where when you look at the diagram on the far right that shows you anti-tumor cell activity, you can see that any CAR T's recognizing epitope 1 keep killing through a higher effector to tumor cell ratio, meaning that these CARs really have enhanced potency. In this slide, I've tried to illustrate some of the advantages that were built into our program that created ALLO-316, our CD70 CAR T. These, that's the preclinical work. But what we think we can do with a CD70 CAR goes beyond what we can do merely by targeting CD70 positive tumors. The reason for this is going back to the biology that these CAR T can attack and kill CD70 positive cells. We're using this platform, we're using our CD70 CAR to eliminate alloreactive cells, and this is a mechanism we call the CD70 Dagger. If we look at the diagram here, we can see our CD70 Dagger, and we can see another CAR T here. This can be a CAR T against any target we like. When we infuse these cells into patients, in circulation they see alloreactive cells, and what they do is they recognize the CD70 that's expressed on these cells when they activate, and they eliminate these alloreactive cells. Normal host T cells that are not recognizing our CAR Ts as alloreactive are not expressing CD70, so these are left intact. The normal T cells that are not attacking our cells are untouched. Here's where the biology gets really interesting because if you remember our selection process, we selected for CARs that specifically don't get exhausted when they see target. Now we infuse our CAR Ts into patients. They see alloreactive cells. Not only do they eliminate the alloreactive cells, but as a result they proliferate and become very active themselves, which makes them very good at seeking out and destroying tumors. The way I would like you to think about this is that we have a CAR T that can eliminate alloreactive cells, so it can slow down, delay allorejection. At the same time, they get a proliferative boost that makes them much more potent killers. We believe that with this technology, we've created CAR Ts that have unprecedented expansion and persistence in an allogeneic setting, and this is our Dagger platform. Now I am very excited to turn you over to Dr. Kotecha to tell you about how both of these activities play out in the clinic. Thank you very much. Hi. It's a really great pleasure to talk about the ALLO-316 TRAVERSE trial. Solid tumors, as you've just heard, represent a really new frontier for CAR T-cell therapy, and they really come with an inherent challenge. It's a real pleasure to talk about the experience that we've seen now with ALLO-316 in renal cell carcinoma or kidney cancer. Advanced renal cell carcinoma is a very common tumor type. We see this in about more than 70,000 new patients in the United States every year, and most patients are treated with two large types of therapies, TKI or tyrosine kinase inhibitors and immune checkpoint inhibitors. You can see here that about 15,000 patients do experience disease progression on both TKI and immune checkpoint inhibitors, which are the patients that are studied here on this trial. Really, it's hard to have a benchmark of what type of treatment options are available for patients after TKI and ICI therapy. Tivozanib, which is another type of TKI, is really the only drug with pivotal data in the third line setting, and it really has an objective response rate of less than 20% and a median progression-free survival of less than 6 months. It's also hard to contextualize that because only a quarter of patients receive an immune checkpoint inhibitor on that study. CD70 has been a really large target in kidney cancer that has been investigated previously, but no current therapies really address that target. It's really exciting that the ALLO-316 program is directed against CD70. You can see here as what was noted, which is the most predominant number of patients, over 80% really have tumors that have CD70 positive expression, so this type of therapy could be potentially more broadly accessible. This is the study design. You can see here on the right-hand side, this is the schematic of patients being enrolled, undergoing lymphodepletion, and then a single ALLO-316 infusion. You can see here the CD70 CAR design was also prevented, as what was noted, to prevent any fratricide and also has both gene edits for both the TRAC and CD52 locus to enable CAR T-cell persistence in controlling GvHD. All patients that enrolled on this study having relapsed refractory RCC with a predominantly clear cell component, which is the most common type of kidney cancer, and all patients have received TKI and ICI therapy. On the bottom left, you can see here this is a 3 plus 3 dose escalation, with different dose level cohorts. Dose level 1 of 40 million up to dose level 3 of 120 million, which is where the study currently stands. On the right-hand side, you can see here there are two different conditioning regimens that are being tested in this trial, both the FC or fludarabine cyclophosphamide and the ALLO-647 anti-CD52 and also the FC without ALLO-647. The latter lymphodepletion regimen is being studied to really test that Dagger effect that you just heard about and also really to test whether we can control rejection in the absence of an anti-CD52 antibody. The primary endpoints of the study are safety and tolerability, with secondary endpoints to evaluate antitumor activity and also pharmacokinetics and also cellular kinetics as well. To kind of walk us through the patient flow so far, 17 patients have enrolled with clear cell RCC. All patients have been previously treated with a TKI/ICI therapy. You can see here this is a very heavily pretreated population with a median number of prior treatments of 3 within the cohort. All patients had stage 4 disease. You can see here also that this is kind of widely disseminated disease with most predominantly lung metastatic disease as expected. There are patients that are being treated that have been treated at all 3 dose levels and also various with the FCA and FC conditioning regimens. Now, in terms of the safety profile we've seen so far, this has been generally manageable. You can see here the things that we look for, particularly with an allogeneic product, is GvHD, which we have not seen any of at any type of grade. If you look at the cytokine release syndrome, we can see here that pretty much most patients had experienced low-grade CRS, with the exception of 1 patient who experienced a grade 3 CRS and really no high grade neurotoxicities, both neurotoxicity or ICANS that are high grade, with some low-grade neurotoxicity that was seen to be reversible in a small number of patients. The highest number AEs you see here on the slide are those patients who do did experience infections or prolonged cytopenias, as seen in other CAR products. Looking at our preliminary efficacy data, this is a waterfall, and it's unique 'cause it's separated on the left-hand side between CD70 negative or unknown tumors and those tumors that on retrospective analysis were found to be actually CD70 positive. Just as a reminder, CD70 positive expression was not a part of