...Really? I was going to wear, like, a suit and things, and I thought, you know, I forgot I spilled stuff on this. I like your socks. Thank you. I bought them when I was in Tokyo. The guy was like: "You got to go to this sock store." By the way, you have not. "You got to go to this sock store. Good afternoon, everyone. Thank you so much for joining us for this panel. It's the outlook for the allogeneic approach, optimizing the clinical profile, and I'm really pleased to have with us David Chang, President, CEO, and Co-founder of Allogene Therapeutics, and Steve Harr, President, CEO, and Co-founder of Sana Biotechnology, and I'm joined by my colleague, Matt DeLaTorre. And I'm especially excited to host this panel because it reminds me of days prior when we would sit up here and talk about, you know, the days of Kite and Juno. But maybe to start here- I have to say, when I found out that Steve Harr will be on this panel, I said, "I'm not going to miss this. Everybody loves a history lesson, don't they? They do. They do. So maybe to start here, both of you were pioneers in the field of autologous CAR T therapy, and you were looking at other modalities as well and looking at other disease areas as kind of the future of where you might go. And you've now both co-founded companies that are focused on, you know, are taking different approaches, right? So help us understand how you think about allogeneic therapy or the allogeneic approach as kind of the next frontier of cell therapy, particularly for hematologic malignancies, but now also for autoimmune diseases. And just frame the current state of the field for us, your respective programs and approaches, and then your upcoming data sets. You want to start? Okay, so I think, you know, Sana and Allogene were founded at about the same time, and both companies were founded with a, you know, very similar mission, really democratizing the cell therapy, I would say. You know, taking the bespoke and manufacturing of autologous to the next step. And certainly, at the time when, you know, I finished Kite Pharma and thinking about the next step, the ideas about different indications, you know, hematologic malignancies and solid tumors, as well as even autoimmune at that time, were discussed. But independent of which indication that you go into, you have to move into a more scalable manufacturing, you know, which is where the allogeneic cell therapy comes. And I would say over the last five years, there has been a lot of advancement that, you know, that everyone in the field has been able to achieve in the allogeneic CAR T therapy. I think everybody now understands probably the most important facet of making the allogeneic cell therapy work is overcoming rejection by the patient's immune system of the allogeneic CAR T cells, which patient's immune system sees as a foreign and tries best to reject it. And, you know, there are different approaches that people are taking. Fundamentally, I think you can simplify it as either cloak or dagger, making CAR T cells invisible from the patient's immune system, or have a way to, you know, counter these alloreactive T cells, patient's alloreactive T cells, from rejecting the autologous CAR T... allogeneic CAR T cells. And I would say that, especially on the larger, which is the way that Allogene has been advancing the pipeline, there has been a lot of advancement and demonstration that allogeneic CAR T therapy can provide the same level of efficacy as well as durability in the heme malignancies. And I would also say that another thing that everybody, and certainly in the morning sessions, there were a lot of discussions about the manufacturing. Now, manufacturing is not just, you know, the facility that we're manufacturing the cells, but also the manufacturing science. How to make the CAR T cells more potent, understanding the critical attributes of the CAR T cells that, so that you can continuously improve, either through manufacturing or by gene engineering, to make the CAR T cells work much better. So, you know, at Allogene, our lead program is cema-cel. This is a product that we have been studying in relapsed refractory setting for some time, demonstrating that as an allogeneic CAR T product, using our proprietary lymphodepletion that is augmented with a, you know, biologic anti-CD52 antibody on top of fludarabine and cyclophosphamide, that we can achieve the overall response rate, complete remission rate, as well as a durable complete remission on par with the autologous CAR T therapy. But as we are advancing the program, you know, there was also sort of changes that's happening in the, you know, in the large B-cell lymphoma space. And more recently, we decided to really differentiate our development strategy by finding a very unique and differentiated approach of advancing the cema-cel into the frontline as a consolidation approach. And this is a study that we are currently conducting as a pivotal study. We announced the initiation of the study back in June of twenty twenty-four, this year. This is a program that's very rich in milestone over the next three years, starting initially with the early readout of the study in mid-two thousand twenty-five. And in two thousand twenty-six, we have the first efficacy analysis at about the time that we expect to complete the enrollment. That's in the first half of two thousand twenty-six, and that leads to the primary analysis. EFS, you know, is the primary endpoint by the year-end, leading to potential BLA filing in two thousand twenty-seven.... Our next program that is sort of a next generation approach towards allogeneic. This is our ALLO-316, which is a CD70-directed CAR T therapy that we have been studying in renal cell carcinoma. So this is a study that we've been doing for some time, and the initial data presentation was made at AACR last year, where we have shown that in the CD70 positive renal cell carcinoma, we can get approximately 30% response rate. This is data that we plan to update, you know, before the year end, in a scientific forum, where we will cover