Updates and Advancements in Cellular Therapy at Roswell Park
Originally Broadcast: Thursday, November 9, 2023 6:00 - 7:30 PM EST
This program is intended for Hematologists, Oncologists, Pharmacists, Pathologists, and other healthcare professionals that care for cancer patients. Featuring presentations by Roswell Park subject matter experts, this event offers a unique opportunity for attendees to stay at the forefront of cancer care by gaining in-depth knowledge and insights into the latest advancements in cellular therapy.
Learn about the latest research and clinical advances in cellular therapy, including new treatments and techniques.
Explore the safety and efficacy of cellular therapy for different types of cancer.
Gain insights into the practical aspects of implementing cellular therapy in clinical practice, including patient management, monitoring, and follow-up.
Identify appropriate candidates for cellular therapy treatment.
Develop an appreciation for the interdisciplinary nature of cellular therapy and its potential to transform patient care.
Rustum Family Endowed Chair in Translational Research
Senior Vice President and Associate Director for Translational Research
Department of Medicine
Professor of Oncology
Vice Chair of Strategic Initiatives
Department of Medicine
Associate Professor of Oncology
Clinical Director of the Pediatric Transplantation and Cellular Therapy (TCT) Program
Department of Pediatric Oncology
Associate Professor of Oncology
Director of Multiple Myeloma Translational Research
Department of Medicine Good evening everyone. My name is Marco Davila. I'm the Associate Director of Translational Research uh at the Roswell Park Comprehensive Cancer Center. I'm a physician scientist in the Transplantation and cell Therapy Service. Uh We want to thank our sponsors, Novartis for giving us the opportunity to meet everyone. There's been a lot of, of, of new faces, new names in our cell therapy operations. I wanted the opportunity to, to kind of meet some of y'all folks. Uh I've been at Roswell Park for a little over a year now and um the person that uh recruited me here is Rainier Brintons, who's the Deputy Cancer Center director as well as the Chair of medicine. And he and I worked at Sloan Kettering before in New York City when he was uh we were both junior faculty there and we helped kind of design and develop the first uh gene engineer cell therapies for uh B cell malignancies. Our technology that we worked on um uh led to the founding of the company Juno, which was bought by cell gene and B MS and was obviously behind some of these uh FDA proof technologies. So, one of doctor Briton's uh major goals in, in him, coming to Roswell and bringing me is making kind of Roswell Park a destination for cellular therapy. And we really want to kind of figure out how we can work with. Our major refers to good partners to be able to offer the standard of care products as well as investigational uh products to their patients. So I've asked, is some of the new names and faces that are associated with, with Rosswell Park Cell Therapy Program to come and talk about some of the different things that we're doing. Um What I'll mention is in, in 2024 you're gonna see clinical trials that are opening uh targeting B cell malignancies, am L multiple myeloma, small cell lung cancer. And then in 2025 our big, we're trying to transition to more solid tumor targets ovarian cancer where we're kind of partnering with another company to develop these novel therapies. So we're hoping that in this process that we'll be able to, you know, reach out beyond just Buffalo and the reaches of Western New York to uh the patients uh to the rest of the patients in upstate New York and bring them in, treat them and then bring them back to their uh primary uh medical oncologist and primary medical team. So, the team I'm gonna have speaking with you today, uh Doctor Brian Betts, um who's our vice chair of strategic initiatives and the strategy that he's focusing on is on cell therapy. He's um uh in the transplantation cell therapy service. He's gonna speak first, but I'm gonna make the other couple of introductions as well. Just so we can kind of move from speaker to speaker. Uh The next speaker will be Doctor Kinal Molly, who's also uh a new recruit. Uh She serves as the clinical director of the pediatric cell therapy program at Roswell and the last person is gonna be doctor as so Mao, who recently joined us from, from Cleveland and he is in the transplantation cellular therapy service as well. And he's our director of myeloma cell therapy research. So with that, let me go ahead and uh pass the uh podium on to my colleague. Doctor Bet. Right. Yeah. Hi, everyone. Um Glad to be here. If you have questions, feel free to ask as I'm kind of going through things. So I'm gonna talk to you a little bit about some of the new things we're doing in cell therapy in general and also some things we're doing with uh transplantation uh with regard to graft versus host disease prevention and also with donor selection. Um And I'll be nice to the med students. I'm not, I'm not gonna pick on anyone may maybe. Yeah. Uh There's my disclosures and that's also my Bernie's mountain dog. Um She pretending to be a cat because my other disclosure is that I have six cats. So I, I apologize if that's socially unacceptable. But I, I do. Uh there, there's the team, the adult uh TCT clinical team, uh led by Doctor Brenin, Doctor Davo myself on the bottom there and the rest of our crew, and you'll be hearing from Doctor Malik too as we go through the evening and we, we actually recently hired another illustrious transplant, which I can't disclose quite yet. But uh it'll be exciting. So we have a, we have a fantastic crew. So one thing you know that that's, that's a major theme for transplantation and cell therapy at Roswell Park is that we want to make it a destination for cell therapy. So, what does that mean? So, in addition to offering quality auto and allogeneic stem cell transplantation, we also want to offer, you know, novel clinical trials for ghd prevention, relapse prevention and also innovative car t that you can only find at Roswell Park. Um We also have other therapies that are available like T cell gr um and soon to be tumor infiltrating lymphocytes uh for advanced Melanoma um and gene therapy for sickle cell disease and beta thalassemia. And we even have a survivorship clinic um which offers support for uh immunizations, gvhd, follow up routine cancer screening and those types of things that are very important post transplant. And within the area of Buffalo, it's, you know, you know, kind of having patients have to relocate to the Buffalo area is affordable and doable just given the amenities that are around the cancer center. We have the Kevin guest house, which is pretty convenient and we're also um working on another uh lodging area for patients undergoing car too. Um And another kind of thing