Samuel Yamshon of NYU Langone Health and Javier Bolanos Meade of Johns Hopkins Kimmel Cancer Center share updates in CAR T-cell therapy beyond CD19 and the latest in bone marrow transplantation practices.
And um I'm gonna get us kicked off here so I think we've already had an excellent morning that we're gonna have uh wrap up the morning talking about some consolidative strategies and some future directions. It's my distinguished pleasure to introduce my uh esteemed uh soon to be associate professor of medicine, uh, Doctor Sam Yamon. He's the director of cell therapy at the NYU Langone in New York City. Uh, he's a dear friend and colleague of mine. He's gonna talk about some updates in cellular therapy beyond, uh, the, the classic B cell receptor, uh, surface molecule, CD19. Doctor Yaman, thank you, my friend. Thank you so much, man. Morning everybody. Um, thanks so much for having me here. Actually, it's now my 4th time in Buffalo. Um, and a couple of important things, uh, about being in Buffalo right now. Number one is that, um, some of you, uh, may know that I, uh, actually collect baseball caps. I own, I own, uh, something like 50 baseball caps, and across the street from this hotel is the global flagship of New Era, which is, uh, actually like one of the, the biggest baseball cap makers in the world, so that was a very cool pilgrimage for me. But also for those of you who are visiting Buffalo, um, the Buffalo Sabres, uh, are in the playoffs for the first time in 14 years. And so I had to, uh, pick, yeah, round of applause for the Sabres. Uh, and so I, I had to pick up a Buffalo Sabres hat and, uh, we'll, we'll be giving my talk in the Sabres hat because as the saying goes, one in Buffalo. So, um, I, I'm excited today to talk a little bit about, uh, updates in, uh, cellular therapy beyond CD-19, and, uh, we heard a little bit in the last talk about, uh, the myeloma CART updates from Ash. And so, um, focusing this talk more on, on lymphoma, given the, the title I was given Beyond CD-19. Um Let's see. Perfect. Um, so, um, importantly, uh, before we even get into some of the newer drugs, I think it's kind of important to establish where, where we're at, which is actually quite good. So, um, CAR T cells do represent, uh, a paradigm shift in the treatment of lymphoma. Um, and, uh, currently there are, uh, 3 FDA approved CAR T cell products, uh, that are approved for, uh, lymphoma. Uh, so you have axicaptogen, siloucel, Axi, uh, Uh, or Yara, which, uh, targets CD19 has a CD28 co-stimulatory domain. You have Togenic lu cell, TCL, or Cambria, which has a 41BB co-stimulatory domain. And you have lysocaptogen marale cell, uh, lyso cell or Brianzi, which also has a 401BB, uh, co-stimulatory domain, but has an extra manufacturing step at the end, which, uh, creates a 1 to 1 CD4 to CD8 ratio. And all of these differences in manufacturing do have slight differences in terms of efficacy and toxicity profile. But importantly, all three products have been shown to produce durable remissions in a subset of patients with diffuse large B cell lymphoma treated with at least 3 prior lines. And as uh Doctor Abramson discussed yesterday, um, in the old days, once patients relapsed after the second line, cures were extremely few and far between. Less than 5% of patients were cured. And with these newer products, uh, we're now curing, I usually quote, you know, depending on the trial you look at, somewhere between the range of 30 and 40% of patients are cured with these products. So it's really a genuine paradigm shift, uh, in a, in a field where we really did not have curative intent options in this setting. And so, given the efficacy of uh these treatments in the 3rd line and greater, and many of those patients on those trials were beyond 3rd line, 4th, 5th, uh, 5th, 6th line, um, the question was, you know, as again, as discussed yesterday, auto is not a great treatment for diffuse large B cell lymphoma, particularly in the chemo refractory patients. And so, Um, we had 3, large phase 3 randomized control trials where patients who had, uh, high risk diffuse large B cell lymphoma as defined by either early relapse less than 1 year from completion of initial therapy, or, uh, truly primary refractory, having never responded to initial chemotherapy. Um, and they were randomized to receive, uh, high dose chemotherapy with the intent to proceed to autologous stem cell transplant, although not all of them did. Um, or to go directly to CAR T cell therapy. And, um, two of these studies, uh, Zuma 7, the ASL study, and, uh, Transformed the Lyso cell study, um, as, as you can see, showed a marked, marked benefit in event-free survival, uh, relative to the standard of care. Um, and importantly, um, Axill also showed an overall survival benefit in this setting, as was discussed yesterday. The Axie Zuma 7 did not allow crossover, while the, uh, while the, uh, transform study, uh, had crossover that was actually pre-specified, neither of which is really like how, how we work in clinical practice, so hard to tease out the differences between these two. But I think what's important to note is that there is likely a survival benefit with both CART products in the setting, and that's essentially how, how we operate in the clinic. But, despite the fact that these have been a paradigm shift, there's still room for improvement even in the indolent lymphomas. And so, uh, this is actually a, a, a slide kind of summarizing. Um, the long-term follow-up data, 5 years for Zuma 1 and Zuma 5, and then the 3-year follow-up for, for Zuma 2. And the, the only reason I, I, these are specific to the kite products is because they're the studies that have the longest published follow-up. Um, but, but these dynamics are, are in all likelihood true for the other products as well. Um, by, by the long-term follow-up, the majority of patients still have relapsed and died, and so there's still, or died. And so there's still, uh, a big unmet need in these patients, despite the fact that we've shifted the paradigm to cure many of them. And so, um, this is a purposefully busy figure because, uh, the question of what makes, uh, lymphomas resistant to CAR T cell therapy is actually quite a complicated question. Um, we're gonna talk about a few of these factors, but, um, as, again, as Doctor Abramson had mentioned yesterday, I think we largely think that, uh, the main mechanism of, uh, car T-cell resistance is actually T cell dysfunction or exhaustion. These, these cells get very tired out over time. Um, there's also tumor intrinsic factors, um, that they, um, uh, lose the actual antigen, they lose CD19, although, as we're gonna discuss, that's actually a minority of patients. And that there, uh, are factors also related to the immune microenvironment, and there's a lot of interplay between all of these factors as well. And so, um, you know, as we discussed, uh, the topic of this talk was beyond CD-19, so I'm gonna focus in the beginning around novel targets for CART. But I think it's important to note that, um, there, there are a substantial number of patients who have CD19 loss, uh, with CART, but, um, it's actually a minority. And so, um, they're, they're, uh, you know, just picking a new target is not necessarily the answer here, um, but I, I, I do think that it's important, and in, in, in many patients, they will benefit from getting, from getting a CAR T just with a different target. So, how do you pick a good car target? And in a lot of ways, we've actually, you know, uh, uh, Rainier, uh, from, from Roswell Park actually gets kind of, kind of annoyed when people say this. But there are a lot of people who say that we kind of got lucky with CD19. In the sense that it is ubiquitously expressed on B cells, pretty much, uh, uh, universally expressed on B cells, and is also expressed pretty much nowhere else. But there aren't a lot of antigens like that, and that's actually a big part of the problem as why other diseases. had such a struggle to implement CART is because you need to find a target that's on what you want to kill, and is on all of what you want to kill, right? All of your tumor has to express that antigen, in theory, and nowhere else. You don't want to kill all the good guys. And so it actually is quite a difficult problem. So there are now several potential non-CD19 targets that are being studied in B cell lymphomas. I'm going to summarize some of the early data, um, but this is kind of a, a, a quick summary