Allogene Therapeutics, Inc. (ALLO) Earnings Call Transcript & Summary

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 many -- 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, but quickly gained the momentum as early reports of complete remission were published a few years later. That got 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, and by the end of 2021, we now have 5 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, and 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. They 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 Hem-Onc 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, and 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, 5 foundational platform technologies to fuel our innovation, over 175 patients treated across our CD19, BCMA and CD70 programs which, by my count, 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, focus 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 this slide. Leadership experience, clinical execution, manufacturing integration and research and translational insights, and we will cover each of these areas today. Over the last 3 years, we have been carefully and stepwise assembling key to unlock the potential of allogeneic CAR T. First, we show the safety and feasibility. We follow that as we will do today by demonstrating durability. We are also working towards scalability, reliably manufacturing AlloCAR 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 advance too fast. Next slide covers our work in 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. And ALLO-182, which we are adding to the pipeline, is directed at Claudin18.2 for gastric and pancreatic cancer indications. Also, 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 potential. BCMA program as we prepare for the potential pivotal Phase II study in multiple myeloma. And 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 cancer, along with Dagger technology, an innovative technology based on CD70 biology. Before I go into the agenda, I want to say something about the durability of allogeneic CAR T, which has been the #1 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 Swimmer's plot of 14 patients we presented last year at ASH. At that time, 10 out of 14 patients were in complete remission, with 7 having complete remission at month 6. All of whom continue to be in CR after that landmark time point. The same swimmer 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 -- a CAR T field for some time, and the durability seen in this swimmer plot and the stability of CR after 6 months is very reminiscent, and I would say, [ mirror ] what autologous CAR T therapies have shown. And I would argue such durability is clinically significant and meaningful and move the field from the possibility to a reality. Next 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. And 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. But 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 want to 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 actually matched, and therefore, we had to work from the beginning to mitigate the risk of GVHD and rejection and optimize clinical outcomes. And this has required extensive investigation across programs, and we have done this by introducing 5 products in the clinic, executing 7 clinical trials across multiple centers to ensure the [ reproducibility ] of the findings. We've treated over 175 patients across 4 different malignancies. Multiple regulatory interactions have taken place. We've obtained regenerative medicine advanced therapy designation for 2 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 2 products in non-Hodgkin's lymphoma. And 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 relapsed refractory large B-cell lymphoma, we will advance the product to early lines of therapy starting with second line, and then we will move into other histologies. This was a process that I want to emphasize to 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 ASH 2001 that we validated the platform with this use of the anti-CD52 antibody, ALLO-647, with determined 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. So 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 the number 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, and then 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. Now I've been telling you that we have been optimizing a number of parameters, and David showed you a 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? So the following Kaplan-Meier curve depicts the published PFS results of the 3 license autologous products in relapsed/refractory large B-cell lymphoma. You can see that there's a plateau in the curve, approximately 40% to 55% of the patients. Here, we have superimposed the curve of our CD19 product at the recommended Phase II dose of FCA90 which we're using in our pivotal trial. The median 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 2 years. The drop at month 24 is due to a single progression event among those patients who were in CR at 2 years and simply reflects the smaller sample size compared to the autologous trials that are depicted in the plot. 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? And here, I want to introduce our proprietary technology of ALLO-647. Immune rejection of allogeneic cells is largely mediated by our reactive T cells in the host to mismatch HLA antigens of the donor, and therefore, reason that affecting a longer window of lymphodepletion with an anti-CD52 antibody could delay rejection and optimize clinical outcome. This graph demonstrates our response relationship between concentrations of the antibody ALLO-647 and the probability of attaining a response. FCA90 shown in the box plot at the bottom leads to higher concentrations at the 4 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 of durability of response. This study will enroll approximately 100 patients, and as I stated, the EXPAND study will study the contribution of ALLO-647 to standard fludarabine and cyclophosphamide doses in a 1:1 randomization of 70 patients to FC alone versus FC plus ALLO-647. The primary endpoint of the study is progression-free survival, and this is the most efficient endpoint that allows us to measure differences in durability between conditioning with FC and conditioning with FCA. The trial is relatively small as the treatment effect is expected to be large based on the existing data that I just showed you, and we're targeting completing the enrollment of these 2 trials in the first half of 2024. Now 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 optimize lymphodepletion. Importantly, and 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 without delay. And 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 or 60 milligrams of ALLO-647, and we have continued to see the durability of the responses. And Dr. Rossi will summarize the updated data. We are planning regulatory discussions prior to initiating the Phase II study and continue to optimize the process for clinical and for commercial manufacturing. [ FCA90 ] allogeneic CAR, the key questions surrounding the field of allogeneic cell therapies where the durable responses can be achieved. And to illustrate the durability of response, this is a swimmer plot shown by Dr. Sham Mailankody from Memorial Sloan carrying at ASH 2021 for those patients that had remained in response, and there were 9 ongoing responses at that time. Those 9 ongoing responses at ASH 2021, 5 remaining 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. So 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, and we have scheduled regulatory discussions under our RMAT designation to discuss a potentially registrational trial, and we continue to optimize manufacturing and expect to source material for the clinical program and commercial launch to be manufactured from our Cell Forge 1 facility. So in conclusion, we have created the most active and global platform of allogeneic cell therapy products in both CD19 and BCMA programs. ALLO-501A can show deep durable responses, and 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, and plans are underway for a potential pivotal to phase trial. So 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. And now, it is my pleasure to pass the floor to Dr. Freddy Locke, who will join us remotely from Moffitt to walk us through the latest results in the CD19 program. And then 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. So Dr. Locke, you have the floor.