I've been working on as I didn't mention that I'm, I'm new to Buffalo, so I've been there for maybe two months now. I made a couple changes on, on the arrival there. One of the things that we're working on is more collaborative work with uh referring oncologists. Um And I'll get more to it in a second but kind of, you know, working with you, you know, for allogeneic transplants, you know, they'll be getting post transplant, cyclophosphamide. So risks of graft versus host disease are very low. Ok. OK. OK. One med student question, I apologize. I apologize. So, what do you think the incidences of life threatening? Grade 34 gvhd right now? You can throw out a number. Why it's actually very low? It, it was OK. If I, if I OK, if I asked you that same question two years ago, you would have been totally correct. So um two years ago, uh risk of grade 34 GVHD around probably 30 40%. And now with using post transplant like phosphide, it's less than 10% probably closer to 5%. If you're in Minnesota, we would say five and I'll say the same thing in Roswell Park. It'll be around five. So the, uh, that, that's important because by the time patients are returned to referring oncologists, they should be off immune suppression. Um, and they'll be working on things like relapse prevention, which is probably the main thing we'd be, should be working on anyways. Um And then last, uh, if you ever need our help, we're always available for rapid consultation. I'm happy to give out my cell phone if people have questions, referrals and telemedicine too. So I kind of hit at this a little bit earlier, but in the year 2023 GHD prophylaxis essentially consists of post transplant cyclophosphamide. I'll get into more of what that actually means, but it's essentially just that given cyclophosphamide in days three and four after the stem cells go in and we still use tacrolimus for a short period of time, typically tapering tac around day 60 or so. So by day 80 day, 100 people should be fully off immune suppression. That's pretty good. Um And again, rates of acute GVHD, very low chronic GVHD, which is also important probably from a quality of life standpoint, the the risk of needing immune suppression, post transplant around 5%. So it, it's phenomenal. These, these are numbers, you know, when I was, when I was a med student, th those are not the numbers I saw. Um So now we're working mostly on relapse prevention um which is still around 20 to 40%. So that's, that's where we can probably do the most good. And that's where car t post transplant, novel inhibitors of various pathways. We're working on an Aurora Kines inhibitor trial um which uh will be presented at ash in a couple of months. Uh But things like that to help reduce that 20 to 40% to something like the chronic DH D thing, like, like 5%. So, if you could do that, we'd be, we'd be doing, you know, spectacular. So why do we use cyclophosphamide post transplant? So this is just kind of illustrating, you know how it works in vivo. These uh mice here are injected with um Lucifer transducer T cells and then you're, they're given um Luciferin which allows those T cells to kind of light up in the mouse and you can image in, in, in real time. But you can see by day three and four, those T cells are rapidly dividing and expanding and by day five, they're essentially everywhere. And that's why we give psy or cyclophosphamide in days three and four to make that mouse more, you know, more look like. Uh the top row. Uh from a mechanistic standpoint, the, the cyclophosphamide, it doesn't really cause uh T cell depletion. It's more T cell dysfunction of the aller active T cells. Um So you still have T cells to, to offer uh antiviral immunity uh in graft versus leukemia, which is the good part of the transplant. That's what, that's what we did in the first place. Um Things like the uh regulatory T cells are T regs which are important for long term immune suppression. And the main reason why we can get people off immune suppression at day, you know, day 60 or so, they're resistant to cyclophosphamide because they have high levels of aldehyde dehydrogenase which are not seen in the conventional T cells that would cause GVH. So this is uh Doctor Holden. she was lead P I for the uh BMTCTN uh 1703 trial, which basically put uh PT SI or post transplant cyclophosphamide as the standard of care. It was practice changing standard of care for GHT prophylaxis and was able to achieve those numbers that I showed you earlier. Now, the kind of um potential question is, you know, does PT SI still uh behave the same way in mylo blade of transplants? Because that uh reduced, the 1703 was in reduced intensity when, when I say that it's basically when you're trying to do a transplant, you kind of have a range of intensity that you can use. So reduced intensity means that if you go through that transplant, the patient's stem cells could come back if they did not receive someone else's myeloablative means it never would come back at all. So it's fully ablative, you know, the the the stem cells are gone. So the uh there was a trial done at University of Minnesota that's back when I was there and also similar trials done at the Hutch out in Seattle and, um, north side down in Georgia, they all have similar outcomes where we're getting two year overall survivals of around, you know, greater than 70% and very low rates of severe graft versus host disease. So, not only can you use P SI and reduce intensity but you can do it in my ablative and that's what we're doing at Russell Park. Everyone's getting PT SI. So that, that's a good thing. Oh And uh Sheeran also plays bass. Uh uh that guy over there that's Buck Page. He actually, he's a real musician. He plays for a band called Empire Down. Uh If you're into punk, check it out and that's Stuart Bloom. He's a, he's a breast oncologist, but he's also a stand up comedian and apparently he works out a lot. I didn't know that. So um access to access to allot transplant. That's a main function too of PT SI. So uh when you're looking at donor selection, you probably, you know, we're trying to match eight different HLAS. So it's ABC and Dr I got that right. Right. Yes. OK. Good. So that, that's eight. So you get two copies. So those are eight. So um you might have heard back in, you know, two or three years ago, we were trying to look for full matches. That's good. But you don't need to anymore. You can actually tolerate mismatch up to about six or seven of eight, which is fantastic because it opens up new options for people that may not have had donors otherwise. Um And it's actually a better outcome than Halo, which I'll show you in a second. But, but with using, you know, seven of eight matches or even a six of eight, those outcomes are spectacular above 80%. So we never got that before. You know, back in 2014, it was more like 30 to 50% overall survival. So by using post transplant P si not only does it reduce gvhd, it also