of those that are, I would say the furthest along in, in clinical development. Um, and importantly, um, there are actually, uh, several different strategies also to target multiple antigens. So, and there are a couple of different ways to do this. One is that you can do sequential CART, so make two different CART products that target two different things. You can do a tandem CART that has one car protein that has two different targets, or you can put two different car proteins onto the same, uh, cell, which is also something that is currently in development with all three. So, currently, um, kind of the, the, the topic of the day is actually, uh, CD20, and at this point, there are actually multiple CD19/20 targeting CARTs that are in late stage clinical development. And so, um, uh, there are currently three products, one from J and J, one from Kite, um, and then, uh, Rhondael as well from Lyle. Um, these differ slightly in, um, you know, the, the, uh, domain. Whether they're bi systronic, bi-specific, the, the, the Lyle one is actually, um, what's called or logic gated, which means that it can actually like switch its target depending on what's being expressed on that individual cell, which is, uh, kind of cool, although I, I, you know, who knows if that makes it any more effective or not, um, but regardless, um, is, is, is interesting. And, um, I, I, the kite product also I think is very interesting in that it, um, The, the different targets actually have different co-stimulatory domains as well for to allow for different pathways of T cell activation. So, actually, currently, all three of these, um, are in late stage clinical development. Um, just for the interest of time, I'm just very briefly summing up, uh, some of the, the data for these, um, looking just at the, the, uh, third line and second line overall response rates and complete response rates in single arm studies. All have had quite impressive overall response rates and complete response rates kind of in all three products, and notably in those third line patients, many of those were patients in all of the trials who had previously seen CD-19 car, and so these products were able to be effective even in patients who had already been treated with CD-19C. Um, importantly, I think, uh, the, the rates in all three, high grade CRS and neurotoxicity were low, which is useful. And, um, importantly, actually, uh, you know, kind of one of the hot topics in my, in my world is, again, we have another situation where we have 3 different CART products that are all in phase 3 trials looking at, uh, at, at very similar questions. Um, all 3 are designs. Differently in terms of the standard of care arm, but the standard of care arm in all three is CD19 CAR T. And so, for J and J and for Lyle, that is gonna be standard of care CAR T. And then for Kite, actually, uh, what's very cool is it's going against Axi. So they are, they're betting against themselves, which I actually like, really appreciate. Uh, it's great design. So, I'm looking forward to seeing those results in the, in the next few years. Um, so, um, there are also, um, CD 1920 CARTs that, uh, have other strategies, um, as I mentioned earlier, um, there are other things that may, uh, impact, um, Uh, CR T cell fitness, and so there's a theory that fresh infusions may be more fit, um, and so, uh, presented at Ash 2024 and then at Tandem 2025, um, Doctor Shaw from, uh, the University of Wisconsin presented data for, uh, Xamtoce from Miltiani which is. Uh, had local manufacturing and so was able to get the cells in quite quickly. Um, they actually have a little bit more, um, long term follow-up data. The results, I would say, look pretty comparable to what we see to, to CD19 CART, and so, uh, need longer follow up to see, and again, single arm, so, so tough to make comparisons. Um, another target that is, uh, or I, I guess I should say, uh, was in clinical development. Uh, Pullawi yesterday, Doctor Torca had, uh, when a, when a study was dead, she had an RIP logo, and, uh, I probably should have those for some of the studies that I'm gonna present, including my own. Unfortunately. Um, but, uh, so this, this, this product gets, gets an RIP. So, so, um, this, this, uh, Furriel was a CD22 CT that was, uh, from, uh, Cargo Therapeutics, but was developed by, uh, Matt Frank and the Stanford Group. And, um, interestingly, initially with the initial press releases, they actually had quite high response rates and so there was a lot of excitement around this product. Actually, when I was at Cornell, I even, I even referred someone with postcar relapse down to NYU where this was open. Um, to get somebody onto this trial, but there were two critical issues with, with this product. One was that it, from a clinical, from a clinical efficacy standpoint against the lymphoma, it just wasn't durable. And so despite the fact that they had very early remissions, they had a 3-month duration of complete response of only 18%, which is much worse than we see with CD19 CART. And so patients responded and then pretty much immediately relapsed, unfortunately. Um, and then they also had an 18% rate of high grade, uh, immunofactor cell hemophagocytic syndrome, which is much, much larger than, than we see in clinic. The Stanford Group, I think, is still kind of like very interested in this target, and they've actually, they've presented several, uh, including at this past to Ash, kind of trying to tease out what the risk factors are for this, but I think people are very nervous to pursue this target moving forward overall. Um, one very, uh, cool target, um, that, uh, was presented at this past Ash was, uh, the BAF receptor. And so, uh, this is the, uh, B cell activating factor receptor. Um, and it's a member of the TNF superfamily, and, uh, again, uh, importantly, is selectively expressed on B cells and on most subtypes of, uh, B cell non-Hodgkin lymphomas. And so, um, this early phase study from, uh, Doctor Buddha at the, at, uh, City of Hope, um, enrolled patients with, um, many different types of, of B cell malignancies, including mantle cell, follicular, margin. Zone and DLBCL and, um, they had, they had very, very impressive response rates, including, uh, 87%, uh, CR at, at 3 months. Um, and all, and especially as, uh, was mentioned yesterday during the mantle cell talk, uh, in the, in the mantle cell patients, and nobody yet has relapsed. So, extremely early days for this product, but, uh, the, the early clinical data certainly looks interesting. Um, another potential target, um, that was kind of an early phase development but is likely not moving forward was, uh, CD37, um, which is, again, an antigen that's restricted to mature B cells but is absent on plasma dendritic cells, which makes it a good target. Um, it's also, uh, because of, um, uh, where it's expressed, it's actually expressed on some T cells as well. And so, um, there, there were actually both B cell and T cell lymphomas and Hodgkin lymphoma included in this study. Um, they did have some clinical responses, but unfortunately had a lot of CRS including, uh, high grade. And then they had, uh, very, very severe prolonged cytopenias and actually two patients required an alloe transplant for their cytopenia. And so, uh, likely, um, you know, it was published in blood, it looks interesting as a concept, but it's probably gonna need to be developed further to deal with those issues. Um, another one that, um, is, uh, actually kind of cool and, uh, in terms of just like pipeline development is, uh, RA one. So we have, uh, an antibody drug conjugate against ROAR1, uh, zillavertumab vedoin. Um, and they actually just took the target and plugged it onto a car and made a ROAR1 C T, which I thought was kind of cool. Um, R1 is kind of an interesting antigen. It plays a role in embryogenesis, um, but is that then becomes repressed prior to birth, but is abnormally expressed, uh, in many lymphomas as part of the tumor biology. Again, very, very early days, but, uh, responses look decent so far and, and not a ton of toxicity. Um, and just to note, there are actually now tri-specific cars that are in very, very early stage development. Um, but, uh, the, the clinical data for that is, uh, extremely early and to the point of being essentially non-existent, so watch this space. So, getting back to my point earlier, so we've talked a lot about new targets. But as I mentioned, actually, CD-19 loss is only present in a minority of relapses, which