the eligibility criteria because of the broad expression when the study commenced. You can see here, out of the 17 treated patients, 9 patients were found to have CD70 positive expression by IHC on retrospective testing, and all nine of those patients really were found to have an antitumor effect. You can see here that sort of deepened with three patients achieving more than a 30% tumor reduction in tumor volume or a partial response. In terms of looking at the overall study, the objective response rate was 18% with an 82% disease control rate. Again, if we look sort of at that CD70 positive tumor patients, we did see tumor reduction to some degree in all patients. You can see here a disease control rate of 100% with three patients or 33% achieving a partial response. Looking through exactly the tumor shrinkage as it relates to CD70 expression determined by IHC, if you look at the bottom left-hand corner, this is on the y-axis baseline H score and on the x-axis, the overall response, where H score is a composite of CD70 intensity multiplied by its actual positivity. You can see here that tumor shrinkage correlated with higher CD70 expression. Now with the development of this companion diagnostic to determine CD70 expression levels in patients, the study has been amended to actually deploy this type of diagnostic as part of entry criteria to enter the study, for patients with CD70 positive tumors. This is a spider plot. This is really kind of to look for the durability and the deepening of response over time. You can see here we've separated things with CD70 negative or unknown, and again, CD70 positive tumor expression here on the right. What you can really tell is that there are several patients that really have not only, the anti-tumor activity that's sort of consistent with what we've shown in the waterfall plot, and that correlates with the positive CD70 tumor expression. Most importantly, you can see that those tumor measurements really track over time, and actually in some patients, can lead to a really deepening of response as well, on the bottom right-hand corner, baseline to day 20 to now even month 8. To kinda give a little bit more context to some of the tumor responses that we've been seeing, it's really nice to kind of look at some of these images to see exactly what we're seeing, more so at the actual tumor sites themselves. This is one of the patients who had achieved a partial response. This is a 68-year-old with metastatic clear cell RCC. You can see here metastatic to the lungs here on the CT cro ss-section. You can see here, this is a patient who was treated in the first dose level, so 40 million cells, which is the lowest dose level, and also conditioned with FC and the anti-CD52 ALLO-647. You can see here at month one, the patient was found to already have achieved a partial response. Really even month six, you can see here that has really only deepened as well. There's really durability to this product. Now, this is another patient who had achieved a partial response. This is a patient who's had clear cell RCC again, with really innumerable metastases to the lungs here that are outlined, as you can see on this cross-section, and coronal image here on the bottom. This is a patient that was at dose level 3, so the 120 million CAR T-cell. You can see here that the patient went through really the first month without any Dose-Limiting Toxicities and was found to have tumor reduction at sort of multiple sites of disease here that even sort of was much more significant even at day 56. Really looking for how these T cells might affect other sites of disease, we can see here the ALLO-316 product really can actually infiltrate even primary kidney tumors. This is a patient who achieved a stable disease. On the left-hand side, you can see a large kidney tumor here on the left, and you can see sort of as progression, significant tumor reduction even at the primary kidney tumor site. As a reminder, this is a patient treated at dose level 2 or 80 million CAR T-cell. Looking at exactly how these cells really expand, and to kind of look through the Dagger effect of whether the anti-CD52 is really needed or not. You can see here this is the plot of how the CARs expand. On the Y-axis, you see here vector copy number, VCN, and the X-axis, really time after infusion. We really saw CAR expansion quite high regardless of whether the patients received FC or FCA in that addition. Most importantly, you can see also that the amount of expansion is quite robust. That really expansion was also not so much dependent on the type of cells that the patient received as far as dose number. We saw robust expansion at 40 million, 80 million, and 120 million. Really one of the limitations for CAR T-cell therapy, particularly in the solid tumor context, is to really understand how these CARs might traffic to a specific tumor microenvironment, especially one like RCC, which is really touted as being one of the most immunosuppressive. You can see here that patients undergo a post-treatment biopsy after cells. On the top left-hand corner, you can see here that this is copy number in relative, in relative from the blood to the actual tumor aspirate itself. We see a significant amount of actually CAR trafficking very quickly after infusion. It actually is much more prevalent in the aspirate itself than actually in the blood. It really shows that they can infiltrate these tumor sites, particularly here as a reference to CD70 you see at the tumor. These are, if you kind of look through on the right-hand side, the actual in the tumor responses over time, you can see here that CD70 expression does deepen over time as well. These tumor cells are able to really infiltrate to these specific sites. As far as a summary, the TRAVERSE trial demonstrates feasibility of using an allogeneic CAR T-cell to treat solid tumors, particularly here in this case, RCC. It has a really manageable adverse event profile, as was demonstrated. Really the anti-tumor activity that's observed in CD70-expressing RCC tumor s, we see that particularly in an enriched CD70 expression. We did see that response is correlated with a higher degree of CD70 expression, and that's what's led now the trial to pivot, to use an in vitro diagnostic companion assay of CD70 expression, now as far as entry criteria for this study. What's notable from the correlative work is really that we did see ALLO-316 expansion at really all cell doses, 40, 80, and 120 million. Really that expansion was there regardless of whether the anti-CD52 antibody was used in the conditioning regimen. The trial itself is continuing to explore not only cell dose but also this kind of lymphodepletion strategy in patients to come. Thank you. Yeah, thank you very much, Dr. Kote-Kotecha for presenting our CD70 data. Certainly there's a lot of interesting aspect of the first solid tumor data that we are presenting with ALLO-316. I understand that those who have joined us online, some of the slide deck was a little bit blurry. We are making the presentation deck available on our website to be downloaded. Today, you know, I have a real pleasure of introducing