Thank you so much, Rafael and David, thank you so much. I am 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. So really, there's 2 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 a native T cell receptor, which could activate these T cells against normal host cells. So TALEN-mediated knockout TRAC locus prevents graft versus 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. And this is achieved here by TALEN-mediated CD52 knockout. And 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 relapsed/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. So 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, and so 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. And 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. So this slide shows the study design for the ALPHA trials. These trials tested out ALLO-501 and ALLO-501A in patients with relapsed or refractory large B-cell lymphoma who had at least 2 or more prior lines of therapy, 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 0, 1. 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, and 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 for ] consolidation with additional ALLO-501 or ALLO-501A was given, and then follow-up -- long-term follow-up. Secondary endpoints include the expansion kinetics of the CAR T cells, the durability of response and ALLO-647 PK studies. So 40 -- I think we went too far there. I actually have control if you want to let me control it here. Thank you. All right. So this slide shows the patient demographics 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, 6 received a single dose of CAR T cells but have less than 90 milligrams of the ALLO-647. 15 patients received additional consolidation therapy with more CAR T cells, and that leaves 12 patients that got a single dose of the CAR T cell therapy with fludarabine, cyclophosphamide and ALLO-647 at 90 milligrams. And it's this dosing regimen that's going to go forward in the pivotal Phase II portion. So importantly, across all large B-cell lymphoma patients, these patients really had advanced disease. About 1/4 had an IPI score of 4. 58% had Stage 4 disease, these are heavily pretreated patients with a median of 3 prior lines of therapy. 17% had a prior autologous stem cell transplant. So really, these are advanced, heavily pre-treated patients who are going on to get allogeneic CAR T cell therapy on ALPHA and ALPHA2. So 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 were treated on the single-dose FCA90 regimen, did have a cytokine release syndrome. However, these were all on the lower end mild, less than grade 3 cytokine release syndrome. And there were neurotoxicity seen in 1/3 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 patents. 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. And neurotoxicity is generally seen in more patients. And I think although they were 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. So I think this is generally what we can expect as we move forward in the pivotal clinical trial. So this slide shows the outcomes on the ALPHA and ALPHA2 studies. And 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 FCA90 who -- and who had the opportunity to be followed for 6 or 12 months had 6 or 12 months CR rate of 50%. So 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. And really, 100% of infused product manufacturer was manufacturing release 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 2 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. And then 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. And frankly, having this product truly off-the-shelf will make a difference for our patients. So David showed us earlier -- Dr. Chang showed us earlier the swimmers plots and the durability of 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. So 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, and this is what we see with autologous CAR T cell therapy. And really, this is very encouraging. We need to treat more patients on the pivotal trial. But 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 going to be able to treat more patients and treat patients more quickly because of the availability of this product. So certainly very excited to launch the pivotal portion of the trial and hopefully see these results with a larger group of patients. So 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 produce deep and durable responses in patients with relapsed/refractory large B-cell lymphoma. Again, these are heavily pretreated patients who have relapsed and refractory disease. And 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 a single cell dosing, and 50% of patients who were treated at least 6 months before in 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. And FCA90 was generally well tolerated with no grade 3 or higher CRS or neurotoxicity. And the safety was aligned with 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 receive the product and 100% of the infused product was manufactured and released per the product specifications. Treatment was initiated within 2 days of enrollment. Again, I can't stress how important that is for patients to be able to get them the therapy rapidly. And so the FDA has granted the RMAT designation to ALLO-501A for relapsed/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. So I thank you for your attention, and I want to 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.

Good 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 cellular therapy program. Can we have the myeloma slide? Thank you so much. I think Dr. Locke really set the stage and did a lot of the work for me. So very similarly, the ALLO-715 is construct this time targeting BCMA. So in multiple myeloma, a separate disease state, but 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 0 graft versus host in our patients as well. And 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. And so 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, and as you see in the diagram, we have patients coming 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 and the expansion protocol specifically looking at the [ FCA30 ] and FCA60 cohorts. So patients receive their therapy, then they are with us for 2 weeks in the hospital followed by 2 months of close observation, then they expand out to the follow-up phase and ultimately go into long-term follow-up. So 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 2 different lymphodepletion protocols, all of them receiving the 320 million dose level 3 ALLO-715. And so very impressively, again, most of our patients getting autologous products require a month to get their apheresis date and then another 1 or 2 months until the product is ready. So when we see medium time between enrollment and cells being 5 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 715 again with 100% manufacturing meeting specifications. This is specifically important, given that our commercially available are really kind of hitting at 50% meeting specification, 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 1/4 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. And so 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 products that we have, about 60% to 65% CRS. Here, all but one patient with Grade 1 and 2, which is easier to manage. Grade 3 is when we start to pay attention, so we've just had that one patient. Similarly, with infections, again, these are patients who have all their white count depleted sometimes for a prolonged period of time, most infections being Grade 1 and 2, so the more manageable. and notably, ICANs which is the neurotoxicity driven by these immunofactor cells, only seen in 1 patient. The neurotoxicity listed in 17, really very broadly defined. I think we had a very low threshold to label patients as such. And no DLTs were seen, so really, a very favorable and encouraging data to date. So deep and durable responses, again, here is the table with the overall response rates. Again, 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. So 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. And so 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. And those that do, again, having been treated long enough and having had the chance to show us, are now lasting up to 24 months. So very impressive, very long-lasting remissions in these patients who are recognized as very high risk with very resistant disease to date. So response is really at least on par with the autologous with much low toxicity. And so 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 715 with the different lymphodepletion cohorts, I think the dose level 3 of 320 million of the 715, with the FC60 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, and then we will have Dr. Munshi who will join us from Dana-Farber as well as Dr. [indiscernible] who is hematologist, malignant hematology expert on the [indiscernible]. And 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 program. So here, in this chart, we've plotted all the data coming from the label of the products that are approved. And we've also plotted both the alloy products as well as the 12 patients treated with FCA90 also with alloy. And I just wanted to remark on what Dr. Locke really mentioned before. Remarkably, we see a very low level of neurotoxicity and CRS, particularly grade 3, in all 45 patients. And this compares really very favorable with these [indiscernible] products, and this is something that we hear from investigators pretty often. These numbers are actually not small for a safety assessment, so it really [ enforces ] really good confidence that at least for these 2 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 recommended Phase II dose studies to FCA90 that you saw. And importantly, we look at durability, particularly the CR rate at 6 months. And across these products, you can see ranges between 31% to 50%. And those for KYMRIAH, YESCARTA and BREYANZI range from 29% to 40% plus. So 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. And 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 what Dr. Rossi just showed you, a 67% response rate with FCA60, VGPR rate of 42% with all the patients in VGPR plus having negative minimal residual disease. And this is also associated with a 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 have [ treated ] within 5 days of enrollment, and we've been able to treat every patient with product on spec, as you would expect from allogeneic product. So we have a greater pool of patients that can gain access to this 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 sub-product as intended, which is listed in the chart. And these are patients that actually are not in the denominator and that number of patients, which is in the 20s, is very different from the number that we see in our UNIVERSAL study. So therefore, we believe that ALLO-715 really can play an important role in the treatment of multiple myeloma. It clearly can reach more patients. And when that is taken into account, the product would have value for patients at large. And as we 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. So with that, I wanted to start a panel discussion and ask a few questions. Some of our speakers are online, so hopefully, the technology will help us.

I wanted to start with Dr. Rossi, who is here, and Dr. Locke, and you both were instrumental in the development of autologous products and you use them routinely in your practice. I would just want to ask you to characterize the data that has been presented with Dr. Locke, how would you view that in the context of existing therapies?

