Precision BioSciences, Inc. (DTIL) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Precision BioSciences reports positive interim results from PBCAR0191 Phase I/IIa trial conference call. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Alex Kelly, Chief Corporate Affairs Officer. Please go ahead, sir.

Okay. Good morning, everyone, and welcome to our webcast to discuss the interim results for PBCAR0191 in relapsed/refractory NHL and B-ALL. Before we begin, I would like to remind you that statements made during this webcast that do not relate to matters of historical fact or relate to future expectations, beliefs, intentions, goals, strategies, plans or prospects are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve known and unknown risks, uncertainties and other important factors including, without limitation, the risk factors in Precision's quarterly report on Form 10-Q for the quarter ended September 30, 2020, which may be updated from time to time in Precision's other filings with the SEC. And the SEC filings are accessible on the SEC's website or on our Precision BioSciences website. All forward-looking statements speak only as of this date, and except as required by applicable law, Precision has no obligation to update or revise any forward-looking statements made today whether as a result of any new information, future events, changed circumstances [Audio Gap] This morning, we want to give you some additional perspective on the data released today. Matt Kane, our CEO and co-Founder, will provide an overview of our allogeneic CAR T program. Dr. Bijal Shah, Associate Professor in the Malignant Hematology Department at H. Lee Moffitt Cancer Center and Research Institute and the principal investigator in PBCAR0191 clinical trial, will share the results, observations and clinical conclusions from the initial protocols and the amended protocols, which we discussed in January 2020. Dr. Chris Heery, our Chief Medical Officer and Dr. Derek Jantz, our co-Founder and Chief Scientific Officer, will discuss our go-forward clinical plans. With that, let me turn the call over to Matt Kane, CEO and co-Founder of Precision BioSciences.

Thank you, Alex, and I'd like to welcome all of you to this important update on our lead CD19 targeting allogeneic CAR T program. Let's turn now to Slide 5. And before we get into the interim results, I want to acknowledge our clinical sites, principal investigators, nurses and staff that have truly been on the front lines during the COVID-19 pandemic and yet have managed to keep their focus on the needs of the patients that have enrolled in this study. But most importantly, we must thank those patients who enrolled in this study and joined us on our quest to improve life. Without them, none of this is possible. I'd also like to commend the Precision team for their tireless efforts to keep our CAR T programs moving forward during this challenging period. Turning to the next slide. Let's discuss how and why we build our CAR T platform the way we have. Today, we have 3 donor-derived allogeneic CAR T programs in clinical trials, all built upon the same fully scaled and modular CAR T platform and all fueled by ARCUS, Precision's wholly owned and proprietary genome editing technology. Now PBCAR0191 is our anti-CD19 CAR T therapy that originates from healthy donor cells. Through a patented single step process, we knock out the T cell receptor by knocking in the chimeric antigen receptor, or CAR, into the TRAC locus. And I'll note that the CAR also contains our patented N6 co-stimulatory domain designed to control the expansion of our CAR T cells. Our manufacturing process delivers consistent batches of cells comprised predominantly of naive T cells and approximate 1:1 ratio of CD4 to CD8 cells. The process itself only takes 10 days and results in a large number of CAR T cells per batch. And the data we're sharing today include cells used from 5 different batches across 4 different donors. And while perhaps not as exciting as some of the other topics we'll be discussing today, we believe that for an allogeneic CAR T to reach its potential, manufacturing really is a critical component to developing a therapy that is highly effective, safe and scalable. And importantly, you cannot make CAR Ts like ours without ARCUS and Precision's intellectual property. Turning now to Slide 7. The safety and efficacy data we're sharing today in 27 patients with NHL and ALL supports our long-term vision of delivering CAR Ts to the community hospitals and other settings where most patients with NHL and ALL seek care. Across all doses of PBCAR0191, we are seeing an acceptable tolerability and safety profile with our CAR Ts showing no dose-limiting toxicities, no graft-versus-host disease and no grade 3 or greater CRS or neurotox. And importantly, we have enrolled a very tough patient population. 100% of the patients had aggressive disease, and we allowed patients with prior auto CAR T and prior stem cell transplants. And despite the difficult patient population, we achieved an 83% objective response rate across NHL and ALL patients and a 75% complete response rate in NHL at day 28 by combining our cells with an enhanced lymphodepletion regimen. And to our knowledge, this is the highest complete response rate seen to date in NHL patients treated with allogeneic CAR T cells. We believe this increased response rate may be attributed to the nearly 100-fold increase in cell expansion observed with the enhanced lymphodepletion regimen. Now this data is early, and we will continue following the patients for durability. But we've also established the longest complete response rate reported to date for an allogeneic CAR T with an 11-month complete response from a patient that was dosed at our second dose level. So stepping back, we believe that the data we are presenting today represents an important and meaningful step forward in the development of allogeneic CAR T therapies and establishes Precision BioSciences as a leader in the field. Turning to Slide 8. Before I introduce Dr. Shah, I wanted to share a case that is representative of the patients that we've enrolled in this study. Shown here is a patient suffering from DLBCL with significant tumor burden. This patient was refractory to 4 of the last 5 prior treatments and, importantly, progressed after getting the autologous CAR T, Yescarta. This was a patient with a tough situation, and we'll return to this patient later in our presentation. The presentation itself will be delivered in a series of chapters. The first, we'll review the findings from our initial protocol as we've gone up in dose and sought to understand the kinetics with our CAR Ts. The second chapter will reveal our findings as we've explored split dosing, repeat dosing and the improvements we've seen in responses using an enhanced lymphodepletion regimen. The third and final chapter will offer a preview of how these recent learnings will inform our path forward. Turning now to Slide 9. It is my pleasure to introduce Dr. Bijal Shah. Dr. Shah is an Associate Professor in the Malignant Hematology Department at the H. Lee Moffit Cancer Center and Research Institute. He serves as the clinical leader of mantle cell lymphoma and acute lymphocytic leukemia as well as the director of translational research initiatives in non-Hodgkin lymphoma and acute lymphoblastic leukemia. He has been a principal investigator on over 15 clinical studies with a focus on investigational immune therapeutics for NHL and ALL, including the groundbreaking autologous CAR T therapies. And now he is the principal investigator of our Phase I/IIa study of PBCAR0191. Dr. Shah?