more patients who have been treated as well as, you know, testing, you know, what we believe is would be the recommended phase II dose, both in terms of cell dose and lymphodepletion. And the third program is really, you know, trying to create more opportunities with the cell therapy overall, and this is, you know, autoimmune disease indications. There were a lot of discussions about autoimmune earlier in the session, so I will not go into why the excitement about cell therapy in the autoimmune space is. So we have a program that was designed from the beginning with the autoimmune indications in mind. So this is our ALLO-329, CD19 and CD70 dual CAR that we are using next generation manufacturing technologies. So manufacturing, you know, we always believe that it has to be simple and scalable. And with the ALLO-329, we are using CRISPR-based gene editing, using a single cut onto which we use AAV virus to introduce the transgene. And this is a program that's also, you know, has two important aspects. You know, one, having a CD70 allows C... This ALLO-329 not only to deplete the B cells, but also deplete CD70-positive activated T cells. And autoimmune disorder is never a B cell or T cell disorders. It's really the combination of two different lineage of lymphoid immune cells that contributes to autoimmunity, and this program is designed from the beginning to address those two aspects, you know, both B cell and T cell aspect of the autoimmunity. And also, I think the CD70 really differentiates what we are doing in the allogeneic CAR T space. CD70 portion brings the dagger technology. So we talked about cloak and dagger. This is the CD70 allows the allogeneic CAR T cells to essentially overcome patient's immune system from rejecting the CAR T. So in ALLO-316 program, we have seen great cell expansion and persistence that's going up to about two to three months easily, you know, using the dagger approach. So this is embedded into the ALLO-329, as we think about the autoimmunity with, you know, a very important goal, which is to minimize or reduce the lymphodepletion as we advance the program to the autoimmunity. Lastly, also, you know, in much of the earlier conversation covered the need to be able to manufacture and, like Lyell, like our advance, we invested early on in our manufacturing facility, and we have a wholly owned manufacturing facility, about a 140,000 sq ft facility, that at the current, you know, at the full capacity, can produce upwards of more than 20,000 doses of products for cema-cel. So just to put that in the context, in 2023, the total number of patients were treated with CAR T commercially. The number is about between 9,500-10,000. That's estimated number. This, a single facility, can produce enough to treat 20,000 patients, and that is really one of the big distinctions and advantages of the allogeneic CAR T as we think about the future of the cell therapy. Let me give it a shot. Go ahead. I'll go back to your original question, you know, the founding of these companies and things, and I was just thinking a little bit about, as David was talking, an answer from Bob Newhart when Larry, Daryl, and Daryl, one of the Daryl's ran for office, and he got up after a talk and just said: Ditto. But I'll try to add a little bit to it. Do that. Yeah, so I'll try to add a little bit to it. Which one of the beautiful things about autologous CAR T cells is that you can get an early indication of how well they're working in a relatively capital-efficient way. I mean, most of these drugs were developed, you know, out of academia and things like that. I think one of the, you know, real challenges that we all learned as we were doing it was that it wasn't just the complexity of manufacturing, which I think is what people really, you know, have focused on, but it's the complexity of release, and it's the complexity of quality and things like that, and it's the complexity for the patient and the physician, the apheresis center, and things like that around scheduling. And so, you know, we really start out, you know, going into the allogeneic side with the idea that we could hopefully eliminate much of that, as David said, by really trying to overcome the biology of immune rejection. I think the challenge of it is, though, and this is a particular challenge in a world like today, is that it's really capital intensive, and it's capital intensive early, right? The supply chains are complicated. You know, just to make a gene-modified product, you're looking at making guide RNAs and mRNA and you know, maybe a viral vector or something like that, before you've ever dosed a patient, and you have to do that GMP, and you're also putting money into manufacturing facilities. The beautiful part of that, though, is if we happen to get the biology right, you know, they truly are scalable in ways, and the cost of goods and our ability to make them feel to a patient and a physician exactly like an antibody is real. So, you know, while it's been painful to put all this capital at risk in an era of increasing cost of capital, I think the upshot is that if we happen to get this right, we have a really quick runway and ability to lock processes and move into scalable registration studies with scalable commercial products. That's kind of like how we've thought about it. We've got a number of different ways we're trying to apply the technology, both within CAR T cells and stem cell-derived therapies, and most of it resides upon the singular kind of insight around what we hope is an ability to overcome allogeneic recognition of these cells, which I'm sure we'll get into as we go forward. But that's a little bit about, you know, where we are and what we're up to and why, if we happen to get these right, these allogeneic therapies can be so powerful for patients. David, let's start with you. So you talked about the ALPHA3 trial here, and you've made the decision to pivot cema-cel to frontline LBCL patients who are MRD positive. Help us understand how the trial is progressing, but also, you know, the ability to identify