Lymphoma side to you. Certainly, in myeloma, we had a lot of [ NV ] because of all the CD19 products that were approved for the lymphomas, really didn't show any kind of enthusiasm in the myeloma cells. So mostly because these are later cells that don't express the CD19. So when BCMA came along, I think there was great enthusiasm. And 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. And in the autologous side of things, as I mentioned, did still require -- we're using their entire T cells, trying to generate a product that is a benefit. And despite the delays, really very encouraging responses in our most advanced patients with their own T cells. So 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 to 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?

Yes, yes. I would agree with all of 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? So 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. But we still have to wait to get those cells. I mean we -- and 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 tumor microenvironment and the systemic inflammation associated with lymphoma or myeloma. And we can circumvent that, we believe, by using these allogeneic off-the-shelf products. And Rafael, you showed the slide. It was very clear. When you see side-by-side, we've got a small number of patients from ALPHA and ALPHA2 with the doses of conditioning we know we need and the single dose of CAR T cells. But 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, particularly, large B-cell lymphoma was approved, how would you use it? How will you make the decision to use this versus an alternative?

Yes. Thanks so much. Actually, if I may make a comment regarding kind of -- let's kind of recognize, this is the first time that I'm aware of that we are actually able to expand allogeneic CAR T cells, and this is -- just the technology itself is quite impressive. I mean we are 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 that 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, part of the difficulty that we have for majority of patients that have relapsed large 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. It 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 as much as 5 weeks. And 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. But 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, certainly, there's a 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 allogeneic product, 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. But my point in bringing that up is really that what I've seen actually personally and what you've 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. So this platform in and of itself actually lends itself to combining with other strategies, but also you haven't limited the patient's options by giving them cellular therapy, which is one of the concerns within 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 [indiscernible], and he has obviously been involved in the development of [indiscernible] 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? And what are the barriers to really get there?

Yes. So I think, first, it's really good to be here virtually, at least. You have brought up an 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 patients, 6 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. And what we observed 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. So with that 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 reasonably assured place in myeloma therapy. We are beginning to use it early. It's being compared with transplant, where there is a very high chance that they'll win over transplant as well. And so there's a really changing field of treatment in myeloma, and not just because I mean all in CAR T-based treatment, we all feel that it will have a very important and 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, we can hear you.

So are there any obstacle to treatment? And I think that currently, the main obstacle to treatment, CAR T cell treatment, is the production time and which is where the allogenic -- the reason we are discussing this is that there is at least 4 to 6 weeks' time required currently to produce it, and the stage in which patients are getting this is a time when there is a reasonable urgency. In one of the study, in the [ ABECMA ] study, for example, 88% patients required what is -- what would be called a therapy during the time the CAR T cells are being produced. And so almost all patients require treatment if we had to wait for 4 to 6 weeks, and I think that is the hurdle that changes its need -- we need to use standard treatment, et cetera. And so I think that would be #1 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 diseases, et cetera. But in relapsed 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, momentarily, I mean, it's expanding with autologous cell therapies, bispecifics, 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 your disposal?

Yes. So I think if you're 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. Now 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 patients 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 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-best treatment with bispecific. Sort of if you could -- that's not the right word, but you could call maintenance or consolidation treatment. That can go on for 3, 6, 12 months. And together, a cellular therapy plus bispecifics would achieve the maximal response. And I think this algorithm is beginning to be established, beginning to be studied in a number of centers, in a number of situations. And I think that's going to be our algorithm where cellular therapy followed by bispecific therapy. There'll still the role for some induction therapy, if we are bringing it up front. And so in the earlier stages, there will be, for drug regimen, induction followed by CAR T cell is what we envision. But at a later stage, it would be CAR T followed by BiTEs would be an algorithm that I envision happening in the reasonably near future.

Fred. I have the same question for you. How would you use all these therapies in your practice?

Well, I think the -- we have to do the trial with more patients, but the hope is that these could be just as effective as autologous CAR T cells. And frankly, that we are able to get the same level of durable remissions in patients with refractory -- relapsed refractory disease as we get with autologous CAR T cells. And we essentially start using these off-the-shelf products for all those patients that we give autologous CAR T cell therapy. And I think that's possible if the safety profile is what we think it is and the durable remissions, the remissions are durable and there's degree that we've seen in the small number of patients that I've presented. Clearly, these have activity. And the bispecifics, they're not quite as forefront in large B-cell lymphoma as they are in multiple myeloma and follicular lymphoma. But having an off-the-shelf CAR T cell product that clearly works well and works as well as bispecifics, I think is going to also be a product that people would use because it can be given quickly. And you've got a patient in front of you who got rapidly progressing disease, you can get them this therapy very rapidly. I think that's going to be most desirable. But 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. So how it will be used? It depends on what -- on the trial, I'm going to 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. But this is definitely something that our patients could benefit from, so I'm excited.

If I may add one more point to Dr. Locke's point, in myeloma, it 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. And in that regard, 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. So there is general clear sense that the cellular therapy achieves deeper response and maybe then, bispecific can be given later on. But 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 setting as well.

I couldn't agree more. And now we get in the later lines of therapy, you have more exhausted T cells. And so if you can get this allogeneic product, that's great. If we use the bispecific, we may be exhausting the T cells, too, right? And so going to an analogous product after a bispecific may not work, but using an allogeneic product may be helpful. And it may be helpful to use it earlier, too, because you won't cause that exhaustion of the T cells, and you can save those bispecifics for later.

I want to ask a question both about lymphoma and myeloma. So maybe Dr. Rossi, we'll start with you in myeloma. 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 various setting, scenarios, lines of therapies. Where do you see the most immediate, subsequent need?

Absolutely. It does make sense as we're saying as the patient's T cells get more and more tired, that is the most unmet need. But the other thing and also in a comparison to bispecifics, 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. So 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. 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 will work for at the moment.

Thank you. Dr. Munshi, your thoughts on that?

Yes. No, I think Rossi really mentioned very appropriately that as we develop these therapies and as we apply 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 the maximum response is? And in myeloma, it's a little bit becoming clearer with 10 to minus 6 MRD negativity. And looking at the results that was just presented by Dr. Rossi about the MRD negativity observed in all the VGPR patients, 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, there is data and approvals in second line. But do you think that this cellular therapy should be moved, particularly allogeneic therapy, to earlier lines of therapies? And in what setting would you do so?

Yes. I mean, I would echo what was already -- what was said a little bit earlier in the sense that part of the concern, for example, with autologous cells, after they have received a fair amount of cytotoxic therapy, there's really some degree of ineffective T cells, whether by exhaustion or depletion of T cells or whatever. And 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 -- and clearly, we know from this data that they are able to expand. And so 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 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 frontline 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.