Hi. Thanks for having me. It's my pleasure to present the interim results and observations on the PBCAR0191 study. Turning to Slide 10. You can see here that really what we've developed are 2 studies in 1. One approach is to focus on non-Hodgkin's lymphoma, and the other patient population we focused on is acute lymphoblastic leukemia, is enrolled in separate cohorts with increasing dose level using a standard 3+3 design beginning at 3 x 10^5 per kilo and going to dose level 3 at 3 x 10^6 per kilo. Our primary objective was to ensure safety and tolerability. We needed to be sure that there would be no evidence of graft-versus-host disease. We needed to understand the kinetics and the severity of CRS or cytokine release syndrome and neurologic toxicity. Secondarily, we wanted to understand whether PBCAR could engender complete remissions and the durability associated with those remissions. Finally, we think it's important to understand how those remissions correlate with the expansion, trafficking and persistence of these allogeneic CAR T cells. Moving to Slide 11. Here, you see the patients enrolled with 16 in the NHL cohort and 11 in the acute lymphoblastic leukemia cohort. I'll call your attention to the area that is boxed out. Overall, 63% and 82% of the NHL and ALL groups, respectively, had over 4 prior lines of therapy before enrolling. You can see here that included both allogeneic stem cell transplant in the lymphoblastic leukemia cohort and autologous CAR T cell therapy in 25% of the NHL cohort. This is a highly refractory population. You can also see that reflected in markers of like the Ki-67, where you'll see here that the median was 70% and ranged up to 100%. You can see as well these for patients with a high tumor burden who were preferentially enrolled to this protocol. Moving to Slide 12. These are the aggregate safety data. You can see here that approximately 50% of patients experienced grade 1 or grade 2 CRS, and approximately 20% to 30% of patients experienced grade 1 or grade 2 neurologic toxicity. We did not see any grade 3 or higher cytokine release syndrome or any grade 3 or higher neurologic toxicity. Importantly, no graft-versus-host disease was observed. We have seen infections, and I think this is important to comment on given the nature of the patients we are enrolling as well as the nature of the therapy. This includes one episode of rhinovirus in the standard lymphodepletion cohort, 2 episodes of pneumonia and 2 episodes of sepsis. One patient did ultimately pass away from sepsis outside the DLT window, and I'll be talking more about that patient later in the presentation. Moving on to Slide 13. Here are our response rates using standard lymphodepletion. And just to catch you up, this is 30 milligrams per meter squared of fludarabine for 3 days and 500 milligrams per meter squared of cyclophosphamide also given for 3 days concurrently. You can see here at the 3 x 10^5, 1 x 10^6 and 3 x 10^6 per kilo dosing across the NHL cohort, we had an overall response rate of approximately 50% to 60% with CRs making up about half of that. In the acute lymphoblastic leukemia group, where partial responses perhaps have less clinical significance, you can see here that about 1/3 of the patients or 1/4 of the patients at dose levels 2 and 3 achieved a meaningful complete remission. Moving on to Slide 14. Here are our expansion data, and what you'll observe here is a dose-dependent increase in the measurable CAR-T cell level blast flow cytometry. This was observed in both the NHL and the acute lymphoblastic leukemia cohorts. What you'll also notice is a peak that occurs around 7 to 10 days following infusion followed by a very sharp decline between days 10 and 14. Moving to Slide 15. We start to now understand why that decline is occurring. Here, you see plotted the host T cell response as depicted by the increase in CD3+ T cells. The T cells begin to recover around day 3 and peak around day 21. Coincident with the rise in T cells is the decline of the CAR T cells, suggesting a host-versus-graft response. Moving to Slide 16. Recognizing these pharmacokinetics, we wanted to explore 3 broad strategies: the first, to try administering a split dose. We understand the concept of effector-to-target ratios, but now the question is could we come up with an effector-to-T cell ratio, meaning a CAR T cell to T cell ratio that overcomes this host-versus-graft response. The second was can we repeat dosing in patients who have lost CAR T cell persistence who are showing progression of disease. The third approach was to say can we enhance our lymphodepletion to give the allogeneic CAR T cells more room to expand, more room to persist and accordingly anticipate a deeper and more durable response. Moving to Slide 17. I want to talk first about the split dose approach. Again, this is without additional lymphodepletion. We administer the first dose on day 1 and the second dose on day 10. You can see that depicted here in a patient with acute lymphoblastic leukemia. The patient had originally received hyper-CVAD with blinatumomab with the development of a complete remission. The plan at this point was to take the patient to an allogeneic transplant, and this patient was receiving a test dose of busulfan when he began to show progression of his underlying leukemia. At this point, he was enrolled to the PBCAR study and received his first dose of cells on day 0, as you see here, with expansion as depicted here. He received his second dose on day 10 as previously described. However, there was no meaningful increase in the CAR T cell level with this second infusion, suggesting that we weren't able to overcome this effector to T cell concept or, more broadly, this idea of host-versus-graft by simply infusing a second dose. Moving to Slide 19. So this led to the question what if we instead administered another course of lymphodepletion prior to the second dose. I want to call your attention to the same patient. This individual came on with 6.5% blasts in marrow, experienced a 1 log reduction by day 28. The patient received a second course of flu/cy lymphodepletion, after which a repeat dose of the PBCAR was infused at around day 30 or so. You can see here the second dose did expand with a peak expansion that was actually modestly higher than what we saw with the initial infusion. The persistence was shorter, lasting approximately 7 days compared to 14 days with the previous infusion but came again with a 1 log reduction in the tumor burden. This reduction was deep enough to facilitate allogeneic stem cell transplantation. Following transplant, the patient achieved an MRD- complete remission. Data highlight beautifully the safety and efficacy of repeat infusions with PBCAR. Moving to Slide 21. The last concept I want to describe is that around enhanced lymphodepletion. Can we achieve more with the first infusion? Moving to Slide 22. The short answer is yes. You can see here that with the enhanced lymphodepletion, we achieved a 100-fold increase in our peak expansion and nearly a 50-fold increase in our AUC. Now I should spend a few minutes talking about what enhanced lymphodepletion is. Specifically, we increased our fludarabine dosing by 1 additional day. So now patients are receiving fludarabine more akin to what was received with the tisagenlecleucel where 40 milligrams per meter squared were given for 3 days. We also increased our cyclophosphamide dosing from 500 milligrams per meter squared to 1,000 milligrams per meter squared. As I'll show in the next slide, the improvement in the pharmacokinetics was also associated with an improvement in response. Before getting there, and I apologize, let me spend a few minutes talking about the host T cell response or the host-versus-graft response. You can see here while the T cells did recover, we were able to overcome that as it reflects -- as reflected here by the peak and AUC now with cells measurable out to day 21. Moving to Slide 24. You can see here that this was not accompanied by an increase in grade 3 or higher CRS. This was not accompanied by an increase in grade 3 or higher neurologic toxicity. And again, we did not see any evidence of graft-versus-host disease despite taking patients who were very immune suppressed prior to coming on to the study. Infection, as I alluded to earlier in the presentation, has been observed, again, with 1 death occurring at day 42, which we'll talk about in more detail later in this presentation. Moving to Slide 25. This is the patient that had passed. The patient was a 64 year old with Richter's transformation of chronic lymphocytic leukemia. The patient had, had 9 prior lines of therapy and had, had prolonged and persistent cytopenias prior to enrollment. The patient initially was screened and was deemed a screen failure due to active infection at the time. The patient rescreened approximately 2 weeks later and was felt to meet the eligibility criteria and was enrolled. The patient received enhanced lymphodepletion followed by cell dosed -- cells dosed at dose level 3 or 3 x 10^6 per kilogram. The patient experienced another episode of bacterial sepsis at day 27 but resolved with antibiotics. On resolution of the sepsis, PET/CT demonstrated a 93% reduction in the tumor area in the 10th line setting. Unfortunately, the patient was slow to recover their counts and again became septic on day 40 and, in this context, did not survive. I think it's worth thinking very critically about what this patient means, more specifically, what does it mean to enroll someone in the 10th line setting with a history of prolonged cytopenias and a history of recurrent septicemia prior to enrollment. I honestly have to stop and take a moment to thank Precision. We take care of these patients every day in the clinic. They don't qualify for other clinical trials. I can tell you, just recognizing this treatment history and the history of cytopenias and the history of infection, there's no way I would have gotten this patient to any other study that we currently have available in our portfolio. I imagine the same is true across the U.S. Precision and the patient, of course, took a chance and experienced the kind of meaningful clinical remission we like to see, unfortunately, with the adverse outcome of sepsis. A large part of me wants to argue that we shouldn't make any changes. These are the patients who benefit most from having an allogeneic off-the-shelf CAR T cell approach. These patients would never survive long enough to receive an autologous CAR T therapy. On the other hand, I think it requires some balance. To that end, we are going to modify the eligibility criteria so that those with prolonged pancytopenia or serious infections within the last 30 days will not be allowed to enroll. I think this balancing will help to avoid similar issues, but again, I want to make sure that everyone on the call here is my own personal perspective, which is these are the patients who need this kind of therapy the most and who have the most to gain from an off-the-shelf therapeutic. And so it's my hope that with these -- with this balancing that we'll be, again, be able to preserve the ability to treat high-risk patients without encumbering excessive mortality. Moving on to Slide 26. I'm delighted to share the overall response and complete remission rates across this trial with the enhanced lymphodepletion approach. You can see here that we've achieved a 100% response rate in our NHL cohort with the 1 PR that I just described showing a 93% reduction in tumor burden by day 28. You can see here the others in the NHL cohort achieved a complete remission. For the ALL cohort, we are now seeing, of the 2 enrolled, 1 achieving a complete remission. Looking at these 6 patients in aggregate. 83% have achieved a response of which 80% have achieved a complete remission, in other words 4 of the 5. These data are very exciting. Moving on to Slide 27. Here, we show the durability of remission associated with CAR T infusion. I want to call your attention to the bottom half of the curve where we were delivering the enhanced lymphodepletion. Beginning with subject 1140-001, you can see here, this patient did receive the split infusion. Now as I mentioned previously, we don't believe the second dose meaningfully impacted the peak expansion or the persistence. Patient achieved a partial remission by day 28 and has deepened to a complete remission by day 90. This patient continues an ongoing CR as of this date. Patient 1179-001 achieved a CR by day 28, was shown to have progression just after day 60 and has now undergone repeat lymphodepletion and repeat dosing. I had mentioned a year ago when we presented this data at ASH that our goal was to live up to the idea that CAR T cell therapy could transition from a cellular immunotherapy to one that was a drug-like cellular immunotherapy, one where we could not only anticipate but deliver repeated doses with the goal of deepening remission over time. You can see here patient 1005-002. This is our patient who unfortunately passed away from sepsis at day 42. I would be remiss if I didn't talk about the first or the top half of this plot as well. Patient 002 was my patient. Patient 002 had a primary mediastinal large cell lymphoma, and she had already progressed after receiving autologous CAR T cell therapy with Yescarta. She received PBCAR and had a remission duration of a little over 6 months. She went on after that to receive a clinical trial study with an immune modulator. She wasn't able to tolerate therapy and came off after a week or 2 of therapy. She still had a large mass that was partially irradiated. This is where I get really confused to be quite honest. She had no subsequent therapy and continues in a biopsy-proven complete remission now 1 year after progressing on the PBCAR. I confirmed with our radiation oncologists to be sure, "Did you radiate the entire mass?" And the answer was no. He couldn't. He just radiated the outer portion of that mass. When I think back on subject 1140-001, who transitioned from a partial to a complete remission, I think back and ask what -- whether there's something that I'm observing with patient 002 along those same lines. These aren't questions that are going to be easy to answer but ones that I find very exciting because while we talk about host versus graft as being uniformly negative, I want to make sure that I say, clearly, we're putting T cells where we want them most, in the tumor microenvironment. And it's not always easy to predict what the outcome of that will be. I also want to spend a few minutes talking about some of the other subjects that I enrolled. Subject 1127-008 is a patient that I enrolled with a blastoid variant of mantle cell lymphoma. He was already progressing on BTKs, and he had a Ki-67 of somewhere around 95% to 100%. He received the PBCAR with around a 2-month or so remission before progressing. After he progressed, we radiated multiple sites. We put him on triple therapy with acalabrutinib, venetoclax and a monoclonal antibody. And we were lucky enough to keep him well so that he can get to the autologous product, the recently approved Tecartus from Gilead and Kite Pharmaceuticals. To my surprise, while he did achieve a CR, he had a remission duration that was identical to what he had received with the PBCAR infusion lasting just under 2 months. We're actively working to determine what we can do for this gentleman to see if we can get him back into remission and, hopefully, to an allogeneic transplant. The other subject I want to describe was not so lucky. This is a patient who also with a blastoid variant of mantle cell with a Ki-67 of 100%, who we tried to get to autologous CAR T cell therapy but he died during the manufacturing phase. This is a reflection of why we need allogeneic CAR T cell therapy. This is a reflection of what I think allogeneic CAR T cell therapy can provide. And I'm hopeful as we further develop this, we'll be able to have a therapy that we can administer in the moment when patients need it most. I want to call your attention to Slide 28 next. This is the acute lymphoblastic leukemia cohort. You can see here at the top half with our standard lymphodepletion our best patient 1091-004 who achieved an 11-month complete remission. The patient has just undergone repeat lymphodepletion and a second CAR-T infusion, and I'm eager to see what will come next. You can see here we are seeing MRD+ CRs. With our standard lymphodepletion, we're also seeing MRD- CRs as well, and that's depicted in the lower half. Finally, with the enhanced lymphodepletion, you can see here that we have an MRD- CR out to 60 days with follow-up ongoing. Moving to Slide 29. Here, you can see the swimmer's plot for our depth of remission. You can see here that patients are achieving very deep remissions with enhanced lymphodepletion followed by PBCAR infusion. This data, in my opinion, are extremely exciting as we move forward. Calling your attention to Slide 30. Here, we can see the types of patients that we enrolled. In this case, this is a 60-year-old gentleman with an overlap of large B cell lymphoma and acute lymphoblastic leukemia. We do see these cases. They're uncommon. You can think of them as the B cell like unclassifiable cases that MD Anderson had reported years ago. This patient received an initial induction with R-CHOP followed by an ALL-based induction with asparaginase, followed by inotuzumab, followed by Blinatumomab, followed by a fludarabine-based induction and was refractory to those last 3 lines. The patient received PBCAR. You can see here the peak expansion was high with cells persisting out to day 14. This is the patient that had a day 28 PR that converted to CR by day 90 and is in ongoing complete remission at day 120 in spite of having received and proven refractory to both Blinatumomab and inotuzumab. Moving to Slide 31. This is the 63 year old we alluded to at the beginning of the presentation. This patient had a high tumor burden. If you look closely at the left leg, which is on the right side of the figure, we'll see the patient had lymphoma encasing the veins with lymphedema or very swollen left leg in that context, also had disease extending along the base of the liver, in the adrenal and upwards in the lower neck, mediastinum. The patient had progressed after anthracycline-based chemo, cytarabine-based chemo, progressed after Yescarta with an only 8-month remission, progressed after experimental therapy with an IRAK4 inhibitor; BRAF inhibitor; a CD20 bispecific antibody, mosunetuzumab; experimental therapy; and finally, progressed after polatuzumab with rituximab and REVLIMID. The patient did achieve a CR by day 28, and you can see here the imaging. Unfortunately, the patient did progress by day 54 with central nervous system disease. But I'd like to take a moment here and ask was it meaningful. I think sometimes we look at these shorter remissions, and we make the argument that it's too short. I really, as a clinical physician, would strongly argue against that. When I look at this gentleman's leg, when I look at where his disease was, and again, it's hard to appreciate what it means to have disease growing under the liver like we're seeing and what that means in terms of causing biliary obstruction, what that means in terms of the consequences of where the nodal growth is occurring and the symptoms that come from it and then to secondarily see a deep remission like this, it means you have a window to help people to feel better. That's fundamentally our goal. And this, again, is in a ninth line refractory DLBCL patient who progressed after prior autologous CAR T cell therapy. This, to me, is meaningful. Moving to Slide 32 to conclude. What we're seeing is incredible. I mean this is not a scientific presentation, so I feel very comfortable taking a step back and just saying wow. I think we are finally reaching that point where we can say we're seeing the efficacy we want with a safety profile that is notable for a lack of severe GvH -- sorry, or for any GvH, a lack of severe CRS, a lack of severe neurotoxicity, we're able to create a controlled T cell product from healthy donors and engender remissions. 83% overall objective response across ALL and NHL in this cohort of patients in the enhanced lymphodepletion group. I think cytopenias, infection and even death from infection are things that not only us but all CAR T folks in the field are going to have to manage as we move forward. I'm hopeful that the balancing that I described will help us avoid further mortality and hopefully allow us to still take these patients who are otherwise without options with extraordinarily aggressive disease who are not apt to make it to standard approved CAR T therapies, we'll still be able to enroll. Again, in a nutshell, I'm excited. And I'm really looking forward to seeing how this develops as we move forward. With that, thank you, and I'll turn over the presentation back.