one of the most amazing panel to discuss allogeneic CAR T, and especially in solid tumor, especially in renal cell cancer. Dr. Arie Belldegrun is here in person, and also joining online, Dr. Malcolm Brenner of Baylor College of Medicine, Dr. Ritesh Kotecha, who just presented the data, and Dr. Robert Motzer, from Memorial Sloan Kettering. Before I, you know, start open up the panel, I just want to, you know, share this slide. Dr. Kotecha talked about this a little bit during his presentation, but this is really highlighting the unmet need in 2+ lines of renal cell cancer. What's shown here is the response data as well as progression free survival from mostly phase III studies. This is these studies are done before the advent of checkpoint inhibitors. Most people who have gone on these studies were checkpoint naive at the time that the study was done. What can be seen here is the treatment effect is modest, mostly reaching in the third-line setting response rate that is less than 20%, with a progression-free survival of less than 6 months. Obviously, the patient population that we studied in our ALLO-316 are patients who have received immune checkpoint inhibitor, sometimes inhibitors, more than 1, as well as people who have received VEGF-targeted TKIs. This really highlights the unmet medical need that exists in the, you know, renal cell cancer, and, you know, one of the reason and one of the drivers for us to advance ALLO-316 in the renal cell cancer. As we think about the program, the way we sort of think is, you know, identify the questions, develop the hypothesis, and stepwise address these questions. Shown here are seven key questions that we feel that we have to address as we advance the clinical program. So far, today's presentation, I think we have shown that ALLO-316 can be safely administered. Also the tantalizing data that we have shown, not just the peripheral cell expansion, but also the cell expansion shown in the tumor biopsy, shows that the CAR T cells can infiltrate into solid tumor and expand within the solid tumor. Also, it's early, but we have shown that ALLO-316 can induce deep objective responses in third plus line renal cell carcinoma. We have more to carry out, and we have already implemented some additional things such as patient selection, as well as considering core expansion as we reach the randomized phase to those levels. And also at the same time, we are considering the use of ALLO-316 together with immune checkpoint inhibitors. All about questions that we will stepwise address as we advance the program. So, you know, with that, I'm gonna start the renal cell panel. And let me sit down. Ari, how you doing? Good. Today, for the first time, Allogene presented CAR T data in solid tumors. You know, we in this panel have two people who have been, you know, in the cell therapy field, you know, from the beginning when most of others were saying, "What the hell are they doing, you know, with the cells and trying to treat the tumors?" You're talking about the days of, I don't think anybody talks about, you know, this term anymore, LAK cells and TIL cells, which are, you know, still being developed. With that, I just wanna pose this question, which is being asked, you know, by a lot of people, and I would say without any, you know, good evidence. There is a, you know, sort of general perception that the CAR T therapy, you know, does not work and will not work in the solid tumors. You know, with that, you know, I just wanna first ask you, Malcolm, you know, what's your view about the future of CAR T therapy in solid tumor? Also, what do you think are the important things that has to happen for the, you know, CAR T therapy to gain more traction and become a part of the clinical practice in solid tumor treatment? Yes. You're absolutely right. It is a kind of dogma that CARs are fine for B-cell malignancies, but you need TCRs to treat solid tumors. I guess like most dogmas, it's not really based on a great deal of evidence. In fact, there's a lot of contrary evidence. It's easy to understand how it's arisen. CARs, antibody-based CARs, particularly recognize unmodified, usually lineage-restricted antigens on the cell surface for greatest effect. That's why they've been so prominent in B-cell malignancies. B-cells are a sort of semi-optional A group of cells with which you can destroy along with the tumor. The same doesn't hold true for most solid tumors, of course, 'cause most solid organs are not dispensable. Conversely, though, TCRs recognize some usually internal protein antigens, mutations, tumor specific, that are then processed and presented on the cell surface in association with HLA molecules, which is an important point I'll come back to, where they can then be recognized specifically. The reality though, of course, is very different because there are, in fact, a great many cell surface antigens that can be recognized that are distinctive on tumors from normal tissues. Some of those, like CD70, are over expressed normal antigens, and some of them are genuine mutations, either in protein sequence or glycosylation and so on. I think really the question we need to address is how do we deal with the major problem of solid tumors, which is applicable irrespective of what immune effector you're using, which is how for most tumors in most patients do you cope with the heterogeneity in space and the plasticity over time of tumor antigen expression? I think that's where it we have to consider not whether it's a TCR or a CAR, but how we are going to deal with that kind of shift in antigen expression and varia bility. That's why I'm sort of excited about.. Well, very excited actually, about the Dagger approach, which we've also been very interested in because you have now not only something that will target tumors and can therefore be combined with other tumor-directed CARs, but that will also allow allogeneic cells to be used because it will destroy alloreactive lymphocytes and allow engraftment and expansion. You have, if you like, a universal component, because that's the way the field is going to evolve. We're gonna have to have these pathfinder binders that can be used to effectively treat many specific tumors, and then we're gonna combine them with other pathfinders, if you like, and develop a true effective therapy that will cure, we hope, most tumors in most patients. This is a very important major step on the way to that, in my opinion. Targets in a combination approach in solid tumor, certainly. Yeah. You know, Arie, I'm gonna ask you the same question. You're my boss, but you're also one of the foremost, urologists in this country. As a drug developer, and also as a physician, as you see the ALLO-316 data, what gets you excited about the data? Let's first talk about the boss. You know, it's a real pleasure working with you almost on a daily basis for so many years. While I'm a boss, it's a pleasure and a really honor for me to work with you. Having said that, what excites me is, number 1, that panel here. Bob Motzer and I go back probably at least 35 years, I calculated quickly right now. You have here, the king of the clinical