All right, so welcome to this fireside Schett with Adicet Therapeutics. It is my great pleasure to welcome Chen Schor, CEO. Welcome and thanks for joining us. Thank you, Michael, for inviting me. Pleasure to be here, always. And so, Chen, you've recently announced new autoimmune disease programs for your gamma delta T cell program. Could you just remind us of your plans here and perhaps also talk about the potential advantages of off-the-shelf gamma delta T cells? Sure, absolutely. You know, I know there's probably a few companies that talked about cell therapy and autoimmune today, so perhaps I'll start with just making sure we all have the same data about what we know in the field. So if you look at multiple publications and posters over the last few years, what really we know so far is that with cell therapy, primarily CAR T cell therapy, either using CD19 and maybe a little bit using a BCMA, if we deplete the CD19 positive B cells for about 45-90 days, we see great efficacy in a couple of autoimmune diseases, primarily in SLE, in lupus, but also in systemic sclerosis, myositis, and myasthenia gravis. So that's pretty much what we know in terms of the information in the public domain. Also, interestingly, when you look at the data with autologous cell therapies, we see that unlike in oncology, the persistence of the Tmax of those CAR T cells is the same as in oncology about day 10, but the persistence is much shorter. So, within about 45-90 days, we see that the persistence of the T cell disappears, and you see the B cell recovery starting between 50-150 days. So we're going to see B cell recovery once the CAR Ts are out of the system, right? Otherwise, it doesn't really make sense. So that's what we know with autologous. Now, let's think about it from patients' perspective. So what we know from patients' perspective in the field of autologous CAR T is, you know, if you read Peter Marks's publication or letter to New England Journal of Medicine, we know that reported to the FDA is a risk of T cell malignancy of 0.1%. We don't know what's the real risk. It's probably not less than 0.1%, but that's a risk. And we know that with CD19 therapies, if you look at the data, we know that with cell therapies there is ICANS/neurotoxicity, but if you dive back into data with antibodies, you'll see that CD19 is actually expressed in the brain. So there's some CD19-mediated neurotoxicity that, but you need larger numbers to see it. So at the end of the day, when you think about the field so far, we know that with autologous cell therapies you can deplete B cells, you're going to see efficacy in a couple of autoimmune diseases, you're going to take a potential risk of T cell malignancy and maybe some neurotoxicity. That's not my data. You know, spend 24 hours and read a bunch of publications. If you don't get to the same conclusions, you'll probably miss the publication. So that's known in the public domain. Now, when you talk to rheumatologists, you know, they really like to obviously potentially cure their patients, but they're not necessarily as one mentioned actually in the previous fireside chat here, they're not necessarily interested in something where they need to connect with the oncology center and do leukapheresis and wait for cells, and then dose their patients. That's a big complication. So going to what we see with gamma delta T cells, what are the potential advantages? When you look at our PK with ADI-001, which is a CD20- targeted gamma delta T cell, interestingly, we see PK that's consistent with autologous cell therapies. If you look at our Cmax, it happens at around day 10, and between DL3 and DL4 you see that it's at or probably higher than all the approved autologous CD19. If you look at our day 28, you'll see that between DL3 and DL4 we're at and higher at DL4 compared to approved autologous CD19. And if you look at our AUC, you'll see that it's consistent with or probably higher than autologous CD19. By month three, we know that our cells are cleared from the system, just like if you look at chat and other publications with autologous CAR T in autoimmune. So the first thing, guys, in cell therapy, we need to make sure that we have enough of the drug in the system. So a big advantage of gamma delta one T cells is that we can get to the same exposure as autologous CAR T. There is science behind it because when you look at the recovery of the immune system following lymphodepletion, NK cells do not attack gamma delta T cells. That's why we see a phenomenal Cmax and great persistence. So we get the right cells in the system. In other allogeneic approaches, you know, spend a day and look at the PK of all the other allogeneic approaches, I'll be shocked if you'll find something similar to us. So same exposure. We've published that we can clear B cells and the cytotoxicity of gamma delta T cells is exactly the same as alpha beta T cells. Actually, at high doses, it's a little higher when we do a fair comparison. Same donor, we see the same. Then let's look at our B cell depletion. Now, that's B cell depletion is coming from our oncology studies, but hey, it's B cells and they have a marker presented on their membrane. We measure although we're targeting CD20, and I'm sure that will be a question later, we actually measure our B cell depletion based on CD19, exactly the same as other publications, and we see the same B cell depletion. If you look, we so far treated 24 patients, and 23 of them went to zero. So same exposure, single