means that the majority of these patients still have CD-19 present. And so the issue likely is actually not, we need a different target, but that we need, uh, we need, uh, we need CARTs that are going to be able to stick around. And continue to fight over time. And, uh, kind of getting back to this busy slide, there are a lot of different ways that we can go about that. And I think that many of us in the field are very interested in ways that we can impact either T cell dysfunction. So allowing those T cells and, and, uh, on some of my trials, I try to explain, we want to turn the T cells into the Energizer Bunny, right? We just want them to keep going and going and going. Um, but also to impact that immunosuppressive tumor microenvironment. And so I'm gonna talk about some of those strategies as well. There are many different strategies that are currently in development to do this. Um, nobody really knows, uh, what the right one is. This is just, uh, a summary, some of which we've discussed already. So double co-stimulation, we've discussed, um, you know, new targets, obviously, um, and then fresh infusions. We've seen, uh, allogeneic CAR T cells. So, uh, in theory, patients who are healthy and have never received chemotherapy have fitter T cells. Um, and so, uh, that's a strategy that's been employed. Armored T cells where they, and I know that Doctor Brenan's here, this is a big interest of his, um, having, uh, T cells that actually have, uh, endogenous cytokine production that, uh, kind of almost like self-stimulate, which is kind of cool. Um, and then there's also some data for, uh, selecting memory CAR T cells or gamma delta T cells, and we're gonna discuss some of this. So, um, car, uh, armored CAR T cells, um, use, uh, secreted cytokines to enhance persistence, as I mentioned. So the one that is furthest along in clinical development, uh, and was actually sponsored, uh, by Kite and was done at the University of Pennsylvania. It's the biggest site. Um, was an ILL an IL-18 secreting CD19 CART, and, uh, importantly, did enroll patients who had previously been treated with CART and actually, I referred multiple of my patients over to Penn to be treated on this clinical trial. So, uh, at least one of my patients is one of those bars on the trial. Um, and importantly, in a post-car setting, um, they did have a very high overall response rate and a CR rate of 52%. So there were some patients who had durable, uh, that who had complete remissions, some of which were durable. I'm sorry, it looks like the, the citation got cut off here, but this was actually published in the New England Journal of Medicine last year. Um, so, um, and then as I mentioned, um, allogeneic CAR T cells use, uh, donor T cells, um, and so the idea is that those are, are much less exhausted. I think we were very, myself included, we're actually very excited about this strategy. Um, but the problem with using allogeneic CAR T cells is you have to prevent the T cells from attacking you because they're coming. From someone else. So you have to do additional engineering steps to make sure that you delete the T cell receptor and don't actually cause graft versus host disease. And the, uh, as we're gonna, I, we're gonna see in a second, I actually, what we found in a lot of these studies is that actually has kind of unintended effects on T cell expansion, and a lot of the allogeneic car T cell products just don't expand all that well. So, um, currently there are several different allergen CARTs that are currently in development. Um, there is Semael, which is the allergene product that we discussed yesterday in the, uh, uh, the MRD response adapted study on the front line in DLBCL. Um, there's, uh, Visbace from, uh, from Caribou, uh, that, uh, knocks out the T cell receptor as well as PD1. Um, there's, uh, Azer cell from TG Therapeutics, that's also a T cell receptor knockout. Um, and then there's one from, uh, the CTX 112 that doesn't even have a name yet, that knocks out actually a number of different, uh, potential receptors that could, uh, lead to graft versus host disease. All of these have early data, but again, I think one thing that we've seen persistently across the allogeneic products is that, is, is the lack of CAR T cell expansion. Um, I mentioned earlier that, uh, memory T cells, um, uh, might have more efficacy. So one study that was exciting at this past Ash was the uh Atalanta One study from Galapagos. Um, and this actually was a product where aph apheresis, they selected for memory T cells. Um, and so, um, they actually saw incredibly, uh, high response rates, uh, in heavily pre-treated mantle cell lymphoma, including in the patients who are MRD valuable, low rates of MRD. Um, and, uh, interestingly, um, they kind of show in this slide here, many of these patients were extremely high risk. So, uh, patients who had TB53 mutations, primary refractory disease, pretty much everybody was totally refractory to a BTK, um, and despite that, they had these very, very impressive response rates. Unfortunately, uh, Galapagos, the company. Um, actually just cut off their car tea business a few months ago. So literally like weeks after Ash, and so this very exciting presentation, everyone's all excited about it, and now it's kind of an orphan drug. So if any of you have the ear of your cell therapy divisions, this, this, uh, this product is, is out there for ac for acquisition. So, so we, we would be interested in using it. Um, so 11 other thing that, that I just briefly wanted to mention is actually some of my work in collaboration, uh, with, um, my colleague Doctor Begelin from, uh, formerly from Cornell and now both of us have since moved to NYU, um, and so, you know, we, we saw a lot about carti manufacturing. But we actually think that a lot of these risk factors, um, including, uh, T cell exhaustion and tumor microenvironment, can actually be impacted by just using another drug alongside CAR T. And unlike Roswell Park that has a fancy $80 million GMP facility that was given by Kathy Hochel, at, at, at Cornell and at NYU we can't make our own CAR T cells. And so, um, I, I, I've been very interested in pragmatic strategies for enhancing CAR T using drugs that are actually already available to us in the clinic. And so, um, we actually had a hypothesis, um, when Wendy, uh, actually was the first to elucidate EZH2 as a potential target in, uh, as, as part of lymphomagenesis and then as a druggable target that actually eventually led to the development of tazamettastat as a drug. And so, our hypothesis, and I don't have time to go into all the pre-clinical data, which is, uh, in cancer cell that was Published last year. But essentially, we think that ECH2 inhibition was actually a, was able to modulate T cell exhaustion, so increase, um, T cell efficacy, reduce, uh, Tregs and the T cell, the tumor microenvironment, and then actually also have an impact on the lymphoma cells themselves and make them more immunogenic. And it was kind of an ideal partner. And so we designed a study in which we actually, uh, kind of a unique strategy where we actually started the drug before apheresis with the idea that we'd actually be able to enhance the CAR T cell product. Um, then we would, the patient would undergo apheresis. They would continue throughout the apheresis period to try to modulate that tumor microenvironment. They'd get the CAR T cells, and then we would give it to kind of, again, make those cells into the Energizer Bunny. Um, and what we actually saw in our study, and this, this included, uh, mantle cell, follicular, and DLBCL, we actually had a 100% response rate on the study. CART is very effective in these diseases, so in a small sample, you know, take it with a grain of salt, but 100% is 100%, um, uh, including a complete response rate of 77%, NPR's of 23%, many of which were, are actually still durable. Um, and so we, we, we, um, also again, like don't have time to discuss all the, all the science here. But what we found, and, and you can look it up in the Ash presentation, um, but, uh, actually, we found that the Tasmatostat reduced those terminally differentiated exhausted T cells, um, and that we were making, uh, in both, uh, an exhaust, uh, a less exhausted CART product, as well as, uh, less exhausted endogenous T cells, which also play a role in tumor control. Um, unfortunately, um, you know, uh, as, as most of you know, um, Tesmetastat was actually pulled from the