Thank you, Dr. Shah, for the review of the trial data so far. It's very helpful to have the perspective of a clinician to keep us focused on what is most important, and that is trying to improve the lives of patients who need therapies the most. In addition, it has been interesting to see, as we followed our own results, the literature with autologous CAR T cells. Following that allows us to take a significant set of learnings from the autologous setting and test hypotheses that we observe rapidly. So let's move to Slide 34. The first finding of greatest interest is one that has direct implications for the results Bijal just shared with you. Multiple recent publications have suggested that the antitumor effect of CAR T cells happens very early, perhaps as quickly as 1 to 2 weeks after administration. Retrospective analyses have suggested that the peak CAR T expansion is the best predictor of the depth and durability of response. Here are 2 such publications: 1 from the NCI group on the top and the other from the investigators of Yescarta ZUMA-1 trial. There are some quotes listed to the right that are of particular relevance. Of note, however, is that these findings are in the context of an autologous product that will have a tail on their AUC curve, and this begs the question of whether high peak expansion without cell persistence can achieve the same results. At this point, it is too early for us to make a clear conclusion on this question. However, we believe the methods we are employing are the first opportunity to directly ask and answer that question. If a short cell persistence can achieve this, it would be an important finding. We expect to know the answer to that question in the next 6 to 8 months when adequate follow-up data can be amassed. And so now we can move on to Slide 35 to discuss our path toward durable responses. On Slide 35, what you see is -- what we have shown you is an identified set of kinetics with PBCAR0191 in terms of cell expansion and rejection. We've also shown you the peak expansion with limited persistence, at least in some cases, can result in durable responses. However, we need more follow-up with more patients who have had high peak expansion and complete responses to determine if this can result in durable responses consistently. We will continue to do that, but there are other ways to increase the area under the curve of 0191 as well. We have broadly defined these here as: first, on the left, increased peak expansion, which I've just spoken about; second, increased cell persistence; and third, repeat dose. Let's turn to Slide 36, where I'll share what we're doing presently in the clinic to address each of these. For increased peak expansion, first, we have shown you that enhanced lymphodepletion has increased the peak expansion and the area under the curve. Because of this, we are continuing to enroll patients with this regimen, albeit with a caveat that we will avoid enrolling patients with prolonged cytopenias and/or a recent history of serious infection for the foreseeable future to avoid any confusion that may occur in patients who are already very ill coming into the study and how that might affect interpretation. Secondly, because we have not observed any DLTs, including no cases of graft-versus-host disease and no grade 3 or greater CRS or neurotoxicity, we can continue to increase the dose of PBCAR0191. We have shown that increasing the dose increases peak expansion so far, and we believe this trend will continue. We now have authorization from FDA to go up further in cell dose on day 0 and are currently dosing at 5 x 10^8 cells as a flat dose. Next, increased persistence. We have recently implemented modifications to our protocol to allow use of alternative lymphodepletion regimens that we believe to be novel and otherwise not yet evaluated in the field of CAR T. We chose these based on discussions with KOLs in the field of stem cell transplant. These regimens only entered the clinic recently, and we do not have enough data to share yet, but we expect to have an update on these regimens at our next data update. It is probably worth noting that both regimens were selected based on historical safety information. Neither regimen includes a biologic agent, and neither is expected to result in prolonged cytopenias based on historical data. Last, repeat dosing. We now think it is possible to achieve deep and durable responses by addressing peak expansion and increasing persistence, but we also want to continue to explore whether we can achieve better outcomes with repeat dosing. To that end, we have planned a group of patients to be treated with standard lymphodepletion followed by cells and then a scheduled more mild lymphodepletion and then another dose of cells. Again, this regimen was designed with the input of our treating physicians with safety as a top priority. We expect to provide a data update by midyear 2021 involving all of these approaches, including longer-term follow-up of the enhanced lymphodepletion regimen discussed today with additional patients. That is a regimen that resulted in a 75% complete response rate in non-Hodgkin lymphoma in a very relapsed/refractory advanced setting. In addition to these trials that are underway in the clinic today, we have a next generation immune evading CAR T technology that we call the stealth cell. We believe the stealth cell may overcome some of these issues of rejection, allowing increased expansion and persistence. And I'm very excited to hand it over to Dr. Derek Jantz to tell us more about the stealth cell.