trials. There have been today probably 10 drugs or so approved for kidney cancer. The list is growing. Still, you heard 15,000 are dying every year from the disease. I think that 80% at least of these patients, did these clinical trials were approved based on recommendation or the PI was Bob Motzer. Hear from him today, of what is important and to put it in the right perspective will be really very important. Thirty years ago... Let me just go back. I'm excited about what I hear today for two reason. Number one, the target. Number two, the clinical trial. The target, after so many years, in our lab and in other labs, we try to look for tumor antigens, kidney cancer tumor antigens, which are specific, and we can use them for immunotherapy. Obviously, you heard TKI, checkpoint inhibitors, combination of the two, combination of the three, and so on. I think it's time to move beyond that and to look at new directions for activating the immune system in an interesting approach. What you heard today from Malcolm Brenner is exactly what it is. It is you get two for one with the CD70. The target is extremely interesting. I don't think that there are so many targets or at all in targets in kidney cancer that are expressed on the tumor, but not on normal cells. In addition, in multiple tumors and that can be expanded, and essentially it's almost like a franchise of the CD70 that one can develop. That's the target. The clinical trial. The clinical aspect are very obvious. What I've seen here is two effect. Maybe I can just to those of you who are not living the kidney cancer as we live it for so many years. Exactly 30 years ago, in 1992, the first immunotherapy drug was approved by the FDA. We were all there. It was a study of 155 patients in kidney cancer, 5% complete responses. 4% complete responses, 8% partial responses. That's how it was approved. However, there were 4% mortality of patients in that study. I just want to make sure that you understand that a complete response is not what you are looking with the DLBCL or what in the hematologic oncology. Is tumors that first we, the surgeons, resected completely, whatever we couldn't resect was treated. The 155 patients were all nephrectomized. I built my career on hundreds, if not of thousands, of patients that I took kidneys out and brought into the lab and analyzed all the tumor markers, trying to look for tissue arrays and analyze something. That's all of them had nephrectomized Interleukin-2, for example, and others, the primary tumor is not affected, so the surgery need to be there in order to do a radical nephrectomy. Very rarely with IL-2, tumors are shrinking, or with checkpoint inhibitors, significantly. What you have seen here is a major response in the primary tumor that shows me it's something different than what I have been exposed with probably thousands of patients in kidney cancer. That's on the kidney cancer side. On the clinical, when you see responses, I see it better than when we started with high-dose IL-2. And by the way, high-dose IL-2 is infusion every 8 hours, 3 x a day, 5 days in the hospital, coming up a week, another 5 days. This is a major... It's not a one-timer single agent. There's a lot of reasons why, I'm excited, but I think we have here the guy to, maybe comment and, tell us a little bit on his perspective of all the rest, the non-IL-2, patients. you know, Dr. Motzer, I'm gonna come back to you. Before that, I'm gonna ask this question to Dr. Kotecha. you know, when we were at Sloan Kettering, I mean, there are so many CAR-T trials, you know, going on in your institution. I, you know, hear that lately there are, you know, several, you know, solid tumor CAR-T trials that are ongoing, in your institutions. you know, with that insight, as you sort of think about ALLO-316, what's your level of excitement? Certainly, you know, target is being considered as one of the most important element for solid tumor. What is your level of excitement for CD70, for a target, for renal cell cancer? Are there any better targets that we can go after? You know, I think it really comes back to, as Malcolm and Arie said, I mean, it really comes back to finding the right target for this type of tumor and really understanding how we can enrich and sort of optimize targeting of that agent itself. You know, CD70 has been thought of in the field. We know that it's really broadly expressed in most kidney cancers, but the variability, as Malcolm had mentioned, about heterogeneity between tumor sites, heterogeneity within a tumor itself, that's really been, you know, a huge focus, I think, for the group here working on 316. I think honestly, when we look at CAR T-cell targets, you know, in kidney cancer, you know, outside of just CD70, I mean, the most famous example of that is CA9, right? When some of the first, CAR T-cells were really developed against CA9, and really that experience was really revealing that, you know, CA9 expression was in gallbladder epithelium, and every patient treated really developed, you know, a significant amount of toxicity and cholangitis. Even when blocking CA9 in that respect, it really led to, you know, lessening of that toxicity, but really only no real partial responses either. It was sort of like a dampened effect even when trying to think through the balance that you're trying to strike between target selection of on-target and off-target toxicities. I think the biggest thing with CD70 has really been commented on is it's sort of a two-pronged approach here. You know, you have high tumor expression you've seen here enrichment, particularly with CD70-positive tumors here, and it really that's gonna I think sometimes drive how we think about this as a target. You can see here that there's also potentially a powerful effect it has on sort of preventing any type of rejection or in that respect too. It's almost like, you know, the treatment sort of targeting CD70 has like a twofold advantage here. Thinking through that outside of just the CD70 world in RCC seems really promising. I must, just interrupt for one second because you mentioned the other non-CD70. You mentioned CA9, carbonic anhydrase IX. Well, we have cloned the gene. We have done a lot of work. We wrote a lot of papers. We started working on a CAR T years ago on CA9 when we realized that somebody at the Netherlands already has done it. Patient were treated, and there were major toxicity with rupture of the gallbladder. We said, "Okay, at that time, enough. That's too much for us, and let's move on." CA9 is a very interesting for diagnostic, and you know, it's approved now, not approved, but the phase III clinical trial was positive. I'm not sure it's a diagnostic tool. Agree. I mean, I use it as an example of how the, you know, knowing that understanding really has helped us better target selection. Now let me move a little bit into, you know, this evolving landscape of renal cell carcinoma. I mean, certainly we have seen tremendous progress in this field over the last 20, you know, years. I remember when I was a fellow, I mean, renal cell cancer is like considered as a graveyard for drug development. Everything