opens up options for people uh that may not have had donors otherwise. So that, that, that's a great thing. And at Roswell Park, we've refined our donor selection algorithm. So what, what turns out to be more important than HL A matching is actually the age of the donor. So um if you have a patient who's in their fifties or sixties and their siblings, even if they're well matched are around that same age, they actually wouldn't do as well as using an unrelated fully matched donor who's less than 40. Um And same is true for mismatches in Halo Halo transplant. So there was a big push maybe 5 to 10 years ago to use haploidentical donors. Um And it turns out a younger match, unrelated donor or a younger mismatch unrelated donors can actually perform better than the halos. So the younger hap low, greater risk for relapse, older hap, low, greater risk for transplant related mortality. So we've kind of shifted things around a little bit where we're doing um, a uh matched unrelated donor. Then the next uh rank below that would be a mismatched unrelated donor and then the halos at the, at the bottom there. Not, not that we wouldn't use them. It's just, it would be our kind of last resort. Um Only because the outcomes are better with using those other donor types. And again, making Rosal Park a destination for cell therapy. So we, we, we offer everything you could think of from uh FDA approves therapy standpoint. So we have Kaya Briani, Sara Tardis, Abema, Karti Kim Raya. Um One thing that's really helpful there is it opens up options for outpatient uh KT which is one of the things we're working on. Uh uh you know, it's an important push for what we're doing right now. And then also T cell engages such as Blen Cyto and the other uh myeloma T cell engages tumor infiltrating lymphocytes which should be out soon. Um I think the FDA is meeting on that shortly. Um And then gene therapy uh for sickle cell disease and beta thalassemia. So what's coming out from the labs at Roswell Park? So, Doctor Breen's has the armored car and essentially that's a car T cell that's designed to bring its own cytokines. So, byoc bring your own cytokines. Um and So it's, it's, it's important because, uh, the, the, the kind of thought there is we want to use car TSE for solid tumors. That's kind of the, the direction we're all going for. Um, the problem with solid tumors is they're really well fortified with things that suppress the incoming cells, whether it's myeloid suppressors or t rags or just cytokines within the milieu of the tumor micro environment. The armored car can bring its own cytokine which can suppress the suppressors to allow it to enter the tumor and kill better. So you get better potency and better long term, you know, outcomes with those car T. So we're working on that for B cell malignancies and small cell lung cancer. Uh Doctor Davila has a double coast in car T this mutated uh uh C 1906, which is gonna be used for BC M Lignan Cies. So it basically has uh several ways to activate that uh that, that T cell and that's when you, when you're thinking about T cell activation, you got signal one, that's T cell receptor, right? So that's CD three zeta. So that's built into the car signal two is co stimulation. So you have CD 28. That's kind of the thing you think of 41 BB, that's the other one. There's other ones like 40 stuff like that. So you'll read about it in Janeway if, if you haven't already. Uh But yeah, those things are are, are, are great to activate the T cells make them more potent. So they can hang around longer and, and, and get better outcomes for our patients. And last coming from Marco and me is the CD A three car T, which we originally designed for graft versus host disease treatment and prevention because 83 is on the T cells that cause GVH. But as it turns out, it's also on leukemia. So that was kind of a, a nice uh eureka moment. So we can use those cars to also prevent leukemia relapse. So you can go after the two main causes of death, post transplant, which is relapse and less. So GVHD. So a little bit about the 83 car. Um So in the corner, I don't wanna, I don't wanna hit Doctor Mao with a laser pointer. Um But over in the corner, there are the um those are leukemia stem cells and you can kind of see 80 three's expression in respect to CD, 33 and CD 123. Uh You can also see its antigen density, that's the the molecular equivalent of soluble fluoro chrome. But you can essentially, it's, it's well expressed on the leukemia stem cell. And then here we have an in vivo model where it's NSG mice that are given luciferase trans duced MV 411, which is a tumor cell line. And you can see the 83 car t essentially cures those mice of leukemia. So that's, that's pretty exciting. That was published not too long ago in uh clinical cancer research. Uh One question is, you know, when you're using a car that goes after myeloid disease, you gotta worry about shared antigens on normal stem cells because you don't want to cause myeloid aplasia. Um So we, we look to see, you know, one is it even expressed on stem cells. We don't see it. I think that's the next slide. But here we actually took NSG mice and then engrafted human cord blood stem cells in there. So they had a normal human hematopoiesis. And you can see over time those carts and graph nicely. That's that human CD 45 you see on the far left, but then over time for the mice that received CD 123 car T uh that, that human chimer drops. So you can get, you know, it's causing myeloid aplasia inside the mouse, but not. So for the CD A three car T, which is, which is good. Um And then also 83 expression for GVH, which is the original reason why we made this car T. So on the top left is patients that do or don't have um acute graft versus host disease. And we're looking at 83 expression on the conventional T cells that cause GVH. And you can see 83 is way up. If you look at um Roc Curves, you can see high expression of 83 on those cells correlates with graft versus host disease. So it's essentially a biomarker for disease. And patients that have high expression of 83 on their T cells have worse survival. So we can see all that in real time, similar for chronic gvhd, 83 is high on B cells. And so T help or follicular same story with the ROC where it correlates nicely with, with disease onset. And again, patients that have high CD three expression on their B cells have worse survival. So we have an antigen that's not only a target for leukemia, but also for graft versus host disease and a potential biomarker. Uh Here, we're just looking at in vivo applications of the 83 car and prevention and treatment. So for prevention, the NSG mice are given human peripheral blood monitoring nuclear cells, they'd normally develop graft versus host disease within a month. In that model, we give all the cells on the same day. So PB M CS go in car ts go in. And that's a prevention model. And you can see the mice that got uh a high or