market, um, just a few weeks ago because of a signal in, uh, the symphony trial, which was Tasmatostat in combination with lenalidomide, uh, and they saw an increased rate of secondary malignancies, and so since the drug, they were about to lose their exclusivity, they just cut bait on the whole drug. Um, I think a lot of big, uh, unanswered questions in this space are on that study they got Tesmetastat for a very long time where it was very time limited here. Um, also, you know, lenalidomide is also known to cause secondary malignancies, so, uh, is it the combo? So we're actually now in the process of trying to tease out, is this whole target dead or, or is, or, or. Is it a combo issue or a timing issue? And so, again, watch this space, but we're also very interested in other, uh, strategies to do similar things actually including, um, my, my colleague at, uh, Northwestern, Reem Karmali, uh, published a similar strategy, uh, actually in the same session at AS using BTK inhibition. So there are other ways to do this as well. So, to sum up, there are a lot of potential strategies to improve uh CAR T cells for B cell lymphoma, new targets, including, uh, uh, and improving T-cell fitness both by manufacturing the product and, uh, by, uh, exogenously trying to improve that fitness in the microenvironment. So, uh, exciting times in our land, and, uh, thanks for listening. Fantastic. Thank you so much, Doctor Yamshan. Next, it's my, uh, distinguished pleasure to introduce, um, a dear friend of Doctor Hernandez and, uh, a legendary figure in the bone marrow transplant space, uh, Doctor Javier Bolanos Meade from, um, the esteemed Johns Hopkins University. Um, he's gonna be talking about updates in bone marrow transplantation after we've talked about reinvigorating allergenic stem cell transplants, uh, thanks to his work and, uh, especially post-transplant cytoxan. Doctor Meade, thank you. Thank you. Um, yeah, so, good morning. Uh, thank you very much, uh, all of you for being here on a Sunday morning. Um, I really appreciate that, um. Also, I'll, I'll try to, to do this as quickly as possible because I know that I'm the only thing in between you and lunch, um, so I try to figure out how to do this and, uh, yes. You will think that you need to know how to do that if you want to go to medical school, but no, um, anyway, um, so we're gonna um. Or not. This green button. Oh, I know, there's two green buttons. Sorry, we'll let you be. Anyway, um, I'll try to do this, um, uh, quickly. It, it, it is, uh, bone marrow transplantation is an odd field in, in the sense that it's incredibly technical, and if you're not into transplant, it's incredibly boring. Uh, so if, if you're, if you're somebody who in the clinic deals with lymphoma and prostate and breast and colon. This is going to be the worst 15 minutes of your life. But um we'll try to, we'll try to um We, we'll try to make it, uh, palatable, um, we're gonna be, um, doing a lot of introduction because again if, if you're not into transplant this will require some explaining so then the last two minutes will make sense. Um, now, as of what's going on in bone marrow transplantation in 2026 is, uh, number one, the, the use of post-transplant transplantation cyclophosphamide has become incredibly popular, uh, to the point in which. The overwhelming majority of, of, uh, transplants now they are are are doing are done using uh PTI, um, not all of them but the overwhelming majority, um, and now they're being some trials trying to start to modulate, uh, we can. Decrease the toxicities of cyclophosphamide and keeping the, the, the effect, um. As well as how to combine uh PTI with the pre or post uh transplantation therapies to make transplant more effective because if you. Have followed the, the field of transplantation in the last 20 years, uh, transplant has reached a plateau as far as how effective it is, right? Uh, the, the odds of curing leukemia in 2025 are the same with transplant alone as they were in 2010. Transplant is not becoming more effective. What we're doing is, is decreasing toxicity, so the probability of surviving a transplant 20 years ago was substantially lower than what it is today. So if, if you have an idea of how good transplant is or not, uh, That hasn't changed really that drastically now um. This is the, the basic schema of post-transplantation cyclophosphamide as it is used in the majority of transplants nowadays. There could be some differences in, in terms of the conditioning, but essentially you give the marrow or do you give the stem cells, and then you will, uh, follow that by, uh, 2 days of high dose cyclophosphamide with mic with or without mycophenolate mofeil and with tacrolimus or cyclosporine or errolimus for. Um, graft versus host disease prophylaxis, but, uh, this is a good schema that you can think of for the rest of the talk at least. Now when this was developed, it was developed for the treatment of mismatch uh transplantation. So this was not, oh, we're gonna transplant Mary from her uh HLA match uh uh sister. No, this was when Mary didn't have an HLA match sister. Uh, this was developed to use. A half-sister or something that it was not a perfect match. And these were essentially the very first results that we had when we first published this in 2008. So what we saw is that the, the rates of severe graft versus host disease were very low and the rates of, uh, of chronic graft versus host disease were very low and. If you See the right side, um, yeah, I think the one that talks about extensive chronic GVH, nobody uses extensive or limited, uh, as, as, uh, classifications anymore, but that's what it was back then. Um, you will see that patients who received 2 days of cyclophosphamide had substantially lower rates of, um, of extensive chronic GVH compared to the patients who receive only 1 day, which is on day 3 or days 3 and 4. This will become relevant in a few slides, so just remember. Um, When, when we start uh doing these transplants, we were, uh, somewhat concerned about well what if. The sister is a 9 out of 10 match instead of a 7 out of 10 or or is there a difference in terms of how much rate of complications you see depending on how. Match or mismatch uh the donor was and what we saw is that it in haploidentical transplantation it really didn't matter uh you were not going to have more trouble or less trouble if um. If, if the matching was uh more accurate, this is important because, um. At least in my mind, this is the first time in which HLA matching became irrelevant in transplantation. If you go and you open a, a textbook of oncology or transplantation from 2010 or 2015, you will see that they, they, they will claim that the most important factor in survival of a patient is, uh, who goes for transplant is HLA matching. And then we say, well, it really doesn't matter as long as you're at least sharing one haplotype between the donor and the recipient, whether you are a 6 out of 10 or a 9 out of 10, doesn't really matter. Um, and, and that, uh, it, it, there are multiple studies and we would really not have time to go over all of them, otherwise forget about lunch, you're having no dinner, but these, these studies actually open the gates to really expand the use of hyproidentical transplantation in many conditions, right, so. We start doing uh patients with uh sickle cell disease, with thalassemia, with a plastic anemia. Yes, I know this is not cancer. But, um, very likely you have a few of those patients in your clinic that that come with sickle cell and, and, and they're very difficult to treat because they have pain all the time, end up in the hospital. Well, you transplant them and the the reason why this became, uh, so important is before we did that. It was only about 1 in 10 patients with a severe hemoglobinopathy that would have a donor because they were coming from uh, uh, either from a family with multiple uh uh members that are uh uh uh afflicted with the condition or because there's some, uh, for, uh, underrepresented ethnic groups they just don't have donors in the registry so we went from having one. In 10 probability of of getting a donor to virtually over 90%. Depending on some family issues, close to 100% having the ability to find a donor. So sickle cell became a curable condition essentially. So before gene therapy, we, we had, we had the ability to cure people with sickle cell and contrary to uh to gene therapy, which uses high doses of chemotherapy for