that went into the development of renal cell cancer never came out until, you know, Bob, you know, you started showing some, you know, amazing data. Before that, after, you know. I'm gonna sort of go back, Ritesh, you're not off the hook yet. 3 patients that you've presented, if I recall, one of the patients, you know, maybe the first patient is somebody you took care of. This is a patient who previously treated with an immune checkpoint inhibitor and VEGF-targeted therapy with more than 1, you know, agent from each class. Patients who have progressed after, you know, such in a prior treatment, what do you do for them? You know, what is their chance of responding to, you know, new therapy at that point? Yeah. I think as Ari mentioned, I mean, everyone is looking for a new modality here. You know, for patients that have been previously treated with TKI IO therapies, it really has come through that the next line therapies are just serial exposures to really TKI therapies and really almost have diminishing returns, right? It becomes challenging because to some degree, some patients might develop potentially toxicities to each of these agents, right? It makes it really limiting to, you know, for example, if somebody had a toxicity to a TKI, then we really eliminated an entire drug class altogether, and the same thing potentially from even an immune checkpoint inhibitor. Thinking outside the box to some degree of what is available for these patients, it's really just serial exposure to the same types of agents. It doesn't really overcome the mechanisms of resistance that might outline the options for these patients. You know, this is a really sort of perfect example that, you know, when I sort of I think on the slide talked about Tivozanib. Tivozanib is, you know, is now really getting a lot of press, particularly because of the approval in the third line sort of space, but doesn't really have the experience that we know of with contemporary agents like combinations and things like that, which is what most patients may have potentially now received. Really the responses that we see again are sort of dwindling in that respect. Thinking outside of a different modality altogether really is on us as a field to kind of move forward from. You know, Dr. Motzer, you know, I've been watching you from distance, you know, about all the accomplishment. You, you know, as a single person, had a hands-on how the outlook of the renal cancer evolved in such a positive way in relatively quick time. Can you sort of walk us through about, you know, how the renal cell cancer is treated nowadays? Yeah, sure. I would be happy to. Thanks for including me in this panel discussion. I, you know, as Ari mentioned, and Ari and I go back decades, as he mentioned. You know, it was a different space years back for kidney cancer. Kidney cancer was really considered to be the cancer with the, you know, worst prognosis. It was almost considered, you know, a tumor in which it was futile to do studies with. Thanks to his groundbreaking work, you know, Interleukin-2 really was the first drug to show some promise, albeit in a small number of patients with toxicity, and also opened the doorway for an interest in immunotherapy in RCC. You know, I, I think the next big gains were the development with VEGF-targeted therapy and the pivotal trial we led with sunitinib compared to Interferon, which established the VEGF tyrosine kinase inhibitors as the new standard of care and led to the development of about 8 of these different molecules that have been approved in various settings in RCC. These are, you know, these are chronically administered drugs. They generally result in partial responses, and they have lots of toxicity over time, cumulative toxicity. I mean, the next really, you know, big gain was with checkpoint inhibitors and the PD-1 inhibitors, Nivolumab and Pembrolizumab, which as you showed in your slide, shows single agent activity in people who had progressed on TKI and now has been incorporated into combination IO therapy. You know, using that approach, the back in the day when Ari and I started, the average survival for people with advanced RCC was only about 9 months. Now it's, you know, it's probably quadrupled and getting longer, each day as the data matures. I think, you know, it has left first of all, a high unmet need for therapy in patients who have progressed on IO combinations. I think that's a window of opportunity for a CAR T. As well, you know, there are really only two established mechanisms of action that we target so far in RCC, the, you know, the VEGF receptor and PD-1. We're desperately seeking for drugs with new novel mechanism of action in RCC. I think that's also, you know, a reason for the really the excitement around this approach. You know, also, the fact that it's, you know, a new technology, highly selective, it's somewhat of giving the example of, with high-dose IL-2 of kind of using a shotgun to stimulate your immune system to battle the cancer. Now, you know, we're in an era with rocket science, with the CAR T. I think that the fact that it's much more selective is also, you know, a real promising point of CAR T. There's widespread excitement across the board. I think that, you know, you speak of CAR T at a renal cancer meeting, and it just like, you know, it really lights the environment up. We're all very enthused about this approach and very interested in seeing it move forward. The data that Ritesh presented, I think, you know, it's somewhat in its infancy. It's early, but it is promising. The fact that we definitely see activity is to me, a clear trigger to move forward and really kind of fully develop this strategy to see if we can, you know, tune in on the responses and see how best to integrate this into standard of care. The, you know, from, you know, Allogene's perspective, not only do we wanna develop this, but we want this to be the standard care, possibly in a CD70-expressing renal cancer in the frontline setting. Any advice on, you know, besides the doing the routine safety, you know, establishing safety and efficacy, any suggestions on, you know, combining it with, you know, other therapies like checkpoint inhibitors, VEGF inhibitors, maybe? Well, I mean, I, you know, I think that, the way I see developing this is really, you know, two paths. One would be to see if you can really identify the group that benefits with this approach as a single agent. You know, perhaps durable responses. To see if, based on patient selection, you can really identify a group with a high likelihood of success and perhaps use it as a single therapy in that group. The second is to, you know, is to combine it with other therapy approaches that are already part of standard of care. I mean, I think that, you know, that whether you use a VEGF targeted therapy or whether you use IO therapy, PD-1 inhibitors, or whether you combine it with both, but certainly IO TKI is a, you know, a viable strategy. I mean, I think part of it depends on, you know, the science that you developed and how you feel, it would. Which sort of of agent or molecule that you think it makes the best sense