low dose of the 83 car are, are essentially GVHD free. And then on the treatment side, we allow the mice to develop some s you know, clinical signs of graft versus host disease. So sometimes it's fur ruffling weight loss, those types of things. So by about two weeks out, they're starting to develop GVHD, we give the 83 car and just melts away. So we can prevent and treat gvhd. And this is just looking at organ, you know, target organs of gvhd. In this model, they have normal lungs and normal livers when they're given the CD A three card, which is fantastic. So in summary, um one of the main things we want to offer is safe and effective transplantation and also novel car T I want to be able to, you know, our, our team to work with the referring oncologist. So by day 30 for autos and um by day 60 or 100 for the ALOS be able to kind of work with you for maintenance therapy. So for like say an allo that's got AM L high risk AM L or high risk M DS by day 60 it'd be nice to have help, you know, working with you all uh to provide like maybe H MA or Bela or a combination of the two for GVH or sorry for relapse prevention. Um And then we can help with all the other stuff with like, you know, if they happen to get GVH, which is kind of rare uh any other related toxicities re staging. And typically we do that at various intervals, post transplant and vaccinations too. We can offer FDA approved car T novel car T and uh other forms of cell therapies. And I think there I'll stop. I'm gonna wait for questions at the end because I think we're gonna go from there. Right. Yeah, thanks. I don't know if it's gonna load. Ok, I'll introduce myself. Um So I'm Ken. Well, Molly, I'm a pediatric hematologist, oncologist at Roswell. I was recruited here from um Fred Hutch Seattle Children's Hospital same time as Brian. So, just a couple of months here. Um And uh I'm gonna talk a little bit about the pediatric program because many of you might not be familiar with our program. It's just a little introduction of what we've got in our program and, and how we collaborate. Um There you go with, with the adult program and then some of the interesting things that we're doing with gene therapy. So I just wanted to point out that um one of the unique things about our center is that we have the opportunity to collaborate between two premier specialty centers. So we've got Roswell Park um you know, comprehensive cancer center and then we have a freestanding children's hospital um Oshi, which really helps with this joint venture between the groups. It allows for a lot of collaboration and best practices in our pediatric patients. Um And also just gives a comprehensive team because kids are not little adults, but we do have some unique things that can apply um broadly throughout. So I just, just to familiarize some of you with our uh providers. Uh Kara Kelly is our uh chair of the pediatric um Oncology department. And then we have a group of UUB MD and uh Roswell as well as blood care uh physicians that work as a group together. And we have five specific transplant, specialized uh therapists, uh uh uh doctors as well as part of the team. Um And Natasha is one of them sitting over here so she can chat with you a little later as well. Sorry, can you? Oh, ok. Um So just a few clinical trials that we have currently open here. Um Obviously, we do a lot of collaboration with our adult colleagues as well. And so a lot of in-house studies can be applicable to pediatrics. Sometimes. Um oftentimes we have to start with adult approval first before getting into, but we do have at least two clinical trials with it for non malignant patients and also for malignant patients. And then we've got some upcoming uh new cellular therapy uh trials coming soon, including some NK specific um therapy for our solid tumor patients um with tissue sarcomas. So, one of the incent initiatives of our program is to try building new cellular therapies. So solid tumors, we're gonna work with our adult colleagues trying to expand the pediatric um non malignant transplant program. And then we're also going to be bringing gene therapy for hemoglobinopathy to the center. So just to kind of highlight again, the collaboration that happens between the pediatric and adult programs. Um We've got uh Ajay Gupta who's in the middle here, working with Renee pension and a group um on the adult side, trying to uh establish adoptive therapy for pediatric solid tumors with um targeting car Ts for surviving and LLRC 15. Um There's a grant currently um submitted and underway and then hoping to get some phase one, early clinical trials started for a pediatric patients. So there's some nice up and coming um innovative research coming out of Roswell for us just to kind of switch gears a little bit because I am a pediatrician. Um I wanted to show you the CIBMTR data on kind of the indications for transplant um in patients under 18 years of age, as you can see here. Um we actually do a fair number of allot transplants compared to auto transplants. Um and actually a good chunk of them, about 40% of them are for non malignant diseases. And that really encompasses a bunch of different disorders, including hemoglobinopathy, primary immuno deficiencies, marrow failure such as PNH um and then some inherited disorders. And it, it really is that we try to do curative therapy up front as much as possible for our patients. Um So with that focus, you know, there's a couple of barriers that we encounter. Um I know Brian went over the nice PT SI that are being used for GVHD prophylaxis on the adult sides. Um Pediatrics, we actually don't see a lot of GVHD partly because we use bone marrow um product instead of blood stem cells. Um But we do have a select group of patients where we do have a lot of gvhd and particularly in the hemoglobinopathy. What some of the barriers for these patients is that we can't find donors. And so you can't actually use seven out of eight or six out of eight for the hemoglobinopathy and PT SI has not been shown to really help this group. Um So it, it's so there are some limitations in this and increasing the registry size hasn't really helped. So that's why we're looking at alternative uh graph sources and I'll talk a little bit about gene therapy kind of moving forward. Um You know, it's, there has been limited referrals for these group of patients, partly because of the concerns with gvhd and increased mortality. There's also a lot of social um and cultural um economic barriers that we still need to overcome. So I wanted to just in interest of time I could spend, you know, a whole talk just talking about transplant for non malignant diseases. But I thought today I would focus on gene therapy because that's one of the um therapies that we're gonna be offering at Roswell soon, hopefully. Um by next year. And so gene therapy just to kind of give a little background of those who haven't really experienced. It really is similar to an