transplant, you don't have to do that. So you have the ability to to preserve fertility, right? Which is a very important issue for for these patients now you need to remind the patients because. They don't necessarily catch it the first time that you will cure their sickle cell but they can still transfer to their children, um. However, we have the ability to, to cure over 90% of patients with very exceedingly low rates of graft versus host disease, um, and, um. And uh preserving the hormonal function it's a, it's a, it was a very impactful um. Um, um, um, change in, in, in the standard of care and the same has happened with the plastic anemia we can cure patients with severe plastic anemia who need transplant as first line therapy or for refractory disease. Now there have been a lot of speakers today talking about T-cell exhaustion and how bad it is for you that you need to get uh uh also uh prophylaxis for the rest of your life, uh, for infections and IgG and so on. And um We don't, we don't have that little problem with, uh, cyclophosphamide now uh clearly uh people after transplant will require a period of time in which they need prophylaxis. But as you can see here. We have, uh, shown that patients recover, uh, their T cell function, uh, relatively quickly as well as their, uh, B cell population to the point in which I have to tell you I haven't given the IgG to anybody getting a transplant since I had hair, so that tells you how long that's, that's been going on and yes, they need to be on PCP prophylaxis or HSB prophylaxis for a year or so, but, but the, the immune reconstitution is actually very robust. No. So what if, if you really don't have a donor in, in, in the family? Well then you'd really need to go and start looking for mismatch unrelated donors, which if you go to the 1990s, which is the very first time in which I think it was seriously attempted, it was a terrible thing to do to a human being. The rates of graft versus host disease were high and the severity of graft versus host disease was catastrophic. So that was not something that you really wanted to recommend your friends to do? But Um, About 12-13 years ago, uh, we published a study in which we were actually doing just that but using cyclophosphamide and um. What we saw is that the results of mismatch and related transplants compared, uh, unrelated compared to happo identical transplants were pretty much the same in terms of rates of graft versus host disease and how effective it was and I was able to take this, uh, into a national study. Which again confirmed our local uh local findings so right now. It is almost impossible to tell a patient that they don't have a donor that those days are gone. When I was a fellow or early in my practice, you go and you, you did a transplant consult and you were telling the patient, well, you know, the big problem here is, uh, to find you a donor. Right now that's just not a problem at all because you can do a full match sibling, a full match on unrelated, you can do a mismatch sibling or or a or a child or a grandson or a nephew, a niece, or you can get Hans in Germany to, to give us uh the bone marrow and even if it's uh uh 7 out of 8 or a 6 out of 8, you can, uh, perfectly do the transplant without, uh, major complications. Now when we start doing this. We were doing it uh using bone marrow because the rate of complications with marrow is less, particularly chronic GVH right now we're publishing data on mismatch unrelated peripheral blood grafts, so. And and this is important because peripheral blood grafts are substantially more commonly used in bone marrow. We hematologists don't like going to the OR to harvest marrow because if I wanted to be a surgeon, I would be a surgeon. Uh, so everybody goes and gets, uh, blood grafts and we are showing that the results are very, very similar. Now the, the thing that took the longest time to develop was doing this on patients getting HLA match, uh, transplants because when you have to go to a mismatch, uh, unrelated or a happo identical transplant is because you really didn't have any other options, uh, so pretty much everything is a kind of fair game if you will, but when, when you have, uh, a sibling who is a perfect match. Developing this and convincing the people that this was better than the tacrolimus and cyclosporine or tacrolimus and uh uh I'm sorry that methotrexate and cyclosporine or methotrexate and tacrolimus that really took some effort. So there are 3 studies that have been done. One was done in Europe and. We're not gonna talk about that study, not because I didn't run it, but because the study was very weird, was modified in the middle of the development, and therefore if you read this study, you cannot be convinced on anything other than, well, it can be done because they did it, but I don't think it is a definitive study. however, we have two trials done in the US. Um, and this is not because the other study was done in Europe. It, it, it, that's not the problem. It's just the way in which it was designed and then modified, but we have two studies in the US comparing, um, cyclophosphamide with methotrexate and other. Uh, Another prophylaxis, the first one was a random, uh, uh, kind of a randomized, uh, phase two in which we were compare comparing three different prophylaxis. One was cyclophosphamide, uh, marabirock was another one, Velcade was another one. And then against, um, uh, uh, control with tach methotrexate. And um essentially this was the the study and without getting into a lot of details what we saw is that of all the potential arms the only one that did better than tack methotrexate was uh cyclophosphamide. The idea of this randomized phase two was to then take whoever arm was going to win into a phase 3 study. Now this is, um, essentially the whole, uh, all the arms and as you can see everybody did exactly the same as that methotrexate, except, uh, for cyclophosphamide. And because cyclophosphamide did so well. We decided to take it into uh phase 3, which is the study, and it is the study made me lose any respect that I had for the New England Journal of Medicine, but um. What this study was essentially is a randomized phase 3 comparing uh cyclophosphamide with methotrexate and we were looking for the better arm into something called GRFS like you need to be uh the outcome is not prevention of graft versus host disease. You have to be free of graft versus host disease. You have to be alive and you have to be in remission, so it's a combined, uh, uh, outcome. Which is uh substantially more interesting but incredibly difficult to accomplish. And as you can see, Cyclophosphamide was substantially superior in almost any of the endpoints uh to tacrolimus methotrexate. There are two little disappointments that I have in this study. Number one, that we didn't, uh, at least at 1 year show an, uh, survival advantage. So that at least as of the one year analysis we don't have and the second one is that there was a uh a little bit increase in the overall rate of infections in patients receiving cyclophosphamide. However, they were not increased on severe infections, so the the the rate of severe infection was similar in both groups, but the, the overall rate of infection was a little bit higher in cyclophosphamide. Uh, there was another paper published in the New England Journal that, uh, kind of duplicate our stu uh uh our findings. This is also a complicated study because. The, the, the prior studies that I showed you are using reduced intensity condition is this is a little bit of a mix between reduced intensity and myeloablation, which in the US is not terribly popular but still is done under some circumstances, but it still show that uh cyclophosphamide is uh superior to tack methotrexate. Now, As I mentioned, there have been a lot of, uh, uh, people that are now trying to say, well, yeah, cyclophosphamide seems to be as good as Diet Coke. However, it's toxic, right? And you're given 50 mLs per kilo for two days in a row. That's not for the faint of heart. It, it causes nausea, vomiting, uh, hemorrhagic cystitis, and people feel really crappy for a couple of weeks. So there's been some interest on trying to dose reduce the cyclophosphamide to see if you accomplish the same results, and this is where I want you to remember the prior, uh, slide that I showed from 2008 in which patients who were receiving less cyclophosphamide had uh had more chronic GVH. Now that clearly was one