scientifically to combine it with. I mean, I think combining it with PD-1 inhibitors seems to me, you know, like a really fascinating approach. I certainly. I think most of us would kind of focus on that particular combination. You know, I could go on with this panel discussion forever. Not only, you know, we are, you know, educating the audience here, but I am personally benefiting and also getting a lot of suggestions on how we should be developing ALLO-316. I see the blinking light that tells me to move on to the next one, which is, you know, general open questions. You know, we're gonna open up the floor for the general question, but, you know, Ari, please stay there 'cause you'll be, you know, part of the, you know, response team. Before going into that, you know, let me just show, you know, conclude, you know, today's presentation, you know, before the general Q&A. What we have presented today, we have presented a lot. In the ALLO-501A program, our CD19 program, we have shown the durability of ALLO-501A treatment. The swimmer plot that I flashed in the beginning of my talk, when you look at that, the durability of the response that you're seeing in the swimmer plot is exactly what I saw when I was a part of the team that was developing Yescarta. Not only that, it's providing a deep response, you know, 57% of the people getting a complete remission after single infusion with FCA90 regimen, which is the regimen that we are moving forward in our pivotal study. We also have answered a lot of questions about the 715, the question about the durability and whether the overall safety efficacy profile, and also being able to give these, you know, our allogeneic CAR T to almost all patients who get enrolled in the clinical study, whether this deserves to get further developed. I think we have answered the question, we are preparing ALLO-715 for pivotal study, starting with a regulatory interaction. Also, we have presented for the first time our ALLO-316 solid tumor data. I mean, clinical responses and all those things are very, you know, interesting and very promising, but as a scientist, I look at the data in many different aspects. What we saw in the cell expansion and the fact that we see the CAR T-cells in the tumor and, you know, see them in access in circulation, that tells many different things, including the question that gets frequently asked, do CAR T-cells get into the tumor? I think data like as we have shown, clearly shows that once the CAR T-cells are activated, there's no barrier to where they can get into, and certainly these bodes well as we start thinking about the solid tumor. Certainly the, you know, somewhat of a surprise and you know, become a very interesting technology is the Dagger technology that Barbara has presented. Not only the concept so sound based on CD70 biology, we are also, you know, beginning to see some evidence of that in the expansion profile of ALLO-316 in patients. This is all towards, you know, how Allogene is working towards realizing potential of Allogene CAR T through innovation and execution. Starting from CD19 program and moving into BCMA and continuing the growth of the Allogene CAR T by moving the program into the solid tumor. At the end, this image is what we are trying to achieve. The next revolution in cell therapy that will transform CAR T therapy to CAR T product. You know, going from a procedure to a product in a vial. That's a vision that we have, and I think we're getting one step closer to that. With that, I will open for the general discussion, general Q&A, and I would also like to invite the presenters, you know, Rafael, Dr. Amado, Alison, and also Dr. Rossi. Dr. Rossi. -to the podium. Also, we will have Dr. Locke, Dr. Kotecha, Dr. Brenner, and Dr. Motzer, online, to answer any questions. Please come on up. We'll begin by answering any of the questions we have here in the room first. In the meantime, for those of you on Zoom, if you'd like to ask a question, please raise your hand so we can identify you if the opportunity presents itself. Request. Request. We'll request that you unmute yourself at that time and then move forward. We're gonna start over here with Tyler Van Buren. Great. Thank you very much for the presentations and the discussion. I have a couple questions on ALPHA or the CD19 franchise regarding the data. The first one is, was the efficacy profile for the 12 Alloy FC90 patients somewhat balanced, or did you have a similar number of responses for ALPHA or ALLO-501 patients versus ALPHA2 or ALLO-501A? I guess looking at least from the CR swim lane plot, it appears that way, but curious to hear what you have to say with respect to the 8 responses in those 12 patients. The second one is, why would Alloy consolidation patients have a lower and less durable response than single-dose FC90 patients? Is it potentially due to the ALLO-647 dose? Curious to your thoughts. Okay. When Tyler was asking question in this room, he wasn't even looking at me. He was looking straight to Rafael. Rafael. I think the first question is very astute because you've looked at the swimmer plots and really gotten the answer. Yeah, they were both ALLO-501, ALLO-501A, the responses were virtually the same. No difference. That's not surprising because it's the same construct. As you know, just with the rituximab and suicide switch removed, but it's the same CAR. You know, with regards to consolidation is an excellent question. You know, the premise of consolidation was that if we give more cells, you know, we may obtain, you know, better outcomes. That arose from the fact that we could redose some patients, and they would respond. What we began to realize is that when we started consolidation, we could only retreat patients that had stable disease or better and that did not have toxicity. They had to have been, you know, a good organ function, particularly good bone marrow function. There were a number of patients that were never able to get the second dose of ALLO-647. The reason for that is that, you know, they were still cytopenic, and some patients progressed after the first FCA60 and never got the second dose of cells. The patients that were able to go all the way through obviously did very well, but that's a subset of patients that is self-selected. I think from the premise that given more cells is better, we sort of switched to the premise that given better lymphodepletion with a larger window of T-cell suppression, to allow those cells, those CAR T-positive cells to expand and kill the tumor, is a superior approach. Obviously, we heard from investigators that obviously had more convenience for their patients and it was a much easier procedure to do. That's why we said even though the data with consolidation is good, it's not as good as single agent with 90. Mark Breidenbach from Oppenheimer. Thanks for this presentation. Maybe one question for Doctors Locke and Rossi first. The safety difference, or the safety profile you're seeing with the allogeneic CAR T versus what we've seen in the autologous products, CD19 and BCMA. Is it your impression that there's something intrinsic to ALLO-501A and ALLO-715 that