autologous stem cell transplant after those um peripheral blood stem cells have been genetically modified and there's two, there's several approaches to doing gene modification. You can either add in um the corrected genes which with, with lent tir vector. So the virus based um transduction, you can do direct gene uh correction. I don't know. Oops, sorry. I don't know if you can see that point to here or you can do um some CRISPR nine editing to do some gene um induction to replace some of the things that we wanna replace in these disorders, specifically in thalassemia and sickle cell disease. We're trying to get um increased beta globin gene production. So there's a lot of advantages. Um it's an autologous product. So there's no risk of gvhd, which is great but, and you don't have to look for an ideal donor. Some of the disadvantages similar to when the cars first came out, it's got a high cost. So we're still working on that and it is still in the early phases. So we don't have a lot of long term um data on the outcomes and safety of this. But so far things have been really promising. So we're working and collaborating with Vertex um Pharmaceutical, which is part of the CRISPR um uh a project and we're bringing XSL to Roswell Park, hopefully, once there's FDA approval. So I'm just gonna provide a little bit of information about this product. Um Essentially what is working on is that we know that in patients with sickle cell disease and thalassemia, there's been, if you have elevated hemoglobin F, you, um it's been associated with decreased mortality and morbidity in these patients. And so if there's a way for us to induce a higher expression of hemoglobin F, we can actually overcome and cure these patients of their disease. And so this is where um XSL uses a non viral. So it's not lent Toral based, it's actually an in vivo sorry X vivo CRISPR mediated editing um where we try where they um editing the enhancer region of BC LL A. And this is a protein that actually um inhibits expression of hemoglobin. F as you, you know, when you transition from early infant to six months of age. So, by inhibiting this protein and this gene, we can actually get increased hemoglobin f production and ideally um cure these patients. So this um is some of the clinical phase three clinical trials that vertex had underway. Um I'm gonna show a little bit of the data on this just so that you can see how promising it is. Um They had AAA clinical trial for thalassemia and then a separate clinical trial for sickle cell disease. It specifically was looking at um enrolling and, and they have enrolled 48 patients on the thalassemia arm and then 35 participants on the sickle cell um arm, the age group just so you're aware was from 12 to 35 years of age. So it does encompass some young adults. Um there are other gene therapy studies that have looked at adults up to age 45. So there's some data on that as well. Um And really, it was kind of defined for the thalassemia as anyone who was transfusion dependent. And then in the sickle cell patients, um they really, they really enrolled only patients who had severe sickle cell disease. Um So having a lot of, you know, inclusive crises or pain crises um within a year. And also you couldn't have any unrelated um match sibling donors. So that was an exclusion criteria for these studies. But um uh I'm gonna show you just kind of this is the the, the uh process in which the patients go through, they get screened. We do uh mobilization with um Polier and G CS F for thalassemia patients and plier alone for sickle cell disease and um those products I then collected shipped off to the manufacturing center at vertex um trans the, the undergo CRISPR um caspase nine editing and then are sent back to us. And then the patient will undergo a mylo blade of preparative regimen with bus suan and an infusion of the stem cell very similar to an autologous uh stem cell transplant. Typically, these patients need to stay in the hospital for about a month um while they wait for engraftment and then um they can be discharged home with some follow up for about two months afterwards. And then hopefully ongoing long term um follow up as well. So just to kind of go over the sickle cell, um uh you know, this is, it's a little complicated, but essentially what I wanted to show here was when they were looking at the primary end points of the study in the sickle cell patients, they wanted to see what percentage of patients who were enrolled um were free of, you know, inclusive crises within 12 months after receiving the product. And um which if you look at a stem cell transplant, you know, um would equate to like an event free survival in those patients. And you can see in this group, they really have about 94% of the patients. Um Again, they're only, they were only able to um calculate this based on patients who had at least 16 months of follow up. So we still have several patients that need follow up. But it's encouraging to see that many of the patients would were without vsoc closes pain by 12 months um after infusion of the product. And actually many of them were without pain within six months. Um which is a great feat for a lot of sickle cell patients. And just to put this in perspective for, for if you were getting a stem cell transplant. Um if you're a pediatric sickle cell patient under 13, the event free survival is great. It's 95%. If you have a match sibling but anyone who doesn't have an uh match sibling donor, the survival really decreases. And in, in the halo or the mismatch setting, it gets down to 65 to 70%. So this is really encouraging um you know, compared to those patients. And also there were a few patients, you know, um three patients who didn't, who still had some voc pain crises. But the frequency and need for hospitalization really decreased in this patient. So that's also encouraging because that's a huge economic burden on the on the health care service and for the families and patients themselves. So, in the thalassemia patients, um they're similarly looking at transfusion independence by 12 years, post gene therapy. And so these are patients that would have otherwise been receiving monthly transfusions for their thalassemia. And about 88 89% of the patients were transfusion free by 12 months, most of them are actually transfusion free by three months um post infusion. So this is really encouraging for them. There were three patients um who didn't receive, who didn't achieve um transfusion independence by the time 0.1 year. Um it's not as clear why that was they've looked at, you know, was it due to the cell dose? Was there something about the specifically about the patients they're still looking into trying to figure out if the if the editing was um inadequate or not. But even in those patients, the frequency of their transfusions decreased. So they no longer needed monthly transfusions. Um They were getting about a third of what they were re