Thank you, Chris. If we could please turn to Slide 38. The stealth cell is an immune evasion technology that we developed with the goal of helping our CAR T cells avoid rejection. As Dr. Shah mentioned earlier, we believe that CD3+ T cells are playing a major role in rejecting PBCAR0191. But natural killer cells, or NKs, are another [ new ] cell type that could potentially cause rejection. And as you can see on this plot from our dose level 3 NHL patients, the NK cells, which are that light blue line in the plot, also returned to baseline levels fairly quickly following standard flu/cy preconditioning, so we also need to take the NK cells into account. If you want to turn to Slide 39, please, the stealth cell is designed to avoid rejection by both of these cell types, the T cells and the NKs. And we do this by adding 2 additional parts to our standard CAR T vector, which is shown at the top of that inverted gray triangle. In addition to the CAR gene, the stealth vector carries an shRNA that suppresses beta-2 microglobulin, which is a component of Class I MHC. Reducing Class I expression on the CAR Ts reduces the ability of that CAR T to be recognized and killed by cytotoxic T cells. Importantly, we don't knock out B2M entirely. We just suppress it to about 10% of normal levels. And we have found that doing so leaves just enough Class I on the surface of the CAR T cells to avoid triggering a missing self-response from the NK cells and thereby inducing rejection by the NKs. And then really just for good measure and because we had some extra room in the vector, we added an additional new part, which is an HLA-E gene that acts as a decoy to the NK cells. So really, it just adds an extra layer of protection against rejection by NKs. Importantly, we do all of this using a single gene edit, and the manufacturing process is essentially identical to the one that we developed for PBCAR0191 and so is able to achieve similar levels of yield and cell quality because, really, all we did was change out the identity of the vector. If we can go to the next slide, please, Slide 40, this works, at least in preclinical studies. In mixed lymphocyte reactions, we found that the stealth cell prevents rejection by both T cells and NKs. On the left-hand side of the slide, is data showing that unmatched T cells can very efficiently kill standard CAR Ts but do not kill stealth cell CAR Ts or B2M knockout cells. On the right-hand side, unmatched NKs efficiently killed the B2M knockout cells but don't kill stealth CAR Ts or standard CAR Ts. Obviously, the results from the first-generation PBCAR0191 that Dr. Shah just shared with us continue to look very, very promising, although we have said from the beginning that we do intend to advance stealth cell CD19 into the clinic irrespective of the results with PBCAR0191 because we want to see what it can do. And I am very pleased to announce that we have completed all of the preclinical work with the CD19 stealth cell and we'll be advancing it into the clinic next year. So please stay tuned for that. And now I will turn it back over to Matt to wrap it up.