dose, same, same B cell depletion. And some of the advantages of the gamma delta T cells is that they have tissue tropism, so more of them go to the kidneys. That's going to be pretty helpful in lupus nephritis, our first indication, because, you know, these patients will have B cell islets in their kidneys. And in other indications that we're going to go after, you'll see that, as well as a common theme. And no, we wouldn't expect any significant T cell malignancy risk because these will be rejected, and it's off the shelf, and the safety profile has been phenomenal so far. This was a long answer. I apologize. Yeah. That's okay. All right. I checked question one through five off here. So, you know, there's a lot of talk about B cell depletion in this area. In your opinion, how important is the, the B cell depletion that we can measure in circulation, you know, as opposed to the one that is harder to measure in, in tissues in, in autoimmune context? And do we know how the length or depth of these, B cell depletion correlates with various clinical outcomes? Yeah, that's a great question. And I don't think we have a lot of information here. What we know, I'm trying to kind of put, arrange. What we know is that the B cell depletion, as short as 45 days and as long as 150 days, essentially gets phenomenal efficacy in autoimmune. And there's many, many patients that had B cell depletion in the range of 45 to 60 or 90 days. Most of them are in that range. There's been a few outliers. So that's what the data suggests, that that reset, if you keep it, you know, in the range of 45 to 90 days, all these patients, you know, essentially almost zeroed their SLE scores. Okay. And then can you talk about your, your studies, you know, what doses are you evaluating at? How does your preconditioning protocol compare to what others are doing? Just, you know, so compare and contrast the Phase 1 study design to some of the others out there. Sure. Absolutely. So in terms of the design, we're going to start the study from dose level 2, and then we'll potentially go to dose level 3 and dose level 4. Dose level 2 is a 300 million that is I'm sorry. That's 100 yeah, that's 100 million cells. That's the first dose level that I believe we're starting with. So these dose levels, this first dose level in our lupus nephritis study has been the second dose level in our oncology study, 100 million CAR positive cells. This dose level has shown the same B cell depletion as other dose levels, overall. And we treated three patients with this dose level in our oncology studies. Two of them had a CR, and one of them had a very durable CR way beyond six months. It seems to be an active dose level in our NHL study, and we'll see how this translates in our AI studies. We can go up to DL4, and in DL4, our exposure is way beyond all the autologous cell therapies. Right. Right. As you know, there's a lot of activity in lupus in particular with cell therapies. There is a lot of autologous CD19 and CD20 CAR T cells being evaluated. Some of them will have data, I believe, this summer. There are companies with CAR NK cells. There's a number of companies with bispecific antibodies. It seems like sort of the lymphoma experience is kind of repeating itself. But how do you think how do you expect the lupus and autoimmune space more broadly to play out in the cell therapy space? Yeah. Absolutely. So I would put it in a couple of buckets. I'll start with bis pecifics, NKs, and then generally allogeneic versus autologous. So I think bi specifics and any antibody type of an approach might have a little more challenges because at the end of the day, these are antibodies. They don't have the best tissue penetration. And if you look at data from obinutuzumab, which is a very potent anti-CD20, you see very nice efficacy in lupus nephritis, better than data with other antibody approaches, but not as much as the potential efficacy with cell therapy. So the biologics, I think, including bi specifics, might not get us to where we need in terms of such an amazing efficacy. NK cell approach, I think it's plausible. It will require multiple doses. Definitely it seems like three doses in the first month and maybe more if, you know, we talked about these 45-90 days of B cell depletion, so maybe more. Maybe there's another round. And if that round comes with another lymphodepletion, then, you know, two lymphodepletions for autoimmune patients, I think it's quite tolling. And if it doesn't come with another round of lymphodepletions, then, you know, once the immune cells recovery, you know, cell therapy auto-allogenic will, it's probably going to be chewed up very, very, very quickly. So with NK cells, I think you'll see multiple doses. And some companies are trying to explore lymphodepletions that are, you know, short of fludarabine and other companies like us can explore it in the future. So I don't know if that eventually in the long run will be a major differentiator. So that's the NK. Bottom line might work. Hopefully, it will work m ultiple doses and maybe more than one cycle. That's what the data suggests a nd then I think when you look at other allogeneic approaches, that's going to be very interesting how this will play out. I think that eventually I mean, not thinking now, thinking three years from now, the conversation with a patient let's say a lupus nephritis patient, a lupus patient, an SLE patient comes into the doctor's office. Usually, there are women in their late 20s. If