Yes. I would totally agree. I think…

So what do you see -- these therapies also in the first, second line? And also just a general question, how would you imagine broadening access to CAR T?

Yes, so I agree. I think we want to see it move up into earlier lines. It'd be great to see allogeneic CAR T in the second-line setting. And in -- exactly as Dr. Eradat said, in the frontline setting for high-risk patients. So I think those are clinical development questions down the road, but I see us heading there based upon the current efficacy and safety data. That's really critical too. So I think CAR T cell therapy has a very bright future. What was the second part of your question, Rafael?

How would you envision broadening access, given that this remains largely confined to tertiary care centers and their waiting lines and it becomes an arduous process?

I think that this is a critical question. I think the safety is the key piece here, right? And so 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 government hospitals. But I think it's a safety question is the main piece there. We need to treat more patients. And just like with autologous CAR T, we've 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 and again, autologous CAR T cell therapy. They should get CAR T cell therapy. They may end up getting a bispecific, which in my view, is probably not the right sequence, but only because they can't -- 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 going to do, so.

There is some time -- Dr. Munshi, do you want to make one last comment?

I just wanted to make a point that the waiting list for the product is so critically important. We need an easy access to it for very, very effective treatment. So I think anything that solves an allogeneic example will solve that. It's going to have an important role in this disease, with myeloma, but I would presume lymphoma as well.

One added point is also that…

Thank you so much, Dr. Munshi. Dr. Eradat?

I was just going to say, I mean, I could -- considering the safety profile here, I could easily envision this being an outpatient therapy in terms of even -- I mean, right now we give the lymphodepletion as an outpatient and admit the patient for cell infusion. But 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. So I think the safety kind of factors in, in that context as 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. [Presentation]

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. So first of all, the organization that we've built over our time. The operations technology organization and the totality of the capability is comprised of 4 separate components that work together on a daily basis. Process and analytical development that develop the processes and characterize our products; the manufacturing organization, which has an excellent track record of flawless execution; and also our Cell Forge 1 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. Also, 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 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 quite challenging. And so 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 Cell Forge 1, we thought about building a flexible design, which we have 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 possibly 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. And under the roof of Cell Forge 1, 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 developed the best methods we can to be able to continually interrogate our process and learn about our product. Then 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 the data architecture that established a data-link so that all of that cross functional data can be available to be analyzed, sometimes almost real-time. And that generates insights that feedback 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 optimized for performance and reproducibility. So 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 and Cell Forge 1. But this cycle will continue and we'll continue those learnings for potential optimization and changes for future products. I feel really proud of the up-stack 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, 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. So 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. So 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. So thank you very much for your attention. And I will now hand over to my colleague, Eric Schmidt, our Chief Financial Officer. Thank you.

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. 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. But I can promise you that Alison does work fairly hard, somewhat hard. And things from my vantage point, are not nearly as straightforward. It takes a lot of time, a lot of money, a lot of resources, 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, many patients. And as Alison noted, we're continuing to iterate and refine that process in the 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 therapy 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. And in some ways, 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. 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. In many cases, it's the other considerations, it's 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 2 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. So I think back to the days when I used to be in the audience at these sorts of events, I can imagine that many of you are kind of keenly focused on the top 2 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. But what 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. And 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 very much a both and, "give me everything I can get," proposition. But if we do take this question, 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, a position 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 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. If 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 underpenetrated, representing the supply limitations that you're all very familiar with. And 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. So in summary, our commercial vision is focused on turning a complex, individualized procedure into a pharmaceutical product. We have the manufacturing and scale that is 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. So thank you. With that, we're going to take a quick 10-minute break before welcoming you all back to a discussion of our solid tumor strategy. It's 2:35, so out of deference to those listening online, we plan to restart right at 2:45 p.m. Thanks very much. [Break]

[ Welcome back ] from the break. Well, we're going to 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. And 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. So where we started so far in our clinical programs for NHL and multiple myeloma, we've established our that 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. So this is great. We're very excited about this, but we believe it's just the tip of the iceberg, and we really want to 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, so 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. So here's the toolkit that we've been assembling over recent years. Firstly, we're starting with high-impact targets, and 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. And 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, and so we're enhancing and growing that platform with 2 more technologies. One called Cloaking, where we make ourselves more invisible to the immune system. And the other one, Dagger technology that I'm going to focus on today, where we use our CAR-Ts as weapons to seek out and destroy alloreactive T cells. So 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, about 80% of clear cell renal cell. It's also expressed in some of the solid tumor indications such as lung and then some heme malignancies. And 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. So 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 get a wave of CD70 expression during the culture. And 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, and so what you end up with is not very much product and not very active product. So 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. And what we actually did was the -- 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. So 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, the 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. So 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 antitumor cell activity, you can see that any CAR Ts recognizing epitope one keep killing through a higher effector to tumor cell ratio, meaning that these CARs really have enhanced potency. So 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. So 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. And the reason for this is going back to the biology, these CARs can attack and kill CD70 positive cells. Using this platform, we're using our CD70 CAR to eliminate alloreactive cells, and this is a mechanism we call the CD70 Dagger. So if we look at the diagram here, we can see our CD70 Dagger age, and we can see another CAR T here. This can be a CAR T against any target we like. Now 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 now expressing CD70, so these are left intact. So the normal T cells that are not attacking our cells are untouched. And 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. So 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. So 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. So 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. And 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.