Thank you, Derek. So 2020 has been a highly productive year for Precision BioSciences. In addition to the PBCAR0191 program, we've also advanced our CD20 and BCMA programs into clinical studies and are now into our second dose levels with each. We've also broadened our pipeline with 4 new funded programs with our partner, Servier, 2 of which are in solid tumors. And finally, as Derek just mentioned, we've also advanced our CD19 stealth cell program and expect to enter human clinical studies with it in 2021. Turning now to Slide 42. As we move into 2021, you can expect a number of updates across our allogeneic CAR T portfolio. We plan to share additional data on the PBCAR0191 program by mid-2021 and anticipate having data on well over 40 patients that will include safety, response rates, durability and all the typical correlatives. We also plan to update on our learnings with repeat dosing as well as early data as we explore increased doses and any additional optimizations that we may make to our lymphodepletion strategies. Finally, we expect to provide updates on our CD20, BCMA and the CD19 stealth cell program. Turning now to our final slide. To conclude, we've demonstrated an acceptable tolerability and safety profile. We've demonstrated a promising response rate in both NHL and ALL with our enhanced lymphodepletion strategy. And importantly, this is an approach that did not require long-term immunosuppression. Moving forward, we plan to enroll more patients into our enhanced lymphodepletion arms, while we continue to evaluate dose levels, repeat dosing and other novel methods to further optimize our dosing strategy. And we expect to be able to use those learnings as we advance our CD19 stealth cell candidate into clinical studies in 2021. So this has been an incredibly productive year for Precision BioSciences. We went from 1 to 3 allogeneic CAR T programs in clinical studies, and soon, we expect to have a fourth. We believe the data we presented today represents an important and meaningful step forward towards the development of allogeneic CAR T therapies and one that really supports our long-term vision of broadly delivering CAR Ts to patients in greatest need. And we look forward to providing you another update on our progress by mid-2021. Thank you, and I'll hand this back over to Alex.

Okay. Thanks, Matt, and thank you to the audience for your patience in allowing us to walk through this very robust data set. We will make time for Q&A, and we are definitely going to try to get through all the people in the queue. So operator, we're ready to take our first question.

[Operator Instructions] Our first question comes from Maury Raycroft of Jefferies.

Congrats on the update and the rich data set, really impressive. And so first question is, for the enhanced lymphodepletion data, you showed the mean AUC at 45x. Can you talk more about how this compares to your standard lymphodepletion regimen? And can you contextualize to what is observed with autologous approaches and how this factors into durability?

Great. Thanks, Maury. I appreciate the question. I'm going to let our Chief Medical Officer, Chris Heery, take that one.

Sure, Maury. Thanks. Good question. So in terms of the increase in the AUC, that is in reference to the standard lymphodepletion regimen at the same dose level. So those were both dose level 3, and the comparison was between the enhanced lymphodepletion and the standard lymphodepletion regimen. With regards to autologous CAR T cells, obviously, it's very difficult to compare between trials and between products because the assays used are going to be different. Some of the methods to assess the presence of those CAR T cells are going to be different. So what we tend to look at then is what are the other biomarkers that tell us when we may be reaching the maximum peak expansion allowable, which historically has been the experience of patients having grade 3 or higher CRS and neurotoxicity. As Dr. Shah mentioned, we haven't had that happen yet, and so we believe we still can further increase that area under the curve by further increasing the peak expansion. And that can be done with higher doses in combination with the strategies we've already employed. If that didn't answer your question completely, let me know. I think that was what you were asking.

Yes. That's great perspective. And then second question is just on the enhanced lymphodepletion regimen. I guess can you parse out or quantify how much the enhanced lymphodepletion regimen is contributing to activity or durability versus the CAR Ts?

We can look at the peak expansion in the area under the curve as a good indicator that the enhanced lymphodepletion has created more space for the CAR T cells to expand. So what we tend to see, if you refer back to the slide that Dr. Shah showed, looking at the peak expansion but also overlapping with the patients recovering CD3 cells, which is Slide 23, what you see is that the CD3 depletion is deeper with the enhanced lymphodepletion, although it does recover at about the same time point. So when we see the CAR T cells starting to disappear, we are seeing recovery of the rest of the bone marrow around that same time frame, usually around day 14 to day 21, albeit at slightly lower levels. So what we think is happening is the depth of depletion in that short time frame is creating more space that prevents allogeneic rejection allowing higher peak expansion. The indication then is -- and some might wonder is it possible that this is an effect of chemotherapy. Unfortunately, I -- no one can answer that definitively, but the best indicators we have are that we wouldn't get high peak expansion if this were a chemotherapy effect. And additionally, one of our patients was refractory to fludarabine and cyclophosphamide, who had a complete response after getting enhanced lymphodepletion plus PBCAR0191. And the other patient who didn't achieve a response was a patient who had a delay of cell administration, indicating that the chemotherapy itself didn't drive an antitumor effect in that patient. So we can't answer definitively yet, but I think we will be able to answer that with more follow-up time.

Got it. Very helpful. And last quick question is just on the novel lymphodepletion regimens. Can you talk more about how these are going to be incorporated into the clinical study? And are these proprietary to Precision?

They are novel, and part of the reason we are not disclosing them is that they are using approved agents. And so we believe it is somewhat of a competitive advantage to evaluate them and understand the kinetics with PBCAR0191 before disclosing them. So they are already incorporated into the study, already under evaluation, albeit very early in evaluation. And so that's why we can't give an update on those today, but we do expect to update with those regimens mid next year.

And our next question comes from Eric Joseph of JPMorgan.

I'm just thinking about the read-through here to the other CAR T programs leveraging CD20 and BCMA. In terms of cell expansion persistency, is there reason to anticipate a different dynamic in terms of cell expansion? And have the trials underway been adapted for the enhanced lymphodepletion scheme?

Thanks, Eric. I'm going to let Chris take that question as well.