these patients, the ability for this to be a successful commercial opportunity, and for the data that you've seen in this subset to translate in the phase III. Yeah. So just on the background about what we announced earlier this year, you know, we were advancing cema-cel in an allogeneic CAR T product, you know, with the mindset of, you know, how we advanced the autologous CAR T. And then it came to a recognition that we are not fully taking advantages of the allogeneic approach, and also not accounting for some of the, you know, the barriers as we are trying to move into the earlier line, where we would expect the most benefit from a potentially curative treatment. So, you know, we made a decision, and this is really coming from, you know, two supporting evidence. One, you know, from the relapsed refractory setting, we knew that cema-cel was as good as autologous CAR T. Yeah, the data set is a small number of patients, but when we compare our, you know, phase I data to the, you know, the pivotal data that supported the registration of Yescarta or Breyanzi, you know, that was very similar. The other thing is really advancement in the other field, which is the, you know, the in vitro diagnostics. You know, this is using the circulating DNA to identify MRD-positive patients. So marrying those two important information together, you know, we came up with a clinical development strategy that is uniquely differentiated and also relatively competition-free, and up in the first-line setting. So first-line setting for the large B-cell lymphoma, they are highly effective treatment. Our Rituximab-based chemoimmunotherapy, they will provide cure in about 60% of patients. Even before that, I mean, 90% or more patients will respond and respond very well. The problem is that about those 30% of the patients who initially have good response, when you watch and wait, their disease will progress, and they will have to go to the second and subsequent line of therapy. The question is, how to improve the initial treatment effects so that those 30% of the patients can be managed, and so they do not have to go through the agony of being told that their disease has come back and then go through the different lines of treatment. What we are doing is letting the patients complete the initial R-CHOP or similar regimen, and at the end of the treatment, testing the patients for the presence of MRD. When they are MRD positive, then they are eligible for the cema-cel ALPHA3 study. This is a randomized study that we are comparing patients with a single cycle of cema-cel versus watch and wait, which is a standard care, and using the EFS and endpoint, and we'll be sort of, you know, carrying out the study. As I've said earlier, this is studies reaching catalyst over the next two and a half, three years. In terms of the study, I mean, much of the work in the first half of the year was trying to get all the ducks lined up to start the study. So announcing that we were moving into the frontline was made in January, and then in June, we announced the site activation. You know, so far we are busy activating both community-based cancer centers, where most frontline patients are cared for, as well as academic centers. The site activation is tracking very well, and we are also testing patients for the MRD using this proprietary assay that our partner, Foresight Diagnostics, has developed, and that is also going very well as we have projected. We are screening the patients, and we're enrolling the patients, and so far all the earlier signs are looking good. And you touched on the CD70-targeted CAR T data that's coming by year-end and some data early next year in a different indication. Just put that in context for us versus the clinical data you've seen to date and, you know, what you're looking for in these two populations. Yes. So, you know, solid tumor data, which is our ALLO-316 program. The goal that we are trying to get is getting enough number of patients, and, and this has to be the right, patient population, and demonstrating the response, that, you know, probably at least like to-- I like, personally like to see more than a quarter, maybe one-third of the patient achieving the response. And then the second question is, you know, what is the durability of the response? And those two are the things that we are really, you know, focusing at this point, at the cell dose and lymphodepletion. And currently, for ALLO-316, which has a Dagger technology, we're using the same lymphodepletion that autologous CAR T therapy is using. So we do not have to enhance the lymphodepletion, even with an allogeneic CAR T. We will be updating the phase 1 data, as I said before, by year-end, with additional number of patients that are evaluable, as well as more durable follow-up on the patients that have already been treated. So Steve, we'll see the IST data in type 1 diabetes, hopefully by year-end, which has been a big focus for investors. Could you maybe just frame for us what you want to see there to move forward with your corresponding iPSC program? So this is. We've changed tacks a little bit here. And this is looking at Type 1 diabetes, and I think most of you recognize Type 1 diabetes as the immune system has attacked and killed all the beta cells in a patient. And because they don't have beta cells, they can't make insulin, and they end up until 100 years ago, they died from glucose intolerance, and now people take insulin. And even with best care today, you know, people have about a 10-15-year shorter expected lifespan. And during that time, there's a lot of complexity for the patient and a lot of complications as well. And so what's known is that there have been, you know, thousands of these cadaveric-derived islets that have been transplanted into patients. In the context of immunosuppression, many patients can go 10 to 20 years with, you know, insulin free, and then some of them are going on longer. We'll have to see, insulin-free glucose control, and they really do quite well. The problem is it's not really a scalable source, nor