to have joining us. Pleasure to have an old friend join us for an interesting cell therapy update. Steve, there's a ton to go through, and we'll jump right into it as well. Maybe I'll let you kick things off, and I know there's a pretty important FDA update from yesterday, which is high on everybody's minds, and it'll be very interesting to get your take, not only from a Sana perspective, but I know you were so involved in this cell therapy space from its very infancy. So it'll just be good to hear from you on how you think about that. Just the FDA stuff? Yeah. So first off, thank you for having us, Umer, and thank you to ISI and people in the room here. And I presume you recognize we'll be making forward-looking statements, and we spend a bunch of time on our risk factors in our K and Q, so take a look. It's usually a pretty good place to learn about the company. So for those who aren't aware, I think many are, yesterday, the FDA put out a warning around autologous CD19 CAR T-cells, more broadly, that are approved in cancer for treating either multiple myeloma, lymphoma or certain leukemias, stating that there may be an increased risk of T-cell lymphomas, right? And so for those of you who aren't aware, all of those tumors are in B-cells, right? The way that CAR T-cells are made is that the genome of a T-cell is genetically manipulated, right? So what has been reported is a number, I think the number is in the mid- to high teens, of T-cell tumors in patients who've received a CAR T-cell. So generally, a couple of things are true. You know, I think the FDA is handling this very appropriately, which was to highlight this may be a risk with these treatments, but it certainly doesn't outweigh the risk-benefit of a CAR T-cell in oncology. You have drugs that are displacing bone marrow transplants, which are known carcinogenic, right, to cause tumors, where it looks like, you know, a third of patients or so are benefiting with l ong-term, durable, complete responses, maybe cures. You have a cancer risk at this point that looks to be one in a few thousand, right? So at its worst. We don't yet know if the genomic manipulation of these T-cells caused a problem, if it just happens to be carried along because patients have risk of lymphoma because they've gotten all kinds of T-cell toxic drugs along the way, right? You know, most lymphoma patients, for example, receive a long course of rituximab and a mix of chemotherapy called CHOP, and it eliminates your T-cells, right? So we don't know the answer to that question, but it's worth taking a look at. But I don't think it will impact any ours or anybody else's oncology program. As you may know, we and others are developing CD19-targeted CAR T cells and autoimmune disorders as well. You know, there's a lot of very promising data that have begun to emerge in the field. We just cleared an IND a few weeks ago, and, you know, we didn't have, you know, any substantive challenges or questions around this particular issue. Can't say it won't happen in the future. We have not heard anything from the FDA. We think we'll be moving forward without any issues. It may, in the long run, impact these really sick patients with late-stage autoimmune disorders. I think that's very unlikely. Could it impact, you know, our ability to go into earlier-stage patients? You never know. Maybe. But, you know, what we're doing here is we're taking patients off of known cytotoxic drugs, right, that are known to be carcinogens and giving them a short course of a CAR T therapy. A couple of other things I'd say, our allogeneic cells, there are reasons to be optimistic that this could be better than an autologous cell, where the warnings are. I wouldn't guarantee that, right? The reasons to be optimistic is we do a lot of quality analytics around the, the genome before we release the product. It just wouldn't be done, right, in an autologous cell. So if it is something, we may pick it up. If it's something in the donor, we can screen it out. You know, some kill, ability to kill these cells if they do. The way we make this, we can get into this, is we knock out two genes and knock one in. If you block the gene we knock in with an antibody, those cells are eliminated. That may give us a safety switch if this does become a problem. So I wouldn't think too much about it, but I wouldn't dismiss it, is what I would say, and we'll try to learn more about it as we go forward. Got it. Maybe just one quick clarification Yeah -on the point you mentioned, Steve, is, you mentioned these are B-cell indications where much of the cell therapies are approved. I don't know if folks in the audience remember, you were obviously at Juno, for much of the time as well. And the FDA focuses on the T-cell malignancies. However, back on some of the secondary malignancies seen with Revlimid, one of the more common ones, among the secondary malignancies was MDS, which is not a classic B-cell malignancy. Right. So isn't there a background rate of these things happening? And I ask in the context of these newfound concerns that any cell therapy going in can result in something like this, regardless of the indication, much more so relevant for autoimmune companies, and I realize people haven't paid much attention on the- Well- some of the I think anytime you're manipulating the genome, right, we're still learning about the long-term implications of that, and I think that's really what this is a lot about, and we just need to, when you start to see anything emerge, take it seriously and try to learn from it, right? It may be something we can monitor, prevent. It may not even be important, right? You're right, every single cancer therapy, more or less, has some toxicities, right? And most of the cancer therapies toxicities include an increased risk of other tumors, right? Right. And so, that, and most of the drugs that are used as immunosuppressants in autoimmune disorders have an increased risk of