Yes. Eric, I think it's a very, very important thing to consider that the dynamics of our cells are -- in terms of kinetics are likely to be similar across programs considering they are all on the same platform. So any modifications to lymphodepletion regimens that we apply in one program should be applicable to others. We have not talked yet about how we plan to implement things we learned from the 0191 program into others, but it stands to reason that things that we learn from 0191 are directly applicable. The caveat I would give there is that, obviously, each disease setting is somewhat different. As Dr. Shah mentioned, there are certain patient populations that are going to be at higher risk for infection regardless of the lymphodepletion regimen used. And so we need to take that into consideration when determining how to apply any given regimen across different programs, but outside of that, in terms of kinetics, they should be applicable across programs. The last note I'll mention on that is that, as Dr. Jantz mentioned, we believe that a next-generation product that avoids rejection, and we've seen that clearly in vitro, should improve all of those kinetics considerably and can be applied to, again, all of the targets that we have in our portfolio as well as others in the future.

And just a follow-up if I could. You guys -- as you look at further modifications to the lymphodepletion scheme, you're consistently -- or anticipating that you're going to stay away from or avoid using a biologic. Can you just talk about sort of what complication's associated with a CD52 depleting regimen? You want to avoid the downside risk associated with that and sort of what the upper -- I guess, sort of the tolerability profile you -- the upper end of the tolerability profile you'd want to kind of stay away from as you look to modify the lymphodepletion regimen going forward?

Right. Yes. I mean I think we take that that's a primary consideration for us. So I think it is -- as we step forward in every step of the long-term plan that we had always outlined, improving safety as we go is also one of those goals. So if there's something that can be done to limit the risk of infection, we will actively pursue that along the way. So for instance, if we find that a lymphodepletion regimen results in a similar cell expansion with lower risk of cytopenia, that would be a preferable regimen. But as of today, what we have observed is with the enhanced lymphodepletion regimen -- for instance, we do have this one patient that had prolonged cytopenias, but that patient had prolonged cytopenias coming into the study as well, and the remainder of the subjects in that group had a recovery of their bone marrow function to reasonably safe levels by day 21. So obviously, we have the outlier. It is a very serious situation to have a patient die on the study, and we acknowledge that, and we look toward ways to mitigate that as much as possible going forward. But we do think that, that is more indicative of the patient population enrolled than the regimen itself. And I don't know if Dr. Shah wants to just say a word there about that, but that's the opinion we've heard from the other investigators on the study.

Yes. That's correct. You summarized it well. I mean I think we have to put anti-CD52 in perspective. There's a reason why we don't use it anymore. I mean I hate to say that -- I hate to put it that bluntly. We had tried combining Campath with fludarabine, Cytoxan and RITUXAN in CLL. And we saw the outcome, which is really a very profound and very prolonged T cell lymphopenia coupled with recurrent severe CMV reactivation. This is just the tip of the iceberg. We know that we can expect a whole variety of infection from PML in the CNS to other viral reactivations like herpes and so on. I spend a lot of time talking to the folks at Precision about how much I'm eager to avoid that because I think that if we find ourselves going down that path, we may, in effect, win the battle but lose the war on the back end. And so we've really kind of pushed hard against this idea of really becoming dependent on Campath -- I'm sorry, on the anti-CD52, sorry. I think it also extends itself into the concept of repeat infusions, right? Because once you marry yourselves to a biologic like this, how then do you think about and pursue subsequent lymphodepletion if your goal really is to translate this into kind of a point-of-care therapeutic along the lines of what we might think of with a monoclonal and [ RepA ] bispecific? You don't want to find yourself having to reach for extremely lymphodepleting therapy every time you want to readminister your off-the-shelf CAR. And so I think that kind of gives you a sense of where I fall on this. If there are additional questions you have about our experience with Campath in CLL and hepatosplenic T cell lymphomas and the like, I'm certainly happy to share them with you. But it's tough therapy is the bottom line.

And the next question comes from Gena Wang of Barclays.

So maybe I'll just follow doctor's comments. And just curious because I don't disagree with you. I think a CD52 could be very toxic, but we did see initial data from Allogene. The DLBCL part, we actually didn't see very severe infection. I'm just wondering, compare that certainly to -- in that as a background and the data what we've seen, so how we did see one grade 5 sepsis and that data that could be related to the enhanced, the flu/cy conditioning regimen. So just wondering any concerns there right down the road regarding the safety with this enhanced conditioning regimen? And then you did mention you try to avoid certain patient population. But also would there be any additional concern or cautious we need to pay regarding this enhanced conditioning regimen?

Thanks, Gena. And Dr. Shah, would you like to comment on the safety profile?

Sure. Sure. I'd be happy to. So the first thing I'll say is, while we call it enhanced, I really want to make sure I put it in perspective. The fludarabine dosing is in total 120 milligrams per meter squared, which is identical to what we did with tisagenlecleucel for acute lymphoblastic leukemia patients. The Cytoxan dosing is a little bit higher, but the anticipated duration of that effect is very short, right? So although we're giving 3 grams per meter squared in total, we know from regimens like Maxi-CHOP and hyper-CVAD and the like that the anticipated immune suppression is going to be in the range of probably 10 to 14 days, after which we're going to start to anticipate hematopoietic recovery. So kind of putting all of that context in place, I don't -- it is enhanced relative to what we were doing previously. But I don't want to give the sense that this is toxic in the sense that my expectation is that patients will recover in terms of the -- particularly in terms of neutrophil recovery within that 21-day time span as Chris had alluded to earlier. In terms of what does it mean specifically for this patient -- and like I said, it's really hard for me because I really and truly see myself reaching out to Chris and the medical monitors with CTI and Precision to say, "Hey, I've got this patient who is in their tenth line setting, who has this very similar background." It's hard because we have these patients, and we want to make sure that we don't exclude them. But we have to balance safety and benefit and keep in mind that if they really have prolonged pancytopenia, pre-dating enrollment to the study that maybe that's a patient who's at higher risk no matter what we do, right? And that's why I also mentioned this isn't a patient who I think would have qualified for any other trial that we have for advanced large cell lymphoma or Richter's transformation. So maybe with that background, we have to be a little bit more conservative about who we put on the study. And did I answer your question? I don't know if I did or not, but I hope I did.

Yes, yes. That's very helpful. I do think that actually other trials you did enroll -- include a patient with the transformation for their DLBCL. So my second part of the...

Richter's, yes. Sorry. But not with the prolonged pancytopenia and recurrent sepsis. So those patients [ had ] episodes before coming on. Yes.

I see. Okay. That makes sense. And then my second question is regarding the durability of the cell expansion. I think that could be debatable and then a few is still evolving. So just wondering, when we look at the other competitors or the other -- I mean I would not say competitor because this is important for the whole field to understand the allogeneic CAR T, how that -- how we should pursue. So for, say, the CRISPR and Allogene data, when we look at the [ FL ] expansion, they -- seems expanded a pretty long time, certainly beyond 28 days. And then when we look at the sCR rate, they actually expanded also. Quite a lot of them expanded 3, 4 months and continue active, maintained CR. So just wondering, from that perspective, now we revisit the peak expansion versus the duration of expansion, how important that is, that I think the autologous CAR T data is not really fair comparison because we don't have -- they don't have a host of T cell coming back at the week 3, 4 to attack the foreign CAR T cells. So just wondering, from that perspective, with that as a background, wanted to revisit Slide 27, the patient 1140-001. So that patient had a split dosing. According to your data, the split dosing should not help much, so -- but we -- the -- why the patient showed a continued response, if you can give a little bit better understanding? I know you discussed on this like Slide 30, I think that was the patient maybe for the key study. If you can discuss a little bit more why the patient can expand it now to 120 while we see all the other patients mostly already progressed.