versus 2 days as opposed to two days with, with those reduced, but. It doesn't, it, it, it is not entirely clear that if you give it less cyclophosphamide, you're gonna accomplish the same results. Now that was the introduction. Um, now, As I mentioned, uh, at the beginning of the talk, um, going into what, uh, uh, going into the field of transplantation for the non-transplant, uh, physicians is, is quite a little bit of, um, um, not particularly interesting endeavor, so. When, when I start. Going over the abstracts that were presented in Ash last year. They, they were essentially a lot of abstracts that were. Technical enough to put me to sleep and I do this 24/7. Um, so I try to, to go into, uh, something that had some real implications for, for people who practice oncology. There were two abstracts that caught my attention. One was in maintenance therapy after transplant. However, there have been already data published in maintenance, uh, transplant for, uh, AML with with FLT3 uh mutation, and I think that that is not new. We all know that it works on some settings, uh, so I decided not to necessarily. Um, dissect that, uh, that, uh, that study, and this is the other one that I thought that was interesting for people who deal with transplant. Now I understand that for people in private practice this is maybe not necessarily the most, uh, pressing question because usually private practitioners don't deal with leukemia, but people who are in, in, in academic centers who deal with leukemia may find this, uh, of interest and. The issue is Uh, how relevant is actually the induction, uh, uh, therapy for acute leukemia that when, when you follow with transplant, and, and this is an issue because. When patients come to, uh, to transplant, uh, actually when patients are diagnosed with leukemia, it's always a question, OK, do I need to give you, uh, intensive chemotherapy? Can I give you, uh, less intensive therapy and then take you to transplant? So we were trying to answer the question, well, does this matter? Um, round green button. So, um. The way in which we answer, uh, or we actually don't know that we answer any question, but the way in which we attempted to answer the question was to look into all our patients, uh, with, uh, leukemia who proceed to transplant and so on. Now obviously all retrospective studies have lots of uh bias, but. It is what we have before you embark in a, in a prospective study and I'm not entirely sure that this prospective study will ever be done so very likely we need to uh uh conform ourselves with the the retrospective data. So we have 243 people that uh were finally uh selected for these analysis of which uh almost 200 receive intensive therapy so that shows that this is perhaps a little bit of a bias towards being aggressive, uh, the intensive therapy with, with, uh, cytarvin and then 53 people who receive, um, 5 as a yin and and Benetoclatz as far as induction now. Uh, this is, uh, the genetic profile of, uh, of, of the patients. Um, there may be in some of, on, on some of these there are clearly a little bit of a, uh, uh, of differences because again this is not a randomized, uh, trial, but the idea was not necessarily to show you that they were all, uh, molecularly similar, but, uh, on the other hand to show you that there was a little bit of everything, right? So we didn't exclude patients with TP53 leukemia which. Every time that I have to transplant one of those, I get cold sweats, uh, or we didn't transplant anybody, it's just everybody was welcome. And what we found is that pretty much no matter how you slice the cake, patients do the same irrespective of how they do transplant. So essentially, If you make it to transplant, how you got there doesn't really matter much. Uh, survival was, uh, similar, uh, relapse was similar, non-relapse mortality was, uh, very similar. So there's a lot of overlap and, and that only tells you that we really couldn't find any, uh, any, any difference. So essentially from, from, uh, these, um. Uh, analysis what we show is as long as you make it to transplant, how you got there doesn't matter. And I think that I'm, I'm not a leukemia doctor per se. I don't give induction to patients, but I think that the field is trying to move away to less aggressive forms of induction. And, and, and obviously there's always always a concern that, well, if, if you're not giving cytarabine, will you have a problem if you move to transplant and so on? Well it looks like maybe you don't. I want to thank you for, uh, for your attention and I will be happy to answer questions now or in 5 minutes after the, uh, after we're ready for that, but thank you very much. Good job. Thank you. Thank you so much for two fantastic talks and uh for traveling here to I think it's actually sunny today sunny Buffalo um so um opening the forum and uh for questions before we go for lunch um um my I have a question and so I sorry to put you on the spot but I know we're generating a lot of car therapy products for B cell malignancies. Um, at what point are we gonna saturate. You know, uh, the, the field with too many cars but very little patience, you know, so how do you pick the winner? Yeah, it's a, it's a huge problem. I, I actually, despite the fact that I talked about probably 10 different strategies to improve CAR T cells, there's actually many that I didn't discuss, right? In vivo CART is one that immediately comes to mind, um, and for, for us, you know, I, I get dozens of companies that are coming to me asking us to open a new product, and it's, it's extremely, extremely difficult and in order to have meaningful data. On, on any of these products you need to have the patience. There are only so many patients, thankfully, uh, with these diseases that, and so, uh, it's, it's, it's a very, very, very thorny problem and, um, I, I. I think that honestly like what it ends up being is a product gets there first and has exciting early data and then realistically like market forces kind of determine uh to some degree like what moves forward because then you know investment pours into that one and there's again in terms of limited resources only so just like from a pragmatic standpoint my wife's in finance so I like think about this stuff a lot. Uh, it, it's honestly a lot of it, a lot of it is pragmatic and so like actually I mean the Tasmetastat story is a good example, right, because there there was a signal on one trial, but their exclusivity window was coming up and so they had no financial incentive to try to answer it. Try to answer this question and so we actually like as doctors now are stuck in this conundrum where we, we wanna do the science and try to figure out this might still be a good target. The PI3 kinase story is also a very similar story where you know PI3 kinase in in follicular lymphoma looked very good and then, you know, there was an OS detriment from infections for one product and then the whole, the whole class was gone overnight and. Maybe there's a way to give those drugs safely, but everyone was scared to pick that baton back up and so I, I, I, I don't know the answer, and it, I, I actually think that to some degree there's gonna be some degree of luck in which of these ends up being the winner that, that, you know, uh, we're, we, we try to tease them out, but there just aren't enough patients to try them all. So I, I, I know that's a very long winded way of saying I have no idea, but. Yeah Um, I, go ahead, Doctor Emmons. I'm very interested in what you two think about the CD7 card data for conditioning, treatment, GBH, prophylaxis, and seemingly successful engraftment without leukemia. Is this a paradigm shift or what do you both think? I, I, I think that we'll see. I, I don't know that we know right now, um. But Yeah, I don't know that we know. Yeah, so the data, the data from the study that you showed yesterday, great presentation by the way, um, what it, it's a very small number of patients, and again I, I, I, I, you know, it, I, I agree with Doctor Blanos that, that, um, it's uh with a lot of these studies, right, a lot of these things I presented today to, you know, Paco's point, we have 5, we're, we're having Ash oral presentations for 5 patients, right. And so it's really hard, same, same issue to like to, to know and so I, I, I thought that data is super cool. I don't treat leukemia myself, but I like it's, it's fascinating to have one product that like carries you the whole way through from an