you look at the median age of SLE, I believe it was 27 or 28-year-old women. They'll come and they'll sit in the physician office, and they probably tried one or two therapies. And if they qualify for cell therapy, the discussion will be, "If you want, we can provide you autologous cell therapies. For that, you'll need to go to a different center, most likely. We'll do the leukapheresis, y ou'll get your therapy. Data suggests that this will work very well. But there's this tiny, tiny, tiny risk of 0.5%-1% I don't know what it is, but it's a big backlog black box warning that you might get T cell malignancy out of it. You might. Hopefully, not. Or we can try an allogeneic cell therapy approach. It has the same exposure as autologous. It has the same B cell depletion as autologous. It shows the same efficacy as autologous. In our in our case, maybe the tissue tropism will be even more beneficial. And if you want to start with that, then go to the nurse, and we'll start the lymphodepletion. And in five days, we have the drug on the fifth floor. So, I will not be surprised if, in this field, eventually, how it will shake up, especially for rheumatologists who want something off the shelf, allogeneic will be a very significant, just in terms of time. I think they have probably one year to catch up with everybody else. Because if you look at all the other companies, there's a couple of IITs, but, you know, there's a handful of patients that have been really treated by sponsor. So, I think everybody's pretty much in the same playing field. Right. And then just going back to your study, remind us what patients are enrolling now and, you know, when we might expect to see first data disclosures from your study. So, we're just our first IND was cleared for lupus nephritis. Let me emphasize. That's our first. As we got it, we expect to initiate one to two additional autoimmune studies. So most likely, we'll have two or three ongoing studies in autoimmune this year. On that front, we expect to potentially start sharing data in the second half of the year towards the end of the year, and into the first half of next year. But this will probably be across multiple indications, not only lupus nephritis. So we're going big into multiple indications here. Right. Okay. And then what are you what are you doing in oncology at this point with, with your lead program, ADI-001? Sure. Absolutely. So with ADI-001, we had to make some prioritization in our pipeline. We're continuing to enroll to MCL. In MCL, to remind everybody, we've seen so far quite nice data. The CR rate was 80%. CR rate beyond six months was 60%. Small N, three out of five or four out of five, respectively. And we continue to enroll these MCL patients. Maybe one of the reasons we see this great durability in MCL is because bone marrow is a significant component in MCL, and gamma delta T cells have tissue tropism to bone marrow. So that might explain the profile in MCL. So we continue to enroll, and we expect to submit an IND and start a clinical study with ADI-270, which is our clinical candidate for renal cell carcinoma. That's the first indication. Happy to talk about the differentiation in that program as well. Yeah. I was just going to ask, so there's CD70 product. It seems interesting, differentiated from what others have tried. Can you just talk about what makes that unique and, you know, where do you see the opportunity? Absolutely. So, except for the name targeting CD70, every single aspect of this program is different than others, and we've learned a lot. So if you look at data from other approaches targeting CD70, the key that we've learned is that if you target the CD70 with a single-chain FV cell therapy, we will see some efficacy in patients with high tumor antigen, high antigen density in their tumor. That's the conclusion if you look at the other data set. So starting with how we engage the tumor, we screen more than 300 different single-chain FVs. we compare them to CD27, which is the natural binder for CD70. CD27 won big times. It's actually now there's two other academic sites that reported the same approach. So we use a binder that requires significantly less tumor sorry, antigen density and should provide also deeper efficacy in more patients. So it's a different binder. Interestingly, that different binder has another co-stimulatory domain. So the cells are more powerful, and you can see this in essentially repeat challenges. We definitely see the benefit of this CD27. So one, it's a potentially better binder for CD70. The second, as with a cell that we know that provides potentially the same exposure as autologous, then we know that we have tissue tropism to kidneys. So probably more cells will go to the kidneys. We added a dominant negative TGF beta, so that should potentially address the hostile tumor microenvironment. So overall, it's a very potent binder with a cell that should provide better cytotoxicity, better persistence as well, because CD27 will also fight back the alpha beta once they start attacking the gamma delta one T cells. These are all aspects that are not you. You can't find them with other approaches, and we have them. Great. And so that IND is going in. Second quarter. Great. So we had a very good pre-IND meeting with the FDA. Great. All right. Well, thank you, Chen. Looking forward to potentially seeing some early data around year-end in lupus and then the IND for 270. Wonderful. Thanks, everybody. Thank you. Thank you for your interest.