Yes. Maybe I can take that, and then, Bijal, if you want to comment. But one of the things that is also highlighted in those autologous publications is that the peak extension also is a reflection of the effector to tumor cell ratio. And so in the higher tumor burden patients, they're more likely to progress early. That's true in autologous setting despite persistence of CAR T cells as well, and Bijal can talk about that in much more detail than I can. But what we also see -- I'll just provide some context to the slide you're talking about, Slide 27. We do have this patient with an ongoing response. We have a second patient who had an early progression but in a very small amount of disease that was not biopsied, and we do not know the CD19 status. We had a patient who had a complete response in the periphery in the body and had a relapse in the CNS. So far, I don't know that any -- anyone has been able to improve CNS disease with allogeneic CAR T cells, so that's a pretty unique situation. And then the last patient also, truly the tumor did not progress. The patient died of sepsis related to prolonged pancytopenias that were probably related to the underlying disease as well as you said, potentially exacerbated by lymphodepleting chemotherapy. So as I mentioned before, it is really likely that when you see increased complete response rate, you are more likely to see durability of response. And so that requires treating more patients and following them up for longer to be able to answer that question. And until we do that, I think it's all just speculation. But there is certainly reason and there are trends within what we're observing to believe that, that is a possible outcome. And Bijal, I don't know if you want to comment on that.

Yes. No, I love the question. And the problem is I could go on for hours and hours, and I would still -- the answer would still be speculative, as you alluded to earlier. I think it is so cool when you see a PR to CR conversion, and I would love to understand better why. I can tell you, in terms of the first part of your question, what is -- how do we come to ultimately understand this concept of peak versus persistence. And as the lead investigator also for the ZUMA-3 autologous CAR T cell therapy based on CD28 in acute lymphoblastic leukemias, I can tell you that peak really mattered. We're able to generate sustained disease control at least out to over 2, 2.5 years with a CD28 product where we don't anticipate any meaningful persistence. I want to come back to that term of meaningful persistence because I think we also look to other CAR T constructs and say, yes, but they're around longer. But the answer is what are they doing. Are they functional? What's really happening as we get beyond that sort of 28-day window? Are we seeing PR to CR conversions? Again, these are all hard things to understand and wrap our heads around, but I have certainly been very impressed with what we've seen with these CAR T cell therapies, both this allogeneic therapy -- I'm sorry, including this allogeneic cell therapy, which has a high peak expansion and does a tremendous job at eradicating what we can see and, with that, seeing these durable remissions in tow. Coming to this question of, again, the speculative nature of what it is we're seeing, I'd like to reflect back on what, again, we saw with our 28 CAR product -- not our CAR product, I'm sorry, with Gilead's 28 CAR product, which is when they were biopsied at day 10, and this is Scott Rodig's data, when CARs were peaking in the blood, only about 2% of CARs were in the lymph node. Now the lymph node was replaced by T cells. These were endogenous T cells or perhaps part of the product. We don't know. The point being that what we're doing by virtue of giving CAR T cell immunotherapy is not just giving CAR Ts. We're inducing an immune response. And in some cases, I think, while speculative, it's possible that, that immune response may come with more than simple CAR T mediated effect but an immune response against the tumor changing fundamentally, the tumor macro environment to make that feasible. So again, lots of speculation. Lots of guesswork, but that's where I -- where my current thinking is as we think about CAR T cell therapies moving forward.

The next question comes from Salveen Richter of Goldman Sachs.

Could you just comment on how you're going to incorporate the levers of optimized dosing and repeat dosing in novel LD regimens with the new stealth cell candidate that's entering the clinic next year and what this means for the broader CAR T program?

Absolutely. Thanks for your question, Salveen. Chris, do you want to take that one?

Sure. Yes. To start out, in the stealth cell program, we are going to start quite simply with a standard comparator. So we will start with standard fludarabine and cyclophosphamide, as we have with all of the programs, to understand the kinetics of expansion and the timing of rejection. Despite the modifications to the stealth cell, which we are very optimistic about, we still believe that any allogeneic product is likely to be rejected at some point. So we would like to understand the parameters of how and when that occurs. So to start, we will be using the standard approach. Of course, once we understand those kinetics, we will want to apply all of what we have learned from other programs, including 0191 so that if we can improve the kinetics in any way with the stealth program, we can apply that rapidly. And the timing for that should be very good. By the time we get into dose escalation and have a dose selected with the stealth candidate, we should have answered a lot of these questions with our first-generation products.

Great. And then for the broader CAR T programs, the other programs that are going into the clinic and have come into clinics, will you be moving forward with the stealth cell candidates for those as well? Or are you going to see what happens here in lymphoma?

Right. There's obviously the ability here to ensure that there's some risk mitigation related to any particular product. I'll let Matt maybe try to answer this question in terms of how we're thinking about risk stratification. But I think your question gets to the point of, can you learn enough from any given one and how much energy and resources need to go into preparation for the stealth candidates. We have said all along that we believe that these modifications are going to be very important in the future and certainly can be applied to the other targets as well.

Yes. Thanks, Chris. That's exactly right. We'll be in a position where, if we see something that is really compelling with the CD19 stealth cell program, that's something that we can apply to both the CD20 and BCMA programs as well. With regards to our newest programs that we announced recently, we're not going to be commenting on those constructs just yet. But again, we're very interested in exploring not only the stealth cell but the other levers that Chris mentioned as we go into 2021.

And our next question comes from Tom Shrader of BTIG.

It's as clean a data set as I've ever seen in this field, so congratulations. I had a question for Dr. Shah and his figure where he got excited in the bottom half of Slide 27. If we take that profile of the cells at face value, which is 1/4 of the people get a profound response, another half of the people either have to be watched very closely for 2 months or routinely retreated, but everybody can be retreated immediately. Is that an attractive profile relative to other approaches already?