immunologic perspective. Perspective, um, but, uh, I, you know, uh, in we've seen before in small samples that you get excited about things that don't end up panning out and so, um, that's, that's a good example of a like you gotta get someone behind that to help that be the winner. And then, uh, two other quick questions. The first is, what is your current dose of cyclophosphamide? And given the data for 50, 40, and 30 times 2, now we still use 50. You still use 50. Got you. So what do you think of the data now for 30 times 2, which doesn't seem to show differences in outcomes or. I'm gonna tell you very likely. I hope I'm mistaken, but very likely we will not know the answer to the question until I'm fully retired. It took me. I mean it took me 14 years to do the studies of psy versus that methotrexate, so the, the, the thing that somebody will come and right now do a 50 versus 30, I, I just don't think it is, uh, going to happen. I can be wrong, uh, but particularly now that Ava is on the on on the game so my feeling is we will not, I, I don't know necessarily that we will know that 30 is better than 50 or 50 is better than 30. At some point in time somebody will come with different package saying well you give a little bit of sigh, a little bit of a bad decept, and then you chop off the the mycophenolate as the people from Australia did and uh some something that is very different from just those reducing the cyclophosphamide. Doctor Valenos you'll be happy to know that uh we're, we're, uh, one of my residents is actually trying to answer this in a little bit of a roundabout way, um, so there have been dozens at this point since 2008 of studies that have that have looked at some of these things that are all very small, but I have a resident who's working on a meta-analysis right now trying to look at this as a both as a continuous variable and a binary variable and. So there's, I agree there's never gonna be a randomized control trial, but this is something that we can kind of try as a back of the envelope way because there have been so many of these small single arm studies that we can try to answer it. So, um, as I'm not an allo transplanter, but I have, uh, this resident, uh, I, I do a lot of meta analysis, and this resident is very interested in this space and so, uh, may retire younger than I am so yeah. And then finally for the healthcare dollar cost of gene therapy for sickle cell. no, no, I, I know, but, but you're not winning in the public consciousness of the relative risk. The companies and the institutions that are doing this are largely paying the money and going the distance with getting gene therapy protocols on. And not pursuing transplant because of this perceived increased toxicity even given the latest data, how do we change that perception and move that forward? Well, I, I, I never saw myself as a as an advertiser, right? Like to say oh I'm gonna have to open a commercial uh campaign to show that transplant is better because I see the merits on both approaches however. Uh, transplant is almost 20% the cost of, of gene therapy. So, uh, and the way in which we do it because our transplants are done entirely outpatient lying, they require the administration of the ATG in the hospital. But so it's 3 days in the hospital and then everything else is outpatient. We have data on fertility preservation that the people doing gene therapy will never be able to do that with high dose of busulfan. Um, And Gene therapy, I'm not talking specifically about sickle cell, but if, if you pull all the papers in the New England Journal that talk about gene therapy, the risk of secondary malignancies is incredibly scary, um, so. I think that there there's room for for gene therapy to get better just like over the last 50 years transplant has become better but uh I I I think that right now there's no comparison but um. But that's not the popular imagination. I mean, we've had a tremendously hard time in Louisville convincing anybody to consider transplant because of this perception that the toxicity in graft versus host disease and long term complications are much higher with transplant than with gene therapy. So what, what I do with, I, I see about 2 new patients with sickle cell every week, and I'm gonna tell you when I. In training I was scared of seeing people with sickle cell because that's that was not my interest in life and the idea of dealing with chronic pain and so on was just like to give me headaches but right now I'm seeing about 2 new patients with sickle cell every week to talk about transplant and what I do is I tell them this is what we get with transplant. This is our these are our rates of GBH blah blah blah um and we don't do gene therapy in the hospital. Uh, I tell them briefly this is what gene therapy shows. I always tell them. You want to talk to somebody who actually does gene therapy for a living. And I have never lost a patient to gene therapy. Uh, I mean, not that that is a competition, but I've never had a patient that after listening to me and then listening to somebody who does gene therapy tells me, you know, yeah, I'm gonna go have gene therapy. Thank you, this was great, but no, I've never had that patient. Does Hopkins do gene therapy or no, we don't, yeah. Yeah I'm sure that that will eventually change. We're talking specifically for for sickle cell, but um the way um the way in which the results are today, it's very difficult in my mind to compare now clearly you do not have graft versus host disease with, with, uh, within therapy which is uh uh uh a major, uh, handicap for us but the rates of graft versus uh of chronic GVHD right now are less than 10%. We just published these two weeks ago. Uh, actually on the 15th of this month, so not even two weeks ago, um, so you have less than 10%, uh, probability of, of, uh, current GBH and. In the patients in which we have uh follow uh fertility, we have people getting having pregnancies after transplant, uh, which is something that uh with gene therapy you will never get and the idea of of transplant or gene therapy is actually to do it as early as you can. This is not something you're gonna do in a 60 year old so if you have a child or a or a teenager, uh, the, the, the, the ability to preserve hormonal function, sexual function. And fertility are very high on their priorities. Um So I, it's very difficult for me to write today to, to really say. That patients will move just a mass uh to gene therapy as long as they know all the pros and cons. But without question it is been and this has been published. This is not just me. Patients with sickle cell have no interest in getting chronic GVH. That, that for sure is a is a major barrier. But if your rates of chronic GVH are less than 10% and the majority of the cases of chronic GVH are mild, um, that puts a lot of people at ease. It's not 100%, but it, it, it certainly helps. Thank you so much, Doctor May. Um, so are there any circumstances where you would not use PTI, you know, older patient, bad cardiac, you know, iffy cardiac function like myelofibrosis, I mean, like when, when would you not use? Um, we published a paper, I think it was in JCO, but I can be wrong, focusing specifically on patients over the age of 70. And granted that's not necessarily the highest uh um. Uh, group of people in, in, in our trials, but patients over the age of 70 seem to be doing the best, uh, compared to younger patients, um, so at Hopkins we don't have an age limit to transplant, so we have done things that I'm not particularly proud in terms of transplanting older individuals, uh, but patients over the age of 70 do very well with cyclophosphamide, so, so we don't have that, um. In fact, the only patient that I transplant who's not the, the last time that I transplanted somebody without sight was for uh BMTCTN 1703 because it was part of the study and I couldn't say no I'm not gonna, uh, randomize patients. I was study chair so I couldn't do that, um, so that was the last time that I transplanted somebody without sight and right now the only way that the only reason for me to transplant without sight would be on a clinical trial that calls for something else. Can I, can I just ask a very quick follow-up question on that? How do you think about who you do hyper hydration post PTI versus mesna rescue? Because that's something that comes up a lot for these like older folks with bad cardiac function. Um, we don't use Mesna. Yeah, well, It's great. It's