are there that many patients for whom lifelong immunosuppression is better than lifelong insulin. We now know, from others in the field that you can take stem cells and make, beta cells, and it's been, you know, reproduced several times now. And that in the context of immunosuppression, you know, again, patients can do quite well over time and stay insulin free. But you still have... That's a more scalable source, but you still have the problem of immunosuppression. So the question we're trying to answer in this immunosuppression, sorry, this investigator-sponsored trial, is: Can we get rid of immunosuppression? So we have, you know, done this in non-human primates and in other animal models and shown that in the context of gene-modified primary islet cells from another, from a, you know, similar from the same species, you can see long-term insulin free, you know, survival in these animals with well, with, you know, normal glucose control. So our goal in this study is a little bit different, right? And so what we wanna see is that these, is that these cells survive, and they function. And it's a phase I first-in-human study, so you have to just take the context, what is the dose and what's the goal? So, you know, so all we want, if we can show that these cells survive and function, I would argue a cure for type one diabetes is inevitable because now you've kind of completed the circle. You know everything you need to do to make it happen. We might not be the one to do it, but it becomes inevitable. And using the gene-modified pluripotent stem cells, make them into, you know, functional islets at scale and transplant them, right? And so the goal of this study is to see this. So there are three ways you can see survival and function. One is you see it on an MRI, and you can see that. There's actually a paper last week in Cell of a patient who had autologous-derived stem cells that were transplant... Autologous stem cells that were made into beta cells that were transplanted in the muscle sheath. And the patient's done amazingly well, and you can see those cells. So that would be step one. Step two would be the C-peptide. And I think that should be where the expectation is as good as we will do, because of the first-in-human dosing. If you recall, the way that a beta cell makes insulin, it actually makes something called proinsulin. And as proinsulin is secreted, it's cleaved into insulin and C-peptide. So all these patients have no C-peptide. If you see C-peptide in the patient, you now know the patient is able to make their own insulin. They're able to do that in a sustainable fashion, right? Without any immunosuppression that we're doing, and it's just, you know, we'll see how that goes. The third would be able to see patients with better glucose control. That shouldn't be your expectation. I mean, it could happen if you get a little bit lucky, and that happens, but that would not be the expectation of the doses that we're dosing at. And it's a. It's demonstrably lower than, for example, with the doses that was in that Cell paper or with, you know, some. So that's a little bit about what to expect. And so how do you translate that into a therapy? Our goal is not to gene modify cadaveric islets and transplant those to patients at scale. Our goal is to gene modify a pluripotent stem cell, grow it into a pancreatic islets, and do that at scale. So to do that, we've said you have to overcome four scientific challenges, really, to go for that. One is to make a gene-modified pluripotent stem cell master cell bank, where you're really confident with genomic integrity over time. Remember, you have trillions of divisions that you'll be looking at over time, and in our body, and we have basically every single mutation you could imagine, right? And we will be growing these cells in a media that's selecting for cells to grow quickly, and that's what you do when you manufacture cells. You want to make sure you're not creating a tumor or something that could be a tumor. And so I, we think we've got that. I think we've got that. It's taken us longer than we thought. It's taken us a few years to really kind of get that right, but we think we have that. Not guaranteed yet. The second is to be able to manufacture these drugs at a purity, potency, and scale to run a phase I study. Again, you should feel pretty good that we got that. Not guaranteed. Once you have to make sure you've got the same every time you like, you change your master, if you get the subclone from a master cell bank, it's like, kind of like a new chocolate for your chocolate cake. You know, it may taste a tiny bit different, and you've got to kind of adjust a few of the other ingredients, and maybe we have to play around with the salt or the vanilla or the sugar, but we'll get it right. The third is to be able to overcome allogeneic and autoimmune recognition and rejection of the cell. Again, you'll learn that from this investigator-sponsored trial. So, you know, very shortly, you should feel really good about three of those four things. The fourth is to be able to make the drug at a purity, potency, and yield that's truly commercially important. And I think, to be clear, we're pretty far away from that. I think that that's gonna take us some time to do. It is not simple to turn these stem cell-derived products into, you know, billions or trillions of cells. We'll get there. The field will get there. I wouldn't be too worried about it, but it's gonna take time. You know, I, I'm guessing that if we happen to get this right, you're gonna be frustrated with us for a long time around the scale at which we're manufacturing this. Partly, that relates to just the overall size of the market, which is, you know, really quite big, and partly that relates to this to where we are in the science of scaling these drugs. Great. So then we'll also see phase I data for your lead asset, CD19, SC291 in autoimmune and B-cell malignancies. Maybe could you just kind of frame your expectations going into those two sets? And then also, how should we think