It's a really great pleasure to talk about the ALLO-316 TRAVERSE trial. So 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. So 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 2 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. And 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 a 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 1/4 of patients receive an immune checkpoint inhibitor on that study. Now CD70 has been a real large target in kidney cancer that has been investigated previously, but no current therapies really address that target. So 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. Now this is the study design. You can see here on the right-hand side, this is a 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 fracture side and also has both gene edits for both the TRAC and CD52 locus to enable CAR T cell persistence in control and GvHD. All patients that enrolled on this study have in relapsed or 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. And on the right-hand side, you can see here, there are 2 different conditioning regimens that are being tested in this trial, both Fc or fludarabine cyclophosphamide and the ALLO-647, anti-CD52 and also the Fc without ALLO-647. The lateral lymphodepletion regimen is being studied to really test the 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. 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. And 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. And you can see here also that this has kind of widely disseminated disease with most predominantly lung metastatic disease as expected, and there are patients that are being treated -- that have been treated at all 3 dose levels and also various with the FCA and SC 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 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 neurotoxicities or high cancer or high grade with some low-grade neurotoxicity that would seem to be reversible in a small number of patients. The highest number AEs you see here on the slide are those patients who did experience infections or [indiscernible] as seen in other CAR products. Now looking at our preliminary efficacy data. This is a waterfall, and it's unique because 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 part of the eligibility criteria because of the broad expression when the study commenced. But 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 9 of those patients really were found to have an antitumor effect. You could see here that sort of deep in with 3 patients achieving more than a 30% tumor reduction in tumor volume or a partial response. Now in terms of looking at the overall study, the objective response rate was 18% with an 82% disease control rate. But again, if we look sort of at that CD70 positive tumor patients, but we did see tumor reduction to some degree in all patients, you can see here, a disease control rate of 100% with 3 patients or 33% achieving a partial response. Now looking through exactly the tumor shrinkage as it relates to CD70 expression determined by IAC, if you look at the bottom left-hand corner, that this is on the Y-axis baseline each score and on the X-axis, the overall response where H score is a composite of CD70 intent to be multiplied by its actual positivity, you can see here that tumor shrinkage is correlated with higher CD70 expression. And then 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. Now this is a spider plot. And again, 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 against CD70 positive tumor expression here on the right. And what you can really tell is that there are several patients that really have not only the antitumor activity that's sort of consistent with what we've shown in the waterfall plot, and that correlates with the positive CD70 tumor expression, but most importantly, you can see that those tumor measurements really track over time and actually some patients can lead to a redeepening of response as well on the bottom right-hand corner, baseline to day 28 to now even [indiscernible]. Now to kind of 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 or so at the actual tumor sites themselves. So this is 1 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 in the lungs here on the CT cross-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 condition with SC and the anti-CD52 ALLO-647. You can see here at month 1, the patient was found to already have achieved a partial response and really even month 6, you can see here that, that has really only deepened as well. So there's really durability to this product. Now this is another patient who had achieved a partial response. This is a patient who has had clear cell RCC, again, we're really innumerable metastases to the lungs here that are outlined as you can see in 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. And you can see here that the patient went through really the first month without any dose-limiting toxicities and was starting to have tumor reduction in sort of multiple sites of disease here that even sort of was much more significant even at day 56. And really looking for how these T cells might affect other types -- sites of disease, we can see here that ALLO-316 product really can actually infiltrate even primary kidney tumors. So 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. And as a reminder, this is a patient to get the 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 and on the y-axis you see here vector-copy number of ECN and the x-axis really time after infusion but we really saw a CAR expansion quite high regardless of whether the patient has received FC or FCA in that addition. But most importantly, you can see also that the amount of expansion is quite robust, and that rate expansion was also not so much dependent on the type of cells that the patients receive as far as dose number. So we saw robust expansion at 40 million, 80 million and 120 million. And 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. So you can see here that patients undergo a post-treatment biopsy after cells. And on the top left-hand corner, you can see here that this is a copy number in relative from the blood to the actual tumor aspirate itself. So we see a significant amount of actually CAR traffic in very quickly after infusion that actually is much more prevalent in the aspirate itself than actually in the blood, so it really shows that they can infiltrate these tumor sites, particularly here as a reference to CD70 that you see in the tumor. And these are -- if you kind of look through on the right-hand side, the actual tumor responses over time, you can see here that, that CD70 expression does deepen over time as well. So these tumor cells are able to really infiltrate to these specific sites. So as far as a summary, the TRAVERSE trial demonstrates feasibility of using an allogeneic CAR T cell to treat solid tumors, particularly in this case, RCC. It has a really manageable adverse event profile as was demonstrated and really the antitumor activity that's observed in expressing RCC tumors. We see that particularly in an enriched CD70 expression. So 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 core of the work is really that we did see ALLO-316 expansion at really all cell doses 40 million, 80 million and 120 million. And really, that expansion was there regardless of whether the anti-CD52 antibody was used in the conditioning regimen and the trial of such is continuing to explore not only cell dose, but also this kind of lymphodepletion strategy in patients to come. Thank you.

Yes. Thank you very much, Dr. Kotecha for presenting our CD70 data. Certainly, there's a lot of interesting aspects 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 decks were a little bit blurry -- so we are making the presentation deck available on our website to be downloaded. And today, 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 are Dr. Malcolm Brenner, from Baylor College of Medicine; Dr. Ritesh Kotecha, who just presented the data; and Dr. Robert Motzer, from Memorial Sloan Kettering. So before I open up the panel, I just want to share this slide. Dr. Kotecha talked about this a little bit during his presentation. But this is really highlighting the unmet need in 2-plus lines of renal cell cancer. What's shown here is the response data as well as progression-free survival from mostly Phase III studies. And this is -- these studies are done before the [indiscernible] and the checkpoint inhibitors. So most people who have count on these studies were checkpoint naive at the time that the study was done. And what can be seen here is that 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. And obviously, the patient population that we studied in our 316 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 renal cell cancer, and one of the reasons 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 identify the questions, develop the hypothesis and stepwise address these questions. And shown here, 7 key questions that we feel that we have to address as we advance the clinical program. So far in today's presentation, I think we have shown that ALLO-316 can be safely administered and also the tantalizing data that we have shown are not just peripheral site 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. And also, it's early, but we have shown that ALLO-316 can induce deep objective responses in third plus line renal cell cancer. 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 reached the randomized Phase II dose 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 with that, I'm going to start the renal cell panel. And let me sit down. Arie, how are you doing?

Good.

So today, for the first time, Allogene presented CAR T data in solid tumors. And we, in this panel, have 2 people who have been in the cell therapy field from the beginning, when most of others were saying, what the hell are they doing with the cells and trying to treat the tumors. You're talking about the days of I don't think anybody talks about this term anymore, lack cells and T cells, which are still being developed. So with that, I just want to pose this question, which is asked by a lot of people, and I would say without any good evidence, there is a sort of general perception that the CAR T therapy does not work and will not work in the solid tumors. So with that, I just want to first ask you, Malcolm, what's your view about the future of CAR T therapy in solid tumor? And also, what do you think are the important things that has to happen for the CAR T therapy to gain more traction and become a part of the clinical practice in solid tumor treatment?

Yes. So 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. And 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 recognized unmodified, usually lineage restrictive actions on the cell surface the greatest effect. That's why they've been so prominent in B-cell malignancies. B cells are 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, because most solid organs are not dispensable. Conversely, though, TCRs recognize 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 there, of course, is very different because there are, in fact, great many cell surface engines that can be recognized that are distinctive on tumors from normal tissue. Some of those, like CD70, are overexpressed normal actions and some of them are genuine mutations, either in protein sequence or glycosylation and so on. So 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 why immune factor you're using, which is how for most tumors in most patients you cope with the heterogeneity in space and the plasticity over time of tumor antigen expression. And I think that's where 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 variability. And that's why I'm sort of excited about -- very excited about the Dagger approach, which we've also been very interested in because you have now not only something that will target tumors and on therefore, be combined with other tumor-directed CARs, but that will also allow allogeneic cells to be used because it will destroy autoreactive lymphocytes and allow engraftment and expansion, so you have, if you like, a universal component because that's the way the field is going to evolve. We're going to have to have these pathfinder of binders that can be used to effectively treat many specific tumors. And then we're going to combine them with other pathfinders, if you like, and develop a true effective therapy that will cure, we hope, most tumors in most patients. So this is a very important major step on the way to that, in my opinion.