receiving before. So, again, really encouraging um data for the thalassemia patients. Um just to, to, as I mentioned, the, the XSL product really works to increase hemoglobin F. And so it's been shown that in sickle cell patients, if you're able to maintain a hemoglobin f, more than 50 or 40% it's very similar to having sickle cell trait. Um And so a lot of the veno inclusive crises and pain um and organ toxicity asso associated with sickle cell disease, really diminishes and with this product, um by three months, they were able to see that um definitely by six months, they were able to see most of the patients had 40% hemoglobin f and then the thalassemia patients um also again, showed similar findings. So really encouraging the toxicities and the safety profile um was really that of what we would do with an autologous bulan based auto. Um really didn't see anything specifically related to the Excel product itself. Um There are some other gene therapy products out there that you may have heard about that have been associated with um malignancies. They have not seen that with this product yet. Again, long term follow up is still only up to four years in these patients. So we've got a long way to go, but it really is um encouraging to, to for these patients. So far um that the risk of gluco genesis um and oncogenesis seems to be low. So just kind of next steps. I it's, I know it's a busy slide. I'll just get to the bottom of it. Um Vertex submitted their uh proof. They submitted their information and um for FDA approval earlier this year in June, they were received um the biologics license application and they're gonna be up for review um for a prescription drug User Act uh for Sickle Cell Disease in December. So hopefully early December, we'll have an FDA approval for sickle cell disease and then the thalassemia um product will be up for review next um early March. Um So what does this mean for us at Roswell? We're working really hard with vertex to get this product available for our patients in upstate, in Western New York. There's a large sickle cell population um in New York, specifically, even within the upstate um and Western New York area. And we really wanna be able to provide them with a curative option for their, for their disease. Similarly, as the thalassemia, we'll have to see what the FDA um you know, actually proves in terms of age groups and um toxicity or, you know, organ um sorry, you know, anyway, comorbidities. That's weird. Um And so we'll see which of our patients will actually be able to be screened and eligible for this product. But we are also talking to Bluebird Bio who has a lentivirus based um vector as well. Their age group goes up to 45. So there's probably a little bit of the patients who can't get this product. Um Maybe we'll hopefully be able to get the Bluebird Bio product. So I'm really excited. I'm very passionate about this. Um I just uh I know we're working very hard with our adult team as well. So pediatrics, we, you know, accept up to 18. Technically, we have an A Y a Young Adult program as well. So we are expanding. Um and considering even some of our younger sickle cell and thalassemia patients to be maybe referred to the pediatric side. And then the remainder will obviously work really closely with our adult team as they work on some of their other cellular therapies. Ok. Ok. Thank you folks for having us. This is a very nice night in Syracuse. So I've been in Syracuse um several times. I have a few friends around here and every time I've been here, really, it's been fun. So uh I appreciate for having us. Uh I came from Cleveland, so I did eight years of um essentially exclusively myeloma transplant as well as cellular therapy lately. And um there um was challenges in terms of um new myeloma structure of care and I wanna talk about that and that's the reason we came out to um really promote this new myeloma structure of care and I'll go through that more. Um more in detail. So we're gonna do this very good. So we look at National Cancer Database that around 100,000 myeloma patients. And it's very important that we recognize the role of the cancer centers that they have low myeloma volume means that less than 55 0 per year, that uh 75% of myeloma patients that are served in these centers. And if you fragment it to less than 25 half of 75% they serve in less than 25%. So the idea that we're gonna concentrate care in the large cancer center and the Anderson Sloan Buffalo and this and that you miss 75% of my patients. So that's very important to build a uh essentially care structure, a collaboration of centers with low myeloma volume as well as with, you know, tertiary centers, big cancer center, so so called comprehensive Cancer centers and so forth in myeloma. It has unique features that um in last two years is getting more important this collaboration. Without this collaboration, essentially, we um we don't serve patients as well as really we could. So cancers cancer centers below myeloma volume, extremely important. Uh why is it important? Few things. So, first of all, uh the patient access, right, the patients that they have myeloma in rural area of New York, they don't get to Buffalo or Memorial Sloan or any of those. So these centers, they are really serving patients in uh local areas. So those are the very important point that really if you wanna change the care, we have to reach to this cancer centers to build collaborations, personalized care, a doctor and community oncology in, in um any small city or even large city, they know limitation of patients, they can individualize therapy. We at the big cancer centers, we are unable to understand patients limitations when they come different uh areas. And those centers are very crucial to bring a cutting edge uh uh research and clinical trials. Obviously, not every clinical trials can happen in the low cancer centers. However, if you don't do that patients, they don't just travel to Chicago and New York and so forth. So we miss 75% of uh myeloma patient. And as well as this cancer centers, the source of uh essentially cancer awareness, cancer prevention and um updating patients about new advancement that in last two years, really, I would say the biggest step in my last two years, what happened? So a little I looked up the Syracuse area and uh Onondaga, I'm pronouncing right. Onondaga County. So uh around 2000, my patient, they diagnosed in uh New York, entire state of New York every year and around 600 or 700 they die from that. And um the interestingly enough, Syracuse uh and you know, the county, the rate of mortality is a slightly lower than the entire state. That's the good things the highest mortality rate is 3.7 for Bronx that uh you know, Bronx has a low um I would say social economy and, and so forth. But uh Syracuse actually is not a bad city to have my overall speaking in last 2016 to 2022. So that's our uh local uh statistics. That was interesting uh for