about read-through, particularly in autoimmune diseases? How think about what? About potential read-through- Yeah. from those early autoimmune sets. Yeah. So what do you know? So we make this drug, right? We put these gene modifications in them. We've shown you a few patients worth of data, and it looks like they look pretty good. They're early. There are no safety issues that we're seeing. They seem to avoid immune detection by the assays that we have, and for, you know, a couple of patients in, we had a few responses. That's all you could really ask for at that point. So I think the real, in oncology, the challenge here has been durable, complete responses, right? And having a profile that looks like the autologous cells. And then if you happen to get that, you know, it you should have an important drug. As David mentioned, it's a very competitive marketplace, and these therapies are now developing long-term survival data, and you have to kind of find your niche, which, you know, Allogene has done quite well. And we have to make sure we find that niche to make sure it's useful to go forward, right? You know, autoimmune, and so in many regards, we have to deal with the context of those that came ahead of us because they're a lot ahead of us. You know, we may or may not be able to figure that out in the near term, right? Because if you're really looking for six- to 12-month, you know, durable response data, I would argue it needs to be 12 months. If you're not in an aggressive lymphoma, then you've got to kind of... A lot of the phase I patients are, you know, indolent lymphomas, then you got to be patient. You know, you kind of know that in January, we gave you data with four patients, and you can't be much better than four at one year, right? So this time, you can't, you know, you can't accelerate it. So that may take longer to understand the drug profile than people hope. The second will be the autoimmune setting, and I think there is very, very different. First off, the data from the autologous cells are, you know, pretty profound, but they're pretty limited to date, right? I mean, as you're just beginning to see the emergence of data from company-sponsored studies where, you know, it's probably a bit more generalizable patient population than what you have in a single center where, you know, the patients are highly selected. You can see, like, the oldest people in those studies would mostly be younger than the youngest person in this room, right? Mm-hmm. And so, you know, once you get into the real world, particularly in the United States and things, you're just gonna have an older patient population with a lot more end organ damage. The second, you already know we can deplete B cells, right? We've shown you that in the oncology data. We've depleted them pretty well. So really, what I'm trying to tell people that all you can really learn in the early parts of this study is: Do we have a safety problem? Hopefully not. Do we deplete B cells in the autoimmune setting like we do in oncology, and does that translate into early clinical benefit? You know, if you really want to understand where we stack up competitively, it's gonna take time. If for no other reason, we don't know where the competitors are yet, right? I mean, they're still... Really, a lot of them don't have much data, or they're just beginning clinical studies, or they've got a handful of patients, and it will take us similarly some time. I think you can tell pretty quickly, do we have a drug or not, right? I'd be pretty surprised if we don't have a drug, right? Just given what we've seen in the oncology setting. But that's what you should hope to learn out of, you know, early data. It's gonna be very difficult to define exactly where it fits against all these different modalities. I think it would be very simple to define whether it's a drug or not. David, just following up on that topic, you have an effort here, which you touched on in, you know, autoimmune diseases. Maybe speak to your approach here, where you are, you know, bringing in CD70, and you're looking to get rid of lymphodepletion. You know, how do you think about the path? Yeah. I mean, you know, our effort into autoimmune, I mean, this is really building on the early data set that's coming from the autologous CAR T that's really influencing us. I mean, you know, I have to say, everybody in this room has to give a lot of credit to, you know, Dr. Georg Schett, you know, for taking autologous CD19 CAR T into the autoimmune space. I would say that we considered that back in 2018, 2019, but we didn't have guts to do that because of the safety concerns. And, you know, when you think about the autoimmune and the B cell depletion therapy, especially with a CAR T, I mean, the goal is here is really, you know, the remission that's durable and going for several years. I mean, I wouldn't say necessarily cure, but, you know, taking the treatment that is chronic, where a patient has to receive treatment either daily for all or, you know, on a, on a, you know, every three to four months, if it's an IV or subQ, to something that you can just get treated and forget about that you had a disease. I think that's where the promise of CAR T in the autoimmune space is, and certainly, in autoimmune also is, from the commercial perspective, this is a different beast from any oncology indications that we're talking about, so you know, with all that in mind, and as I said earlier, we started from scratch. You know, what is the target product profile that you would like to have to advance the allogeneic CAR T into the autoimmune space? We started in a very, very important question. It cannot be just, depleting the B cell, you have to address the T cell component, and this is where the CD70 portion comes in. CD70 is an antigen that gets expressed in the activated T cells, and having the CD70 CAR addresses activated T cells, which we believe plays a role in autoimmune disorders. And another thing that, you know, we thought very carefully is, you know, the question of the lymphodepletion. The