Targets and in a combination approach in solid tumor, certainly. And I'm going to ask you, Arie, I'm going to ask you the same question. You're my boss, but you're also one of the foremost urologists in this country. So as a drug developer and more so as a physician, as you see the 316 data, what gets you excited about the data?

Let's first talk about a boss. It's a real pleasure working with you almost on a daily basis for so many years. So while I'm a boss, it's a pleasure and really honor for me to work with you. Having said that, what excites me is, number one, that panel here. Bob Motzer and I go back probably at least 35 years, I calculate it quickly right now. You have here the king of the clinical trials. We've been today probably 10 drugs or so approved for kidney cancer. The list is growing. Still, you heard 15,000 dying every year from the disease. I think that 80% at least of these patients are these clinical trials were approved based on recommendation of the PI was Bob Motzer. So hearing from him today of what is important and to put it in the right perspective will be really very important. 30 years ago, let me just go back, I'm excited about what I hear today for 2 reasons. 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 2, combination of the 3 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. And what you heard today from Malcolm Brenner is exactly what it is. It is you get 2 for 1 with the CD70. So the target is extremely interesting. I don't think that there are so many targets or at all in targeted cancer that are expressed on the tumor but not on cell or normal cells. But 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. So that's the target. The clinical trial, the clinical aspect, very obvious. What I've seen here is 2 effects. 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. And it was a study of 155 patients and in kidney cancer, 5% complete responses -- 4% complete responses, 8% partial responses, and that's how it was approved. However, there were 4% mortality of patients in that study. Now 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, but first we, the surgeons resected completely. And whatever we couldn't resect was treated. So the 155 patients were all nephrectomized. I built my career on hundreds of thousands of patients that I took kidneys out and bring broadly to the lab and analyze all the tumor markers, trying to look for tissue arrays and analyze something. So that -- all of them had nephrectomized. Interleukin 2, for example, and others, the primary tumor is not affected. So the surgeon need to be -- not to be there in order to do a radical nephrectomy. But 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. So 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 times a day, 5 days in the hospital, coming up a week, another 3 or 5 days, so this is a major -- it's not a onetime single agent. So 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.

Dr. Motzer, I'm going to come back to you. But before that, I'm going to ask this question to Dr. Kotecha, so Memorial Sloan Kettering. I mean there are so many CAR T trials going on in your institution. And I hear that lately, there are several solid tumor CAR T trials that are ongoing in your institutions. So with that insight, as you sort of think about ALLO-316, what's your level of excitement? And certainly, target is being considered as one of the most important elements for solid tumor. What is your level of excitement for CD70 for the target for renal cell cancer? And are there any better targets that we can go after?

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. So CD70 has been thought of in the field. We know that it's really broadly expressed in most kidney cancers, but the variability is now mentioned about heterogeneity between tumor sites, heterogeneity within a tumor itself. That's really been a huge focus, I think, for the group here working on 316. And I think, honestly, when we look at CAR T cell targets in kidney cancer outside of just CD70, I mean the most famous example of that is CA9, right, when for the first CAR T cells were really developed against the CA9, and really, that experience was really revealing that CA9 expression was in gallbladder epithelium and every patient treated really developed a significant amount of toxicity and cholangitis. And even when locking CA9 in that respect, it really led to lessening of that toxicity, but really only no real partial responses either. So 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 have high tumor expression you've seen here in Richmond, particularly with CD70 positive tumors here. And really, that's going to I think sometimes drive how we think about this as a target, and 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. So it's almost like the treatment sort of targeting CD70 has like a twofold advantage here. And thinking through that outside of just the CD70 world in RCC it seems really promising.

I must just interrupt for 1 second because you mentioned the other non-CD70, you mentioned CA9, Carbonic Anhydrase 9. Well, we have cloned the gene. We have done a lot of work. We write like a lot of papers, and we started working on a CAR T years ago on CA9 when we realized that somebody in the Netherlands already has done it. Patients were treated and there were major toxicity with [indiscernible] of the gallbladder. So we said, okay, at that time, enough, that's too much for us, and let's move on. So CA9 is a very interesting for diagnostic, and you know it's approved now for -- not approved, but the Phase III clinical trial was positive, but I'm not sure it's a diagnostic tool.

Agree. I mean, I use it as an example of how -- knowing that understanding really has helped us better target selection.

So now let me move a little bit into this evolving landscape of renal cell carcinoma. I mean, certainly, we have seen tremendous progress in this field over the last 20 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 started showing some amazing data. But before that, I'm going to sort of circle back because you're not off the hook yet. The [ 3 ] patients that you presented, if I recall 1 of the patients, 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 agent from each class. Patients who have progressed after such -- in a prior treatment, what do you do for them? What is the chance of responding to new therapy at that point?

Yes. I think as Arie mentioned, I mean, everyone is looking for a new modality here 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? And it becomes challenging because, to some degree, some patients might develop potential toxicities to each of these agents, right? And it makes it really limiting to, for example, if somebody had a toxicity to a TKI then we really eliminate an entire drug class altogether and the same thing potentially from even an immune checkpoint inhibitor. So 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 I outlined the options for these patients. So this is a really sort of perfect example that when I sort of -- I think on the slide, talked about tivozanib. Tivozanib 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. And really, the responses that we see again, are sort of digging in that respect. So thinking outside of a different modality altogether really is on us as a feel to kind of move forward from.

Dr. Motzer, I've been watching you from a distance about all the accomplishment. You, 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 how the renal cell cancer is treated nowadays?