a little bit of a complex, uh, complex story. The, the, the way in which we see it, and I believe we're right, but some people can disagree, is that the problems in the bladder are usually are almost universally infectious. They're not cyclophosphamide related, so we don't really pay that much attention into. Protecting the bladder because if the bladder is gonna get bad it's not gonna be the drug is going to be either BK or cytomegalovirus or some other virus uh making our life difficult. Um, so, yes, I. I mean we certainly give some hydration but nothing that will actually qualify as massive hydration or something that is difficult for uh individuals to really take or tolerate and I and my other question is, does, does graph source matter with PTI like, you know, I like what's the, what's the final answer on this? I don't think it matters, uh, but without a question. Just like wet methotrexate in, uh, without a question, I, I haven't seen a randomized study, so there's always a possibility of question. In my experience, if you get a blood graft, you're gonna have a higher risk of two things cytokine release syndrome as well as chronic GBH, despite the use of cyclophosphamax. Compared to Marrow Um, Yeah we have a lot of trees. Can you help us OK. Uh, we use patient donors with who are sickle cell traits all the time, so that's not a problem. The Yeah, so um. If I were to see somebody this afternoon, John comes to see me, you know, I have sickle cell disease, blah blah blah, um, so there, there will be a couple of things we're gonna look, uh, we want, uh, we want donors that are a lot younger than 40 if we can. That's not always feasible, but if we can. So we're gonna talk about siblings, we're gonna talk about nephews, nieces. Um, Depending on their age, we may also discuss the parents because if they're very young with the parents may be fair game. Um, And depending on who's uh obviously available we're gonna do typing and we're gonna do uh ABO because the risk of graft rejection in sickle cell. The risk of complications in in in transplants for sickle cell goes up if you have a major ABO mismatch, um. But if otherwise is literally whoever is willing to be a donor is typed and and then that's it we have done also mismatch unrelated transplant sickle cell, not enough to really publish just yet but um but so far we have done and they appear to be good, uh, um, the, the small numbers and kind of short follow up but um. But that's uh we check, we don't care if the patient, uh, if the potential donor is sickle cell trait, uh, as long as, uh, it's asymptomatic, we're all good, um. And so That's uh essentially what we do if that was the question. That's Um, for Roswell, refer to us and we're gonna figure it out. Um, I think we absolutely would be happy to, to see those patients, but, um, if not, we're gonna help connect them with someone who will for sure. But from the point when you call that first. How long? Well, so sickle cell is a little bit more of a boutique type of thing because uh clearly patients need to be transplanted, but it's not like the same as in leukemia in which you really have the time. So in leukemia you want to do a transplant as soon as possible so we can have a transplant ready in 4 to 6 weeks in patients with sickle cell, because many of them are at school or working, I tell them whenever you're ready we'll do it. Uh, because the majority of people that we transplant with sickle cell have very miserable existences, they will tell you, well, let's do it quicker, quickly we can, but um. I can have any transplant ready in 4 to 6 weeks, but patients with sickle cell either usually wait till the summer. That seems to be popular, uh, or if they're in school when they're on some form of recess. Um, It's so, but, but in sickle cell you have a little bit more of a leeway, uh, unless the patient really spends 8 months out of the year in the hospital in which they tell you, you know, yesterday I don't wanna wait, but otherwise if they're really, if they're working or in school, they, we will work with them to come up to do the transplant at the time in which the school is not or the work is not a, a problem. Sorry, just one really quick question. So do, do you see a lot of issues with, you know, all immunization, DSA with, you know, with since they're heavily transfused, and, and then how do you desensitize them or how often do you have to do that? We have transplanted. Close to a little bit less than 100 patients between thalassemia and sickle cell, blah blah blah and as of right now there's only 1 patient that we have not been able to transplant because of uh autoimmunization. Um, we have an, uh, desensitation, uh, desensitization protocol, uh, right now, uh, that is, uh, accruing patients, and we have also a sta a standard approach with rituximab and IgG and tacrolimus, um. But Yeah, that can be an issue that can be a real issue if, if they come and they have antibody levels that are too high to, to really, uh, treat that may not be a patient that can be transplanted. Alright, I have, um, one brief question, um, and then I'm gonna try to break us to lunch so I'll take one more question after my, my own, OK, so just to be fair, but, um, uh, uh, Doctor Yaman, this one, first one's for you, and then I have a follow-up question for Doctor Blois Meade. Uh, first question is, um, as far as Tasmitastat reinvigorating this kind of dead horse, unfortunately looks very promising, more stem like T cells. Um, do you see any strategies where perhaps instead of treating the patient, you know, pre-leukapheresis, perhaps maybe X vivo. Uh, you know, it's part of the manufacturing process. Can you envision a future, say, uh, in that with that approach? Yeah, so, so that's a, that's a, a good question. So, 11 thing about our approach was that, you know, the cells aren't, weren't exposed during manufacturing. And so, interestingly, we actually what we, what we've seen so far is that, um, even exposure pre-aphoresis did actually translate to the product, which is kind of cool, um, that. Work is unpublished as of yet um but yes, I, I, I think that it that it, it that is an area for sure. The problem is that part of the reason why these studies, these types of studies are very pragmatic, right? They're things that like a clinician can do and actually I, I had, you know, people from like University of Colorado or whatnot, especially in patients who had EH2 mutations just asking me how it's done because they can just do it. It's an approved drug and they can just, just give it. We don't control the car team manufacturing. And so that eliminates some of the like, if I want to use Axi cell, I can't like call up Nick and say, hey, Nick, I want you to like give Taz to those cells while you're while you're manufacturing. That's not really like something that we can control although you know through through Roswell we actually potentially could so that that I think is something that you guys are are kind of in pole position to to think about so um but the other piece right is that if you're only doing it on the manufactured product then you lose the impact on the micro environment which I also think is important and so why not both. I agree. Then my, my follow up question for Doctor Bolanos Mead, I saw a little, I'm not a transplanter myself either, um, but I did see and I know enough to be dangerous, and I saw one abstract with, uh, an allergenic, um, adoptive T cell therapy, I believe it was a T regulatory cell. I think it's Orca T is a, is a new product. Any, any hope for the future for, you know, those 10% of patients who might still get GVHD to try to make it zero? So Orca T is a, a very interesting approach. Um, It's a complicated uh thing because it's essentially a mix of is graph engineering uh we don't know what's included in the graph engineering because that's uh. Proprietary so we don't know what it is but uh but yes in in principle what it's using is some combination of regulatory T cells that are immunosuppressive, uh. I think that um. There is a lot of discussion about whether to compare this with cyclophosphamide in a prospective study, um, for which I'm absolutely, uh, interested, um. But I do believe that it's um. Uh, it's one of the options that is being studied and eventually will either show that it's better or not, we don't know, but, uh, I think it is, uh, uh, an, an interesting alternative, yes.
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