rheumatology indications, unlike in oncology, safety stands out as the paramount important aspect, more than in any other diseases. And here, having a chemotherapy-based lymphodepletion, that we always saw as a barrier. Frankly, that was one of the reasons that we did not take CD19 CAR T into autoimmune back in 2018, 2019, in an early state of time. But what having the CD70 allows one to sort of envision is, you know, gradually getting rid of the, you know, lymphodepletion. I mean, the step one is already there. I mean, we already talked about for allogeneic CAR T, you need more lymphodepletion, unless you use a different, you know, cloaking approach. But our experience with ALLO-316, which is a clinical asset that's being studied in renal cell cancer, is that even as an allogeneic CAR T, having the Dagger technology allows you to go to the standard, you know, autologous lymphodepletion that's based on flu-cy. So, and not only that, these cells expand very well and persist, you know, for quite a long time. And, you know, that allows us to really think about, you know, can we in a stepwise address this barrier of lymphodepletion, either reducing it or eliminating altogether? I mean, that's really the target product profile that we thought would meet the demand as well as the opportunities in the autoimmune disorder. So, you know, ALLO-329, which is the CD19, CD70 dual CAR. You know, we have really put a lot of effort accelerating the preclinical work. Since the announcement of the decision to advance into the autoimmune, we are essentially finishing the, you know, the IND work within a twelve-month period, and currently we are planning to submit the IND in the Q1 of two thousand and twenty-five, next year, with a clinical study start by mid-year, and hopefully getting the initial proof of concept by the year-end two thousand and twenty-five. Did you want to comment at all on the lymphodepletion or anything? Tell me what? At all on lymphodepletion or? Oh, lymphodepletion. I mean, I think if you look in the autoimmune setting, the company that can get rid of it will be the company that wins. I mean, it's really something that is super, super sensitive to both the patients and the physicians. It's, you know, it does. I've never seen an exogenous cell therapy product successfully treat patients though, without lymphodepletion, right? So I think we still have some work to do to understand what the magic of it really is and how do we get rid of it. To the extent that you can, it will be super important. You have a challenge. I mean, I think sometimes people forget the math and like autoimmune. Use autoimmune as an example. We all have around three hundred billion B cells, right? And so what you measure in the periphery is somewhere between one and five billion in your bloodstream. So your bloodstream is just a trivial portion of the overall B cell repertoire. And most of your B cells reside either in your tissues, in tissue germinal centers, or in your lymph nodes and spleen. You know, the goal, I think, in autoimmune is to deplete every single malignant B cell, right? And it's a math problem if you, you know, don't have really nice cell expansion and things like that. And it's the same thing with, you know, oncology, where you probably have to eliminate every B cell to eliminate the tumor, right? Because it's gotta be hard to eliminate cancer cells and B cells. And so when you're looking at, you know, lymphodepletion as an example, what it seems to drive is, you know, a great predictor of early, early data in the autologous setting. A great predictor of early expansion is just your IL-7 and IL-15 levels at the time of infusion. ... right? And IL-7 and IL-15 are homeostatic and cytokines that go up when you lymphodeplete somebody. And so you have to, we have to figure out how to deal with that problem to get, you know, the expansion that's almost certainly necessary, because almost no drug that I'm aware of, you know, even like small molecules, very rarely they have 300 billion active moieties. Right, and so if you're really trying to get rid of the malignant B cell, or called the pathogenic B cell, to be, like, maybe less judgmental, then you've got to go after some huge percentage of those 300 billion. Right? And I think that's the challenge for the cell therapy field and getting rid of lymphodepletion. And it's a challenge for any other therapy that doesn't replicate in vivo. You know, when it comes to lymphodepletion, I mean, if you sort of follow the literature and Bruce Levine is here, I mean, he can probably talk about lymphodepletion better than anybody else here. But, lymphodepletion enhances the pharmacodynamic effect of CAR T, and you have shown it with one of your products when you're at Sana- Mm-hmm. You know, going from cyclophosphamide and then heading to fludarabine. But, you know, autoimmune disorders, I mean, when you look at the clinical data, you know, one of the most tantalizing, you know, findings from the autologous CAR T is you don't really seem to need long-term persistence of the CAR T. I mean, it's essentially hit and run. You know, you get rid of, you deplete the B cells and let the normal B cells recover. That has to be part of the equation because people cannot do without CD19 in our cells altogether. So there has to be, you know, treatment, you know, that depletes but allows the B cells to come back. And when you sort of think about it, you know, the idea of, sort of reducing, you know, or eliminating... And I would say the idea of reducing the lymphodepletion has already been tested. Not intentionally, but, you know, if you follow Georg Schett's data, I mean, he talks about now at least two patients, for one reason or another, got much reduced lymphodepletion. And the outcome of those patients treated with less lymphodepletion doesn't seem to be any different than the ones who got the standard lymphodepletion. So, you know, this is where, you know, one can really think about, you know, how to manufacture the, you know, cells to make it, you know, potent and