other tumors, right? And so that's not gonna, it's not surprising that something like this would happen when you play around the immune system. You know... What you even see in the data from the autologous CAR T cells is the drugs seem to work better in earlier-stage patients. That's almost certainly has to do with the fact that as you're getting more therapy, you're beating up the patient's T cells with T-cell toxic therapy drugs, right? Right. And so, you're already going into a population where the T cells have been beat up first in some way and may be at higher risk for T-cell lymphoma, and it's emerging because now patients are living for years, right? So I think we just have to take a deep breath, and, you know, I think the FDA did the right thing by trying to get more information. I doubt this ends up being a large deal for the industry, but I doubt it's a zero either. Right. It probably has something to it. Got it. So, Steve, maybe just to orient everybody on, 'cause the understanding is Sana has a cool cell therapy platform, but I don't think, there's a lot of appreciation for sort of some of the avenues you're going down- Yeah and how rapidly some of the proof of concepts could emerge. Could you just remind us again, what exactly is the construct on the immunology side? What exactly is the construct on the autoimmune indication diabetes side, as well as whether there's any efforts on the oncology side or not? Yeah and we can sort of, then, instead of putting the platform names, 'cause I feel like people get lost, and then- So we started the company around a couple of big ideas, right? And the goal was to be able to really transform the ability to modulate genes and use cells as medicines. And, you know, having been in the field for a while, it's very clear that scaling autologous cells is challenging. It's not possible in most cells that don't exist in liquid, right? So in suspension, something like blood, right? And that lifelong immunosuppression isn't very exciting for people, right? And so what we went after at the outset of the company was trying to figure out: how do we hide allogeneic cells from immune rejection? And we think we've cracked that code. I mean, it's very clear that what we do works in non-human primates, it works in mice, it works in humanized mice. We've said, you know, we have some early human clinical data that led us to, you know, focus our portfolio around the hypoimmune platform. We haven't said yet what that is, but that just gives you a sense that we're encouraged. So that's part one. We then took it, and we wanted to go down a couple of different paths. One is hiding, being able to make allogeneic T cells, right? So those are donor-derived T cells. You might take mine and grow them up at scale and use them in hundreds of people, right? Then you can make that over and over again. The other was the ability to take pluripotent stem cells, gene modify them, and grow them up into some type of a cell and replace a cell that's missing. So the overall goal is to replace a damaged cell or a missing cell with something that works, right? So two big platforms right now are gene-modified pluripotent stem cells and gene-modified allogeneic CAR T cells. Right. Okay. We can get into that. So, you know, with the allogeneic CAR T cells, it's the first place we went into humans. We have two active INDs and a third that we've said- So, just because we're talking about gene-modified allo CAR T right now. Yeah. And maybe just take a step back, 'cause- This is that allogeneic. Allogeneic, yeah. So the key... We've been in this field for a long time, right? We know that allogeneic rejection is a problem of two parts of the immune system, the adaptive immune system of B and T cells, relatively easy to deal with. People have been doing this for a long time. You knock out MHC Class I and MHC Class II. You then have the innate immune system, right, which has evolved in many ways to grapple with cells without that have these challenges. And so when you knock out Class I and Class II, natural killer cells are activated, and they will kill that cell over and over and over again. It's like we've seen this, we've run this experiment many, many times. And so the key insight that the company had, and we can get into how we got there, was that overexpressing CD47 in the context of knocking out Class I and Class II hide cells from both the adaptive and the innate immune system. And you now can transplant an allogeneic cell into, you know, another animal or another person. So we've done this now in multiple different cell types. Are those the only modifications you've made? CD47- Those are the only three you make- MHC I to hide it from the immune system, and these are immune evasive. These are published. We published them earlier this year in Nature and Science. I think we have six different publications around it. I don't think- Did Allogene have any of these modifications? Allogene doesn't hide cells from the immune system. Allogene knocks out the immune system. Right, they give the patient a CD- Yeah 52 antibody to knock out the T-cell, and their T-cells have a CD52 knockout, right? It works. It's a way to hide something. I mean, you don't have the immune system there. I see. Okay, and so- are you using CD52- No mAb? Our drug, but our goal is to make these cells look like an autologous cell, so it's like your own cell. So in, we'll show in type 1 diabetes, we use absolutely no immunosuppression. In oncology, what you see with autologous CAR T cells and in autoimmune, is that there's a lymphodepleting chemotherapy that's given, really to help the T cells grow, right? We can get into why. We use the same regimen as autologous CAR T cell. So in everything- What's that? ... we do, we want these to look like your own cell, completely evading immune detection. And we've, again, shown this in multiple cell types. I think we're close to 45-50 different non-human primates where