Sure. I'd be happy to answer that question. I think -- the question is always hard when we're talking about other approaches in quotes. And I'm going to guess that what you're alluding to here is not so much autologous CAR T cell therapies but perhaps some of the other novel agents that are making their way into the clinic now such as mosunetuzumab and tafasitamab and some of these other antibodies and bispecifics. And I guess the question to kind of put it back on is would you rather receive intermittent therapy. And I'm going to make it up that when we get to a point where we really feel like we succeeded and we're redosing maybe, what, every 6 months, every year, whatever it may be, it doesn't matter, is that better than continuous therapy where what we're really talking about is taking lenalidomide or tafasitamab for a year and then extending that for another however long to achieve the same depth and durability of remission. From my perspective, I think, intermittent therapy, it's easier. We're not, at least as of yet, seeing any significant CRS or neurotoxicity. So I'm thinking about what this means as we move forward in terms of how we deliver the therapy and where we deliver the therapy. What that means and the ease of being able to administer it, I'm pretty excited. And so no, I don't ever want to see anyone relapse. I would love it if we could administer a therapy once and cure the malignancy. And who knows? Maybe as we move into earlier lines of therapy when patients aren't so far advanced, we may start to see some of that emerge. But as it stands now, I'm -- I think what we're seeing is really encouraging, and so I'm not as concerned about that. And I think the other thing that I'll say, and I think it's important, is to not necessarily think about these therapies as competing. While I understand they come from different companies, sort of the flexibility you have with off-the-shelf products means that it functions more as a drug. And so when I presented at the International Working Group for CAR T cell therapy, a month or 2 ago, I really tried to highlight this in my talk. I talked about how CAR T -- allogeneic CAR T was given essentially as conditioning before autologous CAR T. So this is a patient who had -- who didn't have sufficient T cells for collection, so received the allogeneic product, had lymphocyte recovery following the allogeneic product, then was able to go on to receive the autologous product and ultimately an allogeneic transplant, which cured the patient's disease. We're seeing other similar examples, right? And thinking about allogeneic CAR T cell therapy now as a component of multimodality therapy, thinking about what it means now much in the same way we think about bispecifics, right? None of us would bat an eye to say, "Hey, we're going to put a R-CHOP plus a bispecific in frontline therapy for DLBCL or an R-CHOP plus ADC in the frontline." But I want to step back and say, well, look, I've got another point of care therapeutic on my shelf that just requires, again, some modest changes in terms of what we do with regards to lymphodepletion. But how do I incorporate that now into earlier lines of therapy, achieve similar responses or even better responses? So I guess what I'm trying to say is there's nothing that says that these therapies necessarily need to compete with one another, that there are ways that we can begin to think about how to bridge this therapy with other therapies in large part because it's again we're making large batches from single donors and have the ability to, again, access the product quickly. I don't know if that answers your question, but I hope it does.

Our next question comes from Raj Prasad of William Blair.

Just a quick 2-parter. It seems like you had 4 patients that were previously treated on autologous. There's obviously one case study that you presented, but just kind of wondering were these CD19 escape relapses or just kind of your thoughts around potential for retreatment of CD19 escape autologous versus not. And then just looking at the clinical activities kind of underway. It seems like you guys have 3 buckets: peak, persistence and repeat dose. Just wondering if you could maybe put that into context, some of the clinical activities in those 3 buckets on maybe more of a priority list based on the data we're seeing today, how you're thinking about which levers are the most important to kind of look at first both in terms of 0191 and kind of the broader platform.

Great. Thanks, Raj. Yes, Chris, please take that one.

Sure. Yes. So in terms of -- for your first question, all patients that come on to the study have to be CD19+ by either IHC or flow cytometry. So CD19 loss, we have enrolled patients in that setting. We did talk about some case studies that include prior autologous CAR-T. What we have observed is patients who have previously responded to autologous CAR-T are actually more than 50% of those patients are going to achieve a response with PBCAR0191. So assuming CD19 is still present, if there was a prior response, it usually predicts that a patient is more likely to achieve some level of clinical benefit. As Dr. Shah mentioned, sometimes the durability of those responses can be limited, but that may not be surprising considering that there may be other clonal evolution properties to those patients' cancer cells that have now made them somewhat less likely to be durable responses. So while we have seen responses in that setting and gave one such example, we don't think we're going to be able to overcome CD19 loss with this product. However, that may be possible with a CD20 targeted CAR-T or other targets in the future. In terms of the buckets that you mentioned of how we're approaching things, yes, they're all important, and we are prioritizing them by doing them all in parallel. The enhancement for depletion, obviously, we have the most information on because we started that the earliest, and it gives us the first look at high peak expansion. I will also note, though, that part of the reason we started with the enhanced lymphodepletion is we thought it might extend persistence, and we do see some hints that it may extend persistence. So both of those are being evaluated concurrently and aggressively on our part to get enrolled and evaluate these things. So it sounds like there are a lot of things to do, but some of these efforts actually started in the last couple of months anyway. We just don't have enough follow-up data to be able to disclose that information yet. And that's why we think we'll be able to give an update by mid-2021 with all of these levers being evaluated fully.

And our last question comes from Ben Burnett of Stifel.

Congrats on the update. I have just one question for either Dr. Heery or Dr. Shah. I guess can you just provide some more color or your thoughts around the case study that you mentioned on Slide 30, where I think the patient converted to a CR at day 90? And just biologically, does it assume that all the CAR T cells would have been rejected by that point? And I guess if so, what would be driving that increased tumor response?

Thanks, Ben. Dr. Shah, would you like to -- go ahead, Chris.

Okay. Go ahead. No, no, no, go ahead.

No. Like I said, it's a great question, and I don't know the answer. I think that, as I alluded to, there's a couple of possibilities. One is nonspecific PET uptake, right? We thought this patient was in a PR but in fact, had achieved the CR very early. Another possibility is what we measure in the blood is not a reflection of what is in the tumor microenvironment, that is there's a compartmental effect. And I think that it's important to think about that not just with this patient, but again on Slide 27, if you look at subject 002, who had a durable PR lasting for upwards of 6 months, receiving -- I think she was treated at the very first dose level, where we didn't see meaningful T cell expansion in the blood yet saw incredible clinical responses. And so it could be a compartmental phenomenon where the T cells are locked into the tumor microenvironment. A third possibility, as I alluded to earlier in this conversation, is, look, the CAR T cells get there, but they're allogeneic. They drive an NK and T cell response that comes with -- that obviously comes with tumoricidal activity. That's especially relevant for, again, that first patient I just described to have a primary mediastinal large cell lymphoma, which we recognize as being immunogenic and having high PD-1 expression and so on -- or PD-L1 expression, I should say. And so I think there's more than one possibility, and it's not always easy to tease these things out. But when you see them, you get excited. You get excited because it tells you that you may have done something biological that extends beyond the lifespan of the CAR.

Okay. That's super interesting. And maybe...

And Ben, just to clarify, on this particular patient, you know that the conversion to a complete response was due to a biopsy demonstrating no tumor presence indicating that, in this particular case, it is possible that this was an imaging abnormality that -- of a response that happened very early. So that possibility is, I would say, front and center in this particular case.

Okay. Super interesting. Okay. And then maybe, Chris, just one last one. You talked about potentially going to novel lymphodepletion regimen, and I understand that, that's something that's going to be proprietary. But I would just ask about the strategy. And is the strategy based on these data, is the goal to drive a deeper level of lymphodepletion? Or is the goal more about creating a longer window of lymphodepletion? I guess how do you think about that?

Yes. It's actually both and also one other idea. And we haven't obviously talked about it too much, but one other idea is to use some of the characteristics of the immune response to our advantage. So if we understand the mechanism by which rejection occurs and understand the process of allogeneic rejection and recognition, then there are methods that exist to try to induce something more like tolerance to the allogeneic antigens. So in addition to increasing depth, where we've seen that increasing depth of lymphodepletion can cause higher peak expansion and trying to extend the span in which persistence can occur, it may not require causing significant cytopenia to achieve that over a long term. And that's actually one of the major goals of these more novel approaches. The last thing I'll say is if we find that we run into a wall in those settings, and it is just not possible to overcome them, that is why the second-generation stealth cell is so important to us and why we've been developing it for the last 2.5 years to be ready to take it into the clinic.

Great. Thank you. And this is going to conclude our presentation and Q&A. I want to thank you all again for joining us today for this very important announcement from Precision BioSciences. And otherwise, this concludes the call. Thanks.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.