is making their safety profiles milder? Or is it just that we're better at mitigating and treating the side effects of CAR T therapy as we gain more experience? I have a follow-up. I'll go first if that's all right. I would say in myeloma, absolutely, and that's one of the tricky things. If you're looking at data from the early days, we had so much more toxicity because we didn't know, and we were very hesitant to mitigate, especially CRS. We've definitely had a learning curve. I think the impressive thing, at least for the ALLO-715, is how few patients actually require tocilizumab. If you're actually looking, it's not that we're doing more for them, they really haven't needed it. I think both are true. Yeah, I would agree. I mean, the short answer is yes. The reality is there are many factors that go into the expected toxicity rates with the autologous CAR T-cell therapy. There's the costimulatory domain, there's the disease, there's the management strategy and just like in myeloma, in ZUMA-1, in large B-cell lymphoma, we started off very, you know, hands-off with our approach to management of CRS and neurotox, and now we're much more aggressive. I don't think that's the reason here, with the safety results. I don't think it's because of early or prophylactic management that we're seeing low rates of CRS, and ICANS. I think it's probably more related to the construct itself, in that it just has a lower rate of CRS, and ICANS, like some of the autologous products do as well. Maybe a very quick follow-up for Rafael. I apologize if it was indicated on the swimmer plot earlier, was there any particular pattern to the specific histologies of NHL that ended up responding very long term versus the ones who relapsed quickly, which flavors of large B-cell lymphomas? Yeah, we actually looked at patients, you know, very carefully, particularly, you know, patients with poor prognosis like double hit or triple hit lymphomas. There was absolutely no difference between those patients and patients that have normal, you know, cytogenetics, or, you know, gene abnormalities. You know, LDH, I think is a factor. I mean, Fred can attest to that. Patients that have, you know, very high LDH, they don't tend to do well with CAR Ts in general. But we didn't have sufficient sample size to really do, you know, a big analysis. In general, we couldn't identify a single factor that, you know, predicted whether the patient was gonna respond or not. Yeah, I would add to that only that with autologous CAR T, the factors that are associated with response with traditional therapies don't seem to predict response with autologous CAR T. The different flavors, if you will, of large B-cell lymphoma don't predict for response with autologous CAR T. It may be similar with allogeneic CAR T. The things that do start to play out with autologous CAR T are things like tumor size and the pro-inflammatory state, which is sort of immunosuppressive state. That immunosuppressive state is probably just as much associated with poor autologous T-cell function as it is with active suppression after infusion of the CAR T-cell. I'm hopeful that, you know, an allogeneic product can overcome some of those problems with T-cells that are dysfunctional in a, in an inflammatory large B-cell lymphoma. You know, we're excited about the results, as I've already outlined for you guys. Yeah, that's what I would add. I mean, that's a really important point because lymphodepletion is, you know, some patients are not able to have a graft made in the autologous setting. You know, in our case, you know, patients that have low lymphocyte counts, they naturally tend to respond well to ALLO-647, and they have a bigger window of which the cells can expand and kill tumor. In that regard, there's a specific difference that Fred is very correct to point out. Hey, David. Andrea, one on multiple myeloma. Can you confirm your comfort with? Can you just speak into the microphone? Sure. On multiple myeloma, can you confirm your comfort with the ALLO-715 profile to advance into a pivotal trial rather than waiting to fully explore the alternative levers of consolidation dosing or the TurboCAR construct? Personally, I'm beyond excited not only to expand it and again, have this available. Our center has easily another 100 patients. I think Dr. Munshi was saying we all have these dozens and dozens of patients waiting with nothing that we can move forward with. I think we're very encouraged by the data and to move forward with that. I'll say it's not instead of, I would also welcome other approaches, and specifically, for example, for patients with renal insufficiency is one of my personal interests. Maybe there is a different fludarabine-free regimen that we can use for that population specifically. Definitely continue to grow, but I think the current data is strong enough to move forward. To just Kaveh comment. Yeah, just to add to that comment. I totally agree. I think having a two day turnaround time from registration to getting drug is so exciting that there is a need for it, and there'll be use for it to go to the next more definitive trial. Okay. Next question. Who has it? Hey, this is Brian Cheng from JPMorgan. Maybe one question for Frederick. One question on the CD19 side. Going back to your Kaplan-Meier curve, can you provide a bit more color on the patients who fall off at month 24? Are those patients fundamentally different in terms of their stage of the DCs? Just curious if there's any learning here. Dr. Locke. On the, you know, the way a Kaplan-Meier curve works when you get very far out, this curve becomes unstable. You only have a few patients that reach out to that time point. The fact that that drops off does not indicate that we expect a drop off in all those patients. Right now, what I'm looking at on that Kaplan-Meier curve is that flat sort of piece, and we just need more patients to reach out to that time point to really get a better understanding of the durability. That's really what matters for these patients, is durability of response. I would also add, even in the autologous setting, you know, there is a drop-off that happens at a very low rate, but it does occur even after a year or two. As I've said, and having seen the data, both swimmer plot, you know, Kaplan-Meier curve, as well as overall response rate and safety, and, you know, sort of recalling, you know, how, you know, we developed Yescarta in the, you know, five, well, I guess that's almost eight years ago. You know, what we are seeing is, you know, I would say almost overlapping in terms of the, you know, efficacy, including the durability. Next question. This is Reni Benjamin from JMP Securities. I guess for the physicians, are there one or two factors that you would seriously consider or weigh when you're evaluating whether you should be treating with an autologous product or allogeneic? If supply isn't an issue, what kind of factors would lead you to treat one, you know, using one therapy versus another? I guess where I'm going with this is, you know, would you even consider using an autologous therapy after being treated with an allogeneic or if you've