Yes, sure. I would be happy to. Thanks for including me in this panel discussion. So as Arie mentioned, and Arie and I go back decades, as you mentioned. It was a different space years back for kidney cancer. Kidney cancer was really considered to be the cancer with the worst prognosis. It was almost considered a tumor in which it was a futile to do studies with. But thanks to his groundbreaking work, interleukin 2 really was the first drug to show some promise, albeit in a small number of patients with toxicity and also open the doorway for an interest in immunotherapy in RCC. So 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-TRC 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. But these are chronically-administered drugs. They generally result in partial responses, and they have lots of toxicity -- over time cumulative toxicity. So I mean, the next really 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 and people would progress on TKI and now has been incorporated into combination IO therapy. And so using that approach back in the day, when Arie and I started, the average survival for people with advanced RCC was only about 9 months. And now it's probably quadrupled and getting longer each day as the data matures. So -- but I think it has left, first of all, a high unmet need for a therapy in patients who have progressed on IO combinations. And I think that's a window of opportunity for CAR T. As well, there are really only 2 established mechanisms of action that we target so far in RCC, the VEGF receptor and PD-1. And so we are desperately seeking for drugs with new novel mechanism of action in RCC. And I think that's also reason for really the excitement around this approach. Also the fact that it's a new technology, highly selective, it's somewhat given the example of -- with high dose IL-2 of kind of using a shotgun to stimulate your immune system to battle the cancer. And now we're in an area with rocket science with the CAR T. So I think that the fact that it's much more selective is also a real promising point of CAR T. There is widespread excitement across the board. I think that you speak of CAR T at a renal cancer meeting, and it just 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 it's somewhat in its infancy, it's early. But it is promising and the fact that we definitely see activity is, to me, is a clear trigger to move forward and really kind of fully develop this strategy to see if we can tune in on the responses and see how best to integrate this as a standard of care.

From an Allogene's perspective, not only do we want to develop this, but we want this to be the standard of care possibly in CD70 expressing renal cancer in the frontline setting. Any advice on -- besides doing the routine safety, establishing safety and efficacy, any suggestions on combining it with other therapies like checkpoint inhibitors, VEGF inhibitors, maybe?

Well, I mean, I think that the way I see developing this is really 2 paths. One would be to see if you can really identify the group that benefits with this approach is a single agent, perhaps durable responses and 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. Or the second is to combine it with other therapy approaches that are already part of standard of care. And I mean, I think that, that -- whether you use a VEGF-targeted therapy or whether you use IO-therapy, PD-1 inhibitors or whether you combine it with both, certainly, IO/TKI is a viable strategy. I mean I think part of it depends on the science that you've developed and how you feel it would which sort 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 like a really fascinating approach. And so I certainly -- I think most of us would kind of focus on that particular combination.

I could go on with this panel discussion forever. Not only we are educating the audience here, but I'm personally benefiting and also getting a lot of suggestions on how we should be developing 316. But I see the blinking light that tells me to move on to the next one, which is a general open question. So we're going to open up the floor for the general question, but Arie, please stay there because you will be part of the response team. But before going into that, let me just conclude today's presentation 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 [indiscernible] 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 [indiscernible] is exactly what I saw when I was a part of the team that was developing YESCARTA. And not only that, it's providing a deep response, 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 our allogeneic CAR T to almost all patients who will get enrolled in the clinical study whether this deserves to get further developed. I think we have answered the question, and we are preparing ALLO-715 of our pivotal study starting with a regulatory interaction. And also, we have presented for the first time, our ALLO-316 solid tumor data. I mean clinical responses and all those things are very 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 see that 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, this bodes well as we start thinking about the solid tumor. And certainly, somewhat of a surprise and become a very interesting technology is the Dagger technology that Barbra has presented. Not only the concept is so sound based on CD70 biology, we are also beginning to see some evidence of that in the expansion profile of ALLO-316 in patients. I mean this is all towards how Allogene is working towards realizing potential of allogeneic CAR T through innovation and execution, starting from CD19 program and moving into BCMA, and continuing the growth of the allogeneic CAR T by moving the program into the solid tumor. So at the end, this image is what we are trying to achieve. The next revolution in cell therapy, they will transform CAR T therapy to CAR T product. Going from a procedure to a product in a vial. And that's a vision that we have, and I think we're getting 1 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 Rafael, Dr. Amado, Alison, and also Dr. Rossi to the podium. And also, we will have [indiscernible], Dr. Kotecha, Dr. Brenner and Dr. Motzer online to answer any questions. Please come on up.

So we'll begin by answering any of the questions we have here in the room first. [Operator Instructions] But we're going to start over here with Tyler Van Buren.

Great. Thank you very much for the presentations and the discussion. I have a couple of questions on alpha, the CD19 franchise regarding the data. So the first one is was the efficacy profile for the 12 alloy FC 90 patients somewhat balanced? Or did you have a similar number of responses for alpha-1 or 501 patients versus alpha 2 or 501A? I guess looking at least from a CR swimmer plot, it appears that way, but curious to hear what you have to say with respect to the 8 responses in those 12 patients? And then the second one is why would alloy consolidation patients have a lower and less durable response than single-dose FC 90 patients? Is it potentially due to the 647 dose? Curious to hear your thoughts.

Okay. When Tyler was asking the question in this room, he wasn't even looking at me, he was looking straight to Rafael. So Rafael?

So I think the first question is very [indiscernible] because if you look at the consumer lots and really gotten the answer. So yes, there were both 501, 501A and the responses were virtually the same. So no difference. And that's not surprising because it's the same construct as just with the rituximab, [indiscernible] remove, but this is the same CAR. With regards to consolidation, it's an excellent question. So the premise of consolidation was that if we give more cells, we may obtain better outcomes. And 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 would only treat patients that had stable disease or better and that did not have toxicity. So they have to have a good organ function, particularly good [indiscernible] function, and there were a number of patients that were never able to get the second dose of 6 or 7. And the reason for that is that there were still cytopenic, and some patients progressed after the first FCA 60 and never got the second dose of cells. So the patients that were able to go all the way through, obviously, did very well, but that's a subset of patients that is so selective. So 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 plus CAR T cells to expand and kill the tumor is a superior approach. And obviously, we heard from investigators that obviously had more convenience for their patients and it was a much easier procedure. So that's why we said even though the data with consolidation is good, it's not as good as single agent with it.

Mark Breidenbach from Oppenheimer. Maybe one question for Drs. 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 Allogene's 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? And then I have a follow up.

I'll go first. 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 when we were very hesitant to mitigate, especially CRS. So we've definitely had a learning curve. But I think the impressive thing at least for the ALLO-715 is how few patients actually require TOCRDEX. So if you're actually looking, it's not that we're doing more for them, they really haven't needed it. And so I think both are true.

Yes, 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, ZUMA-1 in large B-cell lymphoma, we started off very 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.

Okay. Maybe a very quick follow up for Rafael. So I apologize if it was indicated on the swimmer plot earlier, but was there any particular pattern to the specific histologies of NHL that ended up responding very long term versus the ones who relapse quickly? Which flavors of large B-cell lymphomas?