we've done this. We've done it across a whole bunch of different areas. Did Allogene have, did you look at Allogene's non-human primate cell persistence and compare versus yours? Is, are those apples to apples? I'll let Allogene speak to Allogene's data. Okay. But what I will tell you is nobody has ever transplanted a cell, that we've known of, with no immunosuppression into an allogeneic non-human primate and seen it survive. We've done it over and over and over again. Interesting, interesting. And from your experience, sort of over on cell therapy over time, the relevance of those non-human primate cell rejections versus humans, is there a high degree of comparability? Well, no one's ever done it. Okay. Right? Because no one could do it- No one's ever done it. So what you- Or even on autologous? What's that? Even on autologous? So autologous, the only thing that they've done. They haven't really done it, 'cause the only real experiment was published by Mike Jensen, and they gave the patient, the animal, massive amounts of chemotherapy because they were transplanting in cells with a human CAR. Right? And so you're having to deal with xenotransplant rejection. But, like, it's never been done, and it's. We've done this with beta cells. We've taken non-human primates, given them diabetes, put in a gene-modified islet cell, and normalized their blood glucose with no immunosuppression and no insulin. Got it. Okay. Like, that's never been done before. Makes sense. So okay, so that's... And when do we get- When's the data? I just wanna make sure I capture that as well. Yeah. What's that? When's the first round of data- Yeah -from your allo in cancer? So as we said, what we've done is tried to hide cells from immune system, apply those genetics in a different cell set, setting. So the first IND that cleared for the company was a drug called, is a drug called SC291, and it's being developed in oncology for B-cell malignancies, non-Hodgkin lymphoma, and CLL. That study started earlier this year. We've said you'll have at least a little bit of data this year. That's CD19, right? That's CD19. Yeah, we'll have a little bit of data this year. A lot more going forward- This year, like 2023? A lot more going forward. The second IND that cleared was for a CD19 CAR T-cell, again, this time in autoimmune disorders. That's in three different autoimmune disorders: extrarenal lupus, lupus nephritis, and ANCA-associated vasculitis. Now, that study's just gonna be up and going probably early next year. Okay. So- Steve, I'm sorry to go back. A good bit of data as you go forward. The CD19 for oncology setting, that's data at ASH this year? We don't have. Well, no, you won't see an ASH presentation. Okay, but you could have a press release between now and December? We could have something, yeah. Based on data. We will have something. We will at least have a little bit. We won't- you know, more data coming. Interesting. Number- Okay, I don't know why I thought this was a 2024 thing. What's that? I don't know why I thought this was a 2024 data. Yeah. So we'll have. Well, let me finish the way all the data could be, because the third kind of CTA, so not an IND that cleared, is gene-modified primary islet cells, where what's known today is that you can transplant primary islet cells into a Type 1 Diabetic with substantial immunosuppression. That Type 1 Diabetic can live for years off of all insulin with normal blood glucoses. Generally, they can't tolerate the immunosuppression, and these cells go away. We know from the field now, another company has done that you can take stem cell-derived islets in the context of immunosuppression and transplant, and the patients can do quite well as well. So the key, though, is that there aren't that many people for whom lifelong immunosuppression is better than lifelong insulin. And so the real question is: Can you get rid of the immunosuppression and hide these cells from both allogeneic and autoimmune detection? We've shown you can preclinically. We wanna know what happens in people. So what we are doing is we're gene-modifying primary islet cells. We will transplant them into the muscle in the arm of a patient, and no immunosuppression. And if these cells live, you basically have checked all of the boxes for a potential cure for Type 1 D iabetes. Where, where's these cells isolated from? What's that? What's the source of these cells? So in this case, they're primary islets from a cadaver. The drug product we're taking forward, this is a proof-of-concept study, will be from stem cells. The one in humans, right? The IND that's being filed is on- The IND that's the study that's on that we've just cleared, that's in primary cadaveric-derived islets. Think of it as- What do we know about the health of those cells? About what? About the health of those cells. It's very dependent upon the perimortem stress of the donor. The time. What we know is that people transplant them, you know, hundreds a year are being done, and that they, in most cases, are successful. Not in every, but in most cases, the cells are grafted and actually do quite well. Regardless of the source of the cells, is there, like, a certain QC these cells are passing, whereby we should be interpreting these data? Or is there a scenario where the data comes out and we're like: "Well, they were derived from this source, so we can't really believe this data entirely, and the source would get- There is no- the data would get. So I can think of many ways to have a false negative. Like, cells can just die on graft poorly cells. I cannot come up with a reason there'd be a false positive. If we are able to hide these cells from immune detection, you have to believe that will happen with a stem cell-derived product. Now, there's a lot for us to do to really make a stem cell-derived product consistently at scale. You know, but you have checked all the boxes for some company, somebody, to make a curative therapy