balance out the lymphodepletion and the potency of the drug so you can get the right equation. And And I think that, based on all the scientific findings as well as emerging early clinical data, is, you know, something that's doable. Maybe it's going back to scalability. Obviously, that's one of the key advantages of allogeneic therapies. But how do you all think about scalability, especially in these larger I&I indications? And where are you most focused on the supply chain or manufacturing side? Say again what? Where are you most focused on the supply chain and manufacturing side? For I&I - For I&I. Look at large indications. For autoimmune? For autoimmune, yeah. Yeah. So for autoimmune, I mean, let's just start with the delivery is super complicated, right? So forget the manufacturing for a second and think through the idea of having a patient who's on some kind of immunosuppressant that you have to taper off because you can't have all that immunosuppressant in your plasmapheresis bag as you begin your manufacturing process, right? And then you have to, you know, find an apheresis slot and hope they don't flare, and then while you're making the drug, re-immunosuppress them, and after the drug's released, take them off. So that portion is really complicated. Now, obviously, what's beautiful about this autologous stuff is it really works. We know that, right? We already know it works, but that's complicated. And then when you're getting into scalability, so we'd like is for this to feel, again, as much like a antibody as possible for the physician. So it's ready when they can get the patient off of the drug and, you know, and when they get them off their lymphodepletion, whatever their immunosuppressant is, and begin lymphodepletion to treat them, right? The scalability, I think, of what I heard from David is, you know, a number that's very similar to what I would say. I mean, the hard part is you have to invest in the supply chain early, right? Guide RNA, there's no one. We use CRISPR-Cas12b. No one's ever commercialized that. There's super long guide RNAs. It's a very complex mRNA. We've had to create a, you know, a GMP supply chain, started with a clinical trial GMP and now a commercial GMP supply chain. That is not straightforward, takes time, and unfortunately, it takes capital, right? But those things are kind of done, and then after that, it's really the release is more complicated than it is for autologous because we've done all kinds of genetic modifications to these drugs, and because we can make hundreds of drug product or more per, depending upon the dose, per manufacturing run, you want to get it right, right? And so your ability, it's gonna hit more people. So then the second, and then the last thing you have to make sure that you control is donor or donor variability, right? So if your T cells are used to make one product, mine are used to make the next, you have to make sure that you have a predictable safety and efficacy profile for the patient. So if you get past, you know, those elements, it's actually, you know, it's not that complicated. I mean, it's really not that different than what you do on the autologous side. I don't know if you'd say anything different. It's just a massively different scale. I've never met a business where you can make 500 widgets with one business, and the other business can make one widget, and the 500 widget didn't have a distinct competitive advantage. We just have to make sure we make widgets and not midgets, right? But if we truly make a comparable drug, it has an amazing ability to be accessible to patients. This is when I can simply say ditto, but I won't say that because there's a lot more to talk about here. Yeah. I mean, an allogeneic, first of all, takes away all the complex logistics. I mean, leukapheresis, even in oncology, there is a limited leukapheresis chair, and in autoimmune indications, where the number of addressable patients could go up by tenfold, even more, I mean, you know, that's a, you know, great barrier. And then having to sort of, you know, follow the product during the manufacturing, scheduling, and all those things, taking up the immunosuppression and bring it back on. I think all these can be addressed with allogeneic off the shelf that can be provided to the site in a vial. So that's one. And another thing that, you know, I would say is, yes, it is true, you know, manufacturing of cell therapy products is always capital intensive, but you heard it this morning, the cost of manufacturing is coming down in the autologous setting. Yes, they have to scale up and probably build not just a football field, but, you know, ten times the football field to, you know, to provide the capacity that's needed. But, you know, the benefit of the allogeneic is in this setting, you know, from a single manufacturing, depending on the cell dose, you can treat hundreds of patients. And that's just where we are right now. And as we, you know, work on the potency enhancement, and Lynn was talking about what, you know, Lyell is doing, these will reduce the cell dose requirement, and the gene engineering is something that can be easily done in the allogeneic setting. So, you know, path to innovation is never a straight line. You know, look at how long it took for antibodies to get to where they are. Look at how long it took ADCs to get where they are. It is a stepwise, you know, the path that, you know, we will improve along the way to make the target in a product, you know, workable, not only in terms of the benefit it brings to the patient, which is the most important thing, but the manufacturing and the ease of the, you know, administration. I'm just gonna, you know, yak it again. If we get rid of the lymphodepletion, I mean, this is really, you know, opening, you know, probably the biggest door, you know, for any, you know, drug development in modern times. Just given the number of players that there are right now in this field, how difficult is it to activate sites and recruit patients for your trials? Excuse me? How difficult