progressed from an allogeneic? Thanks. You know, we do have some experience in reusing T-cell redirection, be it CAR T followed by bispecific or vice versa, or a CAR T using a specific target followed by a CAR T targeting something else. I don't know how excited I would be to repeat the same target with the same modality necessarily. In general, using the patient's own T-cells might be interesting in the upfront, which are currently being investigated. As these cells get tired and as these patients start to relapse, you know, they have much shorter time to relapse and much more aggressive relapses. Even if I could get them to pheresis, I am still thinking about a two to three-month lag time to getting the cells into the patient. I think that will always be a very distinguishing feature between the two. I mean, if you're comparing them. The other- Sorry. I was just gonna say, if you're comparing head-to-head, it's efficacy, safety, and frankly, you know, ease of administration and cost, the burden on the patient and on the system. All these things, these go into it. Hey, Jason Gerberry from BofA. Thanks for taking my question. Just wanted to put the RCC update in a little bit more context. You know, as we see the data mature, just curious, it would seem like you're heading down a pathway of some sort of PFS superiority, you know, comparison against the TKI monotherapy. Perhaps because you're looking at CD70 positivity, perhaps there might be some open label accelerated pathways. Just curious, how you're thinking about that and what sort of haircut to the sort of second line market would we need to be even be thinking about with CD70 positivity? Thanks. Okay, Rafael, do you care to answer? Yeah. I mean, there's a possibility obviously that for particularly selected patients, where there is response rates that are very durable, as was mentioned before, single-arm studies can lead to accelerated approval. You know, normally the endpoints that are chosen there are response and durability. We continue to explore both cell dose as well as lymphodepletion to see if we can find responses that are durable and in the order of, you know, what you've seen David present. We will obviously discuss this regulatory-wise to make sure that, you know, this is a viable path. At the same time, we will explore combinations as we mentioned before. Doing a randomized trial of cell therapy and CAR Ts with any drug is a very difficult endeavor. Dr. Kotecha, anything to add? Yeah, I mean, the, you know, the landscape is, you know, quite changed from this sequential therapy of doing TKI or IO therapy to really combinations. This study, you know, is treating patients just who have been previously TKI and IO exposed. There are patients, for example, that this could actually impact on the second line, who have had really refractory disease really in the first line setting to those agents too. There really is an opportunity here to sort of lever a whole another type of mechanism. Hey. Benjamin Burnett from Stifel. I wanna come back to something that was mentioned earlier. You guys talked about the importance of ALLO-647, the amount of ALLO-647, you had that curve. You also showed that the infection rates, especially in the NHL setting, the grade 3 infection rates are quite a bit lower than the autologous setting. Kind of coming back to an earlier question on safety, I guess could you provide a little color as to why that rate was so low? With those learnings and what you've implemented there, is there any appetite to boost ALLO-647 higher in the multiple myeloma setting? Yeah. Good question. I mean, I will answer the question about lymphoma. We were obviously very pleased to see, you know, 8% grade 3 plus infection rate. You know, when that was really critical for us to be able to, you know, move up to FCA90. I would say that, you know, part of the reason why, you know, that infection rate has gone down is because, you know, there's more experience from the investigators on how, you know, to anticipate the potential of these infections. You know, check for viral infections, institute prophylaxis, et cetera. You know, it's like when, you know, what happened with any other therapy, investigators really start understanding how to manage this toxicity. With regards to increasing ALLO-647, as you saw in the curve, we can really get with 90 milligrams, even though the box plots, you know, have relatively high confidence intervals. You can get to, you know, 100% if you get to a given, you know, concentration of about 200, you know, microns per ml of ALLO-647. We don't really think that increasing the concentration is gonna really get us further and, you know, we are very happy with an 8% infection rate of grade 3 plus. We probably have time for one more question. Two more? Okay. Hey, guys. Over here. It's Michael Schmidt with Guggenheim. Thanks for the presentation. I thought it was pretty impressive to see the efficacy data, especially for ALLO-501, ALLO-501A in large B-cell lymphoma with the Alloy manufacturing process. I was just wondering if there was perhaps one particular item or one step in the process that, you know, makes the difference here in the manufacturing, you know, process. Also, if you could comment, how many patients in the ALLO-715 study were treated with the Alloy process versus the legacy, yeah, process. Okay, I was looking for Alison. Yeah, there she is. I'm right here. She is. She is. She didn't go home. Allison. My slide on the Alloy process was intended to say that there are subtle changes related to multiple unit operations that, over time we've been able to understand better play out in the product performance in certain ways. There's no sort of single modification to that process. That was the first question. The second question? In the multiple myeloma study, you know, what proportion of those were treated with the new process versus the prior? In the multiple myeloma study, all patients so far. Right. have been treated with material from the Alloy process. Thank you. Okay, the last question. Last one. Raju Prasad, William Blair. I'll keep it quick 'cause I know we're over. you know, we've talked about the speed with which we can get Allo to the patients, and we've talked about kind of the percentage of patients that, with autologous that, you know, can't be treated. I know we've talked about the responses, but I was just curious, is there a way to identify patients where at the outset, where there's gonna be a manufacturing failure? Sadly, not least for the commercial products. You mean we really don't. We've had a couple dozen patients. You know, we do have a pretty good volume. So far there's nothing a priori that helps us predict about the disease, about the patient, about the prior therapies, the timing of therapies. so far it's and I think it's surprisingly high for anyone. No one expected it to be quite so high. With that, I would like to conclude Allogene R&D showcase. Thank you very much. Time is very precious, and I really appreciate you spending three hours with us as we go through our groundbreaking data across multiple programs. Have a great afternoon.