me. So why this new idea of myeloma care pattern is very important because this is a very busy slide. And intentionally I put it here because in last two decades, as you can see lots of new FDA approved drug coms and so forth and is for a community oncology practice. It was very complex. I would say that what patient we're gonna do what and all of those, but in last two years is very simplified. Why is that? Because we had Cardell and uh hold on. They told me and I OK, I got it Caroline by specific, basically Carico and by specific, they put bars so high that agents that they had a low efficacy essentially, whether they were pulled from market or nobody is using them anymore. Because you know, the age of myeloma that we have and agents that four months gonna prolong remission time is over. We have car right now that you have three years. Uh PFS, four years, maybe you have, you have oral response rate of over 92% you have by a specific around 65%. Therefore, oral response rate of like 30% or this four months of overall survival uh is not really the bar. So essentially the mindset is very simple. You have three main class of anti myeloma agens, immune modulatory pos of inhibitor and CD 38 anti 38. And after that, you go Carico and BC ma. Very simple. This is the basically therapeutic uh framework. We, we publish this, We look at the uh basically new benchmark triple class refractory. If you have this three class, essentially, the survival is very short. As you can see, regardless of your Penta exposed or Penta refractory. As long as you have refractory disease to triple class to three class, you do wars and that's where the corti cell and by specific come to come to horizon. Essentially, let's start with the case. So all this case, this is a very classic case that comes to any uh community oncology or even in myeloma clinic in a specialized center. So you have a, let's say, um she's a 62 years old Igak, a standard risk diagnosed five years ago, had VRD transplant maintenance, rev limit and Dora pod de had remission of 1.5 years and car carfilzomib des or KRO sticks for six months remission. So for this patient, what we gonna do. So we, as you can see, this is a uh here you have a triple. Basically, you have the three main class. You have the Velcade rev laid and Doro here. So we like to patients to see at least latest here. I'll convince you that probably we should see patients here next year because we have a corti available here after first line of therapy. But in this question, as you can see only six months with carfilzomib de So we really like to see patients here to plan the Cardell using card X instead of seeing patients here that relapsing with bone pain and renal failure and is too late essentially for car. So um I will go through the card, the new uh the latest advancement that hopefully next year gonna be FDA approved for first line of therapy essentially for here after patients progressing on rev limit. So this is a cart tude four is a trial of Corti BC MA is a randomized trial. So a standard care, a standard of care control arm is Dora Palm Deck or Paldo Velcade D. This is mostly European, this is most in America. So a year ago, that was the most potent regimen that we could give anybody if you could, you know, in the first three las, as you can see this patients got Dora Palm De a year ago. That was a standard of care that if you go to any academic center, they will say uh Dora Palm. But this trial essentially randomized between Coryell and uh to a standard of care, Doral D for patients that are li refractory, they are uh relapsing in the face of rev. And in the first to three lines of after 1 to 3 lines of therapy and in the history of randomized clinical trial of myeloma in last 20 years, this is the hazard ratio of 0.26 is the strongest signal. Really we had is massive difference between uh Carol and control arm. And after almost 30 months, you still, you haven't reached to uh essentially the media and pfs yet. So, uh based on this trial, hopefully, next year, we're gonna have FDA approved for first after first line of therapy. Right now, this one is FDA approved for four lines of therapy. But uh soon enough, we're gonna have for first line of after first line of therapy. So, coming back to that patients. So if you refer these patients to Roswell after this line of therapy and instead of patients goes 1.5 years, 1.5 years, continuous therapy with Dora Palm, that pal you know, contraception, the uh blood thinner Dora every uh week or every two weeks, come here, get decks and doro and all of those continuous therapy versus one time corti that patient doesn't have any maintenance therapy. This is another beauty of corti versus continuous therapy. For the first time. My normal patients, they can enjoy a chemo free time, you know, always my own patient, they were on something is incurable. Disease maintenance or some continuous therapy. But right now, we have opportunity to offer a therapy that patients goes 234 years without any chemotherapy and surely comes to your office, get just ivig or myeloma check and so forth. So instead of going to 1.5 years only go continuous therapy with lots of side effects and so forth, we can offer a Cortico that side effect, let's say two months, maximum, three months and usually everything is reversible and there is no ongoing chemo uh side effect with chemo free period. Um So that's the uh game changing and that's what we need. If we want to serve patients as best as we can, we need a very strong collaboration between centers with low volume myeloma and centers that they are offering cards so they can pull car its very fast, very robust and so forth. So this is regardless of you have research on car tiel or not. I think that's the most for myeloma. I put this uh forest blood as a different subgroups that um essentially all subgroups as you can see very strong signal uh in any subgroup, high risk uh line of therapy exposed to Dora or not exposed to Dora and all of those uh details. And um as I said, the most of the uh the side effects from corti uh they're reversible. And in the long run, if let's say patients one year after corti, we don't expect that much side effects from carti everything resolved. There is no ongoing this car or active cellular alive therapy in patients that they last. Uh um usually in a couple of years based on, based on the data that we have. And um it's not just on c cultural always c cultural, they're criticized. That is the cherry pick. There is the selection virus and so forth. This is with another product, Car TL BC MA with the AEC but real world also, they could produce that 84 85 response rate that in clinical trial of Adema was there. So um in real world also really, we can produce such a good result. Obviously, there is lots of this is just infancy. I would say cores for myeloma as well as my colleagues. They mentioned other uh malignant him and other um uh cancers. But there