is it to activate sites and recruit patients, particularly with autoimmune as you look to, you know- How difficult it is to get patients? Activate the sites. Oh, activating sites is gruesome. I mean, it's not the end of the world, but, you know, you'd have to remember that activating sites generally is challenging, right? And now you're activating sites, and even when you're all done with it, you're maybe there splitting the revenue between oncology and rheumatology and nephrology, and they've got all their internal dynamics to deal with, but it's doable. It just takes time. The first ones were done pretty quickly for us, and it's getting more and more of them online. And if you look online, you see that some of these autologous programs in big pharma have 50-60 sites that are activated, right, across the world. And so I... You know, I wouldn't sweat about that as being the rate limiter for progress here. You know, sites, I've said enrolling patients, again, just takes time, right? It just does. There's no way around it. When you're going through dose escalation, you know, you may have one patient per month, and I've yet to see us be able to enroll patient on day 28. Seems to always be a little longer than that, and so, you know, it just takes time. But again, it's not that challenging to find these people. They're out there. You know, they may screen fail for various reasons. You have to start over again, but it isn't like that's the real problem either. I mean, it just takes time. I don't think there's any way around that, and that's the challenge of some of the drug development. One of the beauties of small molecules is you can sometimes dose escalate within a patient, and one of the beauties of cell therapies, we get the opportunity to talk about curative intent. But our challenge is that sometimes early on, it takes more time because of that dose. That dose escalation period is just longer than it is for some other modalities because the drugs stick around for a little longer. I loved Steve's response early on, you know, what, eight months for the first five patients and eight weeks for the next five patients. I think, you know, this is a field that is beginning to learn about the CAR T. I mean, you know, when you talk about most rheumatologists, I mean, you know, this is a new concept. You know, there is a little bit of activation barrier that will eventually, you know, be reduced. When that happens with the kind of clinical data that we continue to see, I think there will be a lot more excitement on of enrolling patients to CAR T trials. I don't think many rheumatologists had in their mindset a few years ago that you might be able to treat patients with curative intent, right? I think that is such an awesome opportunity for them. Obviously, you know, they're they have to grapple with the challenge of toxicity, but, you know, the Actemra and steroids and things that are used to treat, you know, side effects of CAR T cells actually come from the rheumatology field. So I think they're perfectly competent in doing almost everything. Just to follow up on that, so curative intent or, you know, improving upon durability of response or whatever it might be that we need in cancer here, help us understand how you're thinking about that and bringing in tools and, you know, just optimizing as you look to your oncology portfolio on the forward. Optimizing tools for what? Your oncology portfolio, more broadly. Yeah, I mean, durability response. I would say just generally, you know, we've got to get these. Make sure we took a lot of risk to understand could we overcome immune recognition of these cells? And see that the drug behaves like an autologous product. We have to nail that, right? And after that, we get the privilege of going out and take on more biology. You know, assuming that we get the privilege of doing that, as David said, one of the beautiful parts of these allogeneic products is they already are being genetically manipulated, and so our ability to do, you know, one or two more genetics to improve the profile is quite straightforward. You know, if it works, it's highly modularizable too. So we've got, you know, a CD22 that's in human testing. I can't imagine that one would work and the other wouldn't. They both could fail, but I can't imagine that because the underlying biology is so similar, right, what we're trying to do. We just have to continually go after, understand why patients fail, and develop therapies that benefit the, you know, the mechanism of resistance. You know, I would also say that. I mean, earlier panel talked about, you know, the attempts to move the CAR T into the solid tumor. I mean, I think this is, you know, probably one of the, you know, another exciting area that people are sort of failing to recognize. You know, the addressable patient population in solid tumor, you know, far exceeds what you can do in malignancies. And this is where, you know, additional engineering, you know, to make the CAR T cells functional for longer time, as well as overcoming immune suppression. And all these are, you know, scientifically and certainly some data has already been presented, possible through gene editing or gene engineering. And this is where probably another, you know, great excitement in the cell therapy will unfold in next few years. Yeah. I don't think there's been a new mechanism of resistance since the first presentation we did for June in 2013 or 2014. Not every effort to overcome those mechanisms of resistance has worked, right? But I think we know what we need to do as a field, and hopefully we'll make progress for that in the next, you know, 5 to 10 years for these patients. Yeah. I mean, the way we think about is target first, you know, especially for solid tumor. The next thing is, overcome the, you know, allogeneic rejection, as I talked about. And third is, you know, this enhancement approach. With that, David and Steve, thank you so much. Really appreciate it. Thank you, Salveen. Thank you very much. Thank you for having us. Everybody, appreciate it.