in type 1 diabetes. It may not be Sana. We may fail. But every scientific question will have been asked around how to do it. Got it. Steve, in the last couple- Ask and answer ... minutes. We will have a couple, a bit more data as well, out of another CAR T-cell, CD19 failures. It's a CD22 CAR- Okay -for CD19 failures. So that belongs back in that first- That's an IND that's- Modified allo CAR T, CD22. modified allogeneic CAR T-cell. Okay. But- So, I remember in one of our prior conversations, you mentioned autoimmune and some of those indications sound like a long path, but there might be a way to deliver a lot of proof of concept very rapidly. Can you just remind us how that would look like? Well, at the end of the day, the entire rheumatologic field has been turned on its head by the original five-patient study that was presented by Dr. Schett in Germany, right? And really, what you saw was that at three months, every patient, you know, they had more or less 100% complete renal remission. So you have a very rapid path to proof of concept in definitely lupus nephritis, almost certainly in ANCA-associated vasculitis, right? And extrarenal lupus, you know, it should be pretty clear as well, right? So, these drugs seem to be working in the vast majority of patients to date, everybody. I doubt that will continue. They work at predictable doses, which are lower than what's necessary in oncology. And they, you know, seem to be well-tolerated in the short term at least. It actually is something where I don't think any of us ever thought 10 years ago about the idea that a patient might have a chance to be cured for at least some period of time of an autoimmune disorder, right? But now you have patients who are multiple years off of all therapy and living a normal life. Could we have some sort of proof of concept from the autoimmune by summer next year? By when? By summer next year. Sometime next year. Yeah. Sometime next year. That would be the very first dose in cohort, something along those lines? The very first data- The very first dose level. First dose? Very first dose level. For us? Yes. So the first data we'll have is oncology, then Type 1 Diabetes, and B-cell-mediated autoimmune disorders. You'll have some data next year around that. You probably have proxies when you look at the cancer data. Are you able to deplete B cells? And ultimately, that's all you're doing in autoimmune disorders is just deep depletion of B cells. So you can get a pretty decent idea if this will work or not from, you know- Got it ... early oncology data. Would you, Steve, while these trials are going on, let's say we sit down again in March timeframe, would you have visibility on rejection rates on a blinded basis or no, across these trials? Sorry, to do what? On body rejection rates across these trials on the cells? I'm sorry. Do I... So by March, while these trials are ongoing, data's not out yet, but will you start to have some early sense for the rejection rates, how long the cells are surviving or not? Oh, rejection's really simple. Like, in diabetes, you'll know in a couple weeks, and there's nothing after- Will you- We will know in a couple. Like, you'll know it a few weeks after a transplant, right? Mm. In the cancer setting from an immune response, when your CAR T cells come... Sorry, when after immunosuppression, NK cells and T cells come back. So our product is some fully modified cells, some partially modified cells. What should happen is any partially modified cells killed by the immune system. So even within a month, what you should have left is only fully modified cells, and then you have cell survival in the context of an intact immune system. You, you then will have how long these cells actually persist in the body with a CAR T cell. That's a function mostly if we have immune evasion of quality of the T cell. You want 'em to live for three, four months in cancer, right? I mean, that seems to be in lymphoma, where they're, they're-- you get less than that. That's the- There's a pretty high rate- -autologous. What's that? For the- From the autologous data- Three months or- ... that's been the key, right? Right. If you look at Yescarta, they're- That's the bar you're keeping for the allo. That's the bar we want. We want our data to show comparable data to an autologous cell. Got it. The data to date from allo approaches has been sub 1 month on- From what? For the existing allo approaches has been what on persistence? Well, I think most of the allo approaches, what you see is as soon as the immune system comes back, if you knock out Class I and Class II alone, NK cells come back within a week or two, and as soon as they come back, the cells go away. You will not see any cells left in a month. And the only one that that's not true on is allogeneic because they knock out the immune system, right? And when the immune system come back, the cells go away. But generally, within a month, the cells are gone. I haven't seen any real data that suggests anybody has cells in a month. Got it. Excellent. Um- Well, listen, it sounds like there's a very active readout phase coming up here. Yeah. Good luck into 2024. You know, we went public early, right? We're kind of a preclinical company, and it's taken a while to get to where we get to clinical data. We, you know, by the end of this year, we hope we'll have four different programs going in seven different indications, and where you'll get data next year from, you know, all of them. You know, and probably have data from, you know, I don't know, 40, 50, 60 patients by the end of the year. So it's... And different places where there's different bars for what you need to do from immunologic perspective. We're optimistic this works. We're excited to get some more data, and hope we have a chance to share it with you soon. Outstanding. Well, thank you for joining. Looking forward to being in touch. Thank you. Excellent. Appreciate it. Take care. See you.