Yes. We actually looked at patients very carefully, particularly patients with prognosis like double head or triple head lymphomas. There was absolutely no difference between those patients and patients that have normal cytogenetics or gene abnormalities, and LDA checking is a factor. And I mean, Fred kind of tested that patients that have very high LDH. They don't tend to do well with CAR Ts in general, but we didn't have a sufficient sample size to really do a big analysis. And in general, we couldn't identify a single factor that predicted whether the patient was going to respond or not.

Yes. 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. So the different flavors, if you will, of large B-cell lymphoma don't predict for response with autologous CAR-T. So 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 an immunosuppressive state, and 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 cells. So I'm hopeful that an allogeneic product can overcome some of those problems with T cells that are dysfunctional and in an inflammatory large B-cell lymphoma. So we're excited about the results, as I've already outlined for you guys. But yes, that's what I would add.

I mean that's a really important point because lymphodepletion is -- some patients are not able to have a graft made in the autologous setting in case, patients that have low lymphocycones, they actually tend to respond well to ALLO-647 and they have a bigger window of -- which the cells can expand and kill tumor. So in that regard, there's a specific difference that Fred has very correctly pointed out.

[indiscernible] myeloma, can you confirm your comfort level...

Can you speak to the microphone?

Sure. On multiple myeloma, can you confirm your comfort with the 715 profile to advance into a pivotal trial rather than waiting to fully explore the alternative levers of consolidation dosing or the turbo CAR 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. So 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. So maybe there is a difference for there being free regimen that we can use for that population specifically. So definitely continue to grow, but I think the current data is strong enough to move forward.

I'll just add to your comment. Yes. Just to add to that comment. I totally agree. I think having a 2-day turnaround time from registration to getting drug is so exciting that there's a need for it and they'll be used for it to go to the next more definitive trial.

Okay. Next question.

This is Brian Cheng from JPMorgan. So maybe one question for Frederick. One question on the CD19 side. So 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 PCs? And just curious if there's any learning here?

Dr. Locke?

So the way 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. So the fact that, that drops off does not indicate that we expect a drop off in all those patients. So right now, what I'm looking at on that [indiscernible], 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.

And I would also add, even in the autologous setting, there is a drop-off that happens at a very low rate, but it does occur even after a year or 2. So as I've said, I mean having seen the data, both swimmer plot, Kaplan-Meier curve as well as overall response rate and safety and sort of recalling how we developed YESCARTA in the -- I guess that's almost 8 years ago, what we are seeing is, I would say, almost overlapping in terms of the efficacy, including the durability. Next question?

This is Reni Benjamin from JMP Securities. I guess for the physicians, are there 1 or 2 factors that you would seriously consider a wait when you're evaluating whether you should be treating with an autologous product or allogeneic. So if supply isn't an issue, what kind of factors would lead you to 1 -- using 1 therapy versus another? And I guess where I'm going with this is, would you even consider using an autologous therapy after being treated with an allogeneic or if you've progressed for the allogeneics?

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. But in general, using the patient's own T cells might be interesting in the upfront, which are currently being investigated. But as these cells get tired and as these patients start to relapse, they have much shorter time to relapse and much more aggressive relapses. Even if I could get them to [indiscernible], I am still thinking about a 2- to 3-month lag time to getting the cells into the patient. So I think that will always be a very distinguishing feature between the two.

I mean if you're comparing -- sorry, I was going to say, if you're impairing head-to-head its efficacy, safety -- and frankly, ease of administration and cost, the burden on the patient and on the system. So all these things, these go into it.

Jason Gerberry from BofA. Just wanted to put the RCC update in a little bit more context. As we see the data mature, just curious, it would seem like you're heading on a pathway of some sort of PFS superiority comparison against the TKI monotherapy, but perhaps because you're looking at CD70 positivity, perhaps there might be some open-label accelerated pathways. So 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?

Okay. Rafael, do you care to answer?

Yes. I mean this 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. Normally, the endpoints that are chosen there are response and durability. And so our -- 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 what you've seen that we present. And we will obviously discuss this regulatory wise to make sure that this is a viable path. And at the same time, we will explore combinations as has been mentioned before. But doing random astral of cell therapy and CAR Ts with any drug is very difficult in that order.

Dr. Locke, anything to add?

Yes. I mean, the landscape is quite changed from this sequential therapy of doing TKI or IO therapy to real combinations. And this study is treating patients who have been previously TKI and IO exposed. And so, there are patients, for example, that this could actually impact on the second line. We've had really refractory disease really in the first-line setting to those agents, too. And so there really is an opportunity here to sort of lever a whole another type of mechanism.

Ben Burnett from Stifel. I want to 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. But you also showed that the infection rates, especially in the NHL setting, the grade to infection rates are quite a bit lower than the autologous setting. So 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? And then with those learnings and what you've implemented there, is there any appetite to boost 647 higher in the multi myeloma setting?

Yes. Good question. I mean I will answer the question about lymphoma. We were obviously very pleased to see 8% grade 3+ infection rate. When we -- and that was really critical for us to be able to move up to CD19. I would say that part of the reason why that infection rate has gone down is because there's more experience from the investigators on how to anticipate the potential of the infections, check for viral infections is to do prophylaxis, et cetera. So it's like what happened with any other therapy investigators really start really 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 have relatively high confidence intervals, you can get to 100% if you get to a given concentration of about 200 micro [indiscernible] of ALLO-647. So we don't really think that increasing the concentration is going to really get us further, and we are very happy with an 8% infection rate of grade 3+.

We probably have time for one more question. Two more? Okay.

It's Michael Schmidt with Guggenheim. Thanks for the presentation. I thought it was pretty impressive to see the efficacy data, especially for 501 and 501A in large lymphoma with the alloy manufacturing process. And I was just wondering if there was perhaps 1 particular item or 1 step in the process that makes the differential in the manufacturing process. And also, if you could comment how many patients in the 715 study were treated with the alloy process versus the legacy process?

Okay. I was looking for Alison. Alison?

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. So there's no sort of single modification to that process. That was the first question. The second question?

In the multiple myeloma study, what proportion of those were treated with the new process versus the prior?

In the multiple myeloma study, all patients so far have been treated with material from the alloy process.

Okay. The last question.

Last one, Raju Prasad with William Blair. Keep it quick because I know we're over. But we talked about the speed with which we can get out to the patients, and we've talked about kind of the percentage of patients that autologous that can be treated. And I always talk about the responses, but I was just curious, is there a way to identify patients where -- at the outset where there's going to be manufacturing failure?

Not least for the commercial products, you mean we really don't. And we've had a couple of dozen patients. We do have a pretty good volume. And 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.

So with that, I would like to conclude Allogene R&D showcase, and thank you very much. Time is very precious, and I really appreciate you are spending 3 hours with us as we go through our groundbreaking data across multiple programs, and have a great afternoon.