are a variety of aspects that we are attacking um to, you know, hopefully we can cure myeloma at some point. The one of the uh main things is how we can make corti stronger, how we can make coric persist longer. Myeloma is one of those cancers that they have a very suppressive mi micro environment. So uh that uh car armor that bring your cytokine is very important. Hopefully, we can have it in myeloma space. There are a very push for allergenic Carico that uh instead of collecting from cells we can do off shelf Carol, uh there is lots of further genetic engineering to uh enhance uh carol ability to persist to um uh have a higher cyto toxicity and so forth that um is very exciting. I think 2 to 3 years you're gonna hear from Cardell way more than you know, right now, obviously. So I put uh some biosci uh data also to compare to some extent because by specific is very important also. So this is a phase two study essentially that uh tsum of 1.5 mg per kg, sub Q tsum is a biosci with BC MA. So the way it works, it brings T cells, patients T cells to myeloma cells that they are targeted with BC MA. So whatever has BC MA, it brings patients immune cells. So we are not genetically engineered BT cells like car T cell, we genetically engineer T cells and we re inject by specific, we rely on patients T cells, right? And bring it to myeloma cells with using a target is like bringing cops to bad people, right? If you have 10 cops, you can enhance their effect equal to 1000 cops by bringing them just like to bad guy, right? So, and overall response rate is around 63% here. So it's lower than cortisol across the board, but still it is very significant. This is after four lines of therapy and the problem with uh by specific, first of all is uh continuous therapy. So you have to get the treatment, to get the benefit of that. Um And another one is infection risk. As you can see, infection is especially first year or so, uh stays very high um and kind of a allergenic level of infection CMV activation, EBV, activation, mucormycosis PC P. All of those that uh is and the reason for that by specific because they use patients immune cells, patients T cells and already they are exhausted, it cause further exhaustion of the uh patients T cells. So instead of corti cell that we um essentially genetically engineer carti cell, you know, car hasn't been in nature, the molecule of the car we synthesize that right. Um And so with, with corti essentially, we elevate immune cells immune system to a new level. And um for by specific, not surprisingly, patients T cell fitness before by specific is very determinant of the response. Essentially, if you don't have a uh ft cells, you cannot rely on by a specific because by specific use patients own native T cells to bring it to cancers. And I wanna um this is conceptually is very important. Obviously, there are new targets for BC MA as well as cortisol. They are on the market already and they will be more and more. However, this is the fundamental difference between by specific and cortisol and future, let's say next 10 years, the let's say for biosci, this is the patients uh native T cells that are already exhausted. And this is the uh essentially uh target on myeloma cells. So this molecule bring these T cells next to myeloma cells, let's say, start with target A. So you have a good response. This is eekc, you have a good response and it further exhaust. If it lead to further exhaustion of the native T cells, you change the target B, you have more exhausted T cells, you have less efficacy. You go to C you have less efficacy and D at some point you get flat. Basically, you, this is a, a limiting factor for BCI that because you rely on patients immune cells at some point, you get to uh essentially sealing and that's the limiting factor. However, with car T cell because we genetically engineer T cell so you hit for A, you go a and patient relapse, let's say we losing A, you change the target to B you freshly genetically engineer another one. So really there is not much limit and you can sequence target to target and get uh patients to remissions long remissions. However, by a specific, because they rely on patients immune cells at some point, it will plateau is a conceptual framework for this the way I I think about that at least. And um I think it's important in future that because by a specific we can give to uh cancer patients that are in cancer in low volume centers, right? Um However, still this is main limitations and but Corti is another total animal. And uh next 5, 10 years, I think those gonna be main major player rather than this right now by specific, they are hot because we are in a still maybe B A mostly. But when it takes uh more time, I think the value of cortisol, it will be more uh I would say prominent and that collaboration between low volume centers and uh you know, big centers like Roswell Memorial. All of those, they're extremely important because if I wanna come back to that patients scenario, if really we don't see patients here and we go do upon, first of all, is suboptimal. If you go here, really, it is too late. If patients comes with renal failure and so forth, immune system is low and patients have myeloma symptoms and so forth. But uh I wanna just raise this awareness that we uh we, this is the really path of myeloma that is going forward and we are excited to build this collaboration. And uh uh I think my email everything, my phone is available anybody any time of the day or time week. Uh I'm available and my colleagues uh and we like to build this relationship uh to serve our patients. I think there is a lots of untapped resources in for myeloma patients in West New York that with card with the center like Buffalo, that gears to our Carol, especially for myeloma across all cancers. Obviously, but especially in my, because the pattern of care is evolving toward cortic base, those are very important. And I, and I stop here. I think I'm done here. Yep. Thank you so much for um the church. Ok. Yeah. Yeah, I know. Well, thanks to all of our speakers, they're gonna do a little bit of um re modification just to allow uh for some kind of Q and A I wanna again, thank our um sponsors of this Novartis. Uh to the left is Dennis Tripp. If you can stand and say hello, Dennis. There he is uh interesting fact about Dennis. He played football at the University of Florida and the New York Giants. So any, hopefully you have some Giants fans, Dennis is a great person to know. Great. Um And also uh shout out to the servers who've been doing an amazing job somehow navigating this very kind of small cramped space and get everyone of their food. Uh So I'm just gonna open this up just for questions from the audience. We also have some uh web-based uh I guess from the folks online with questions, but let's see if there's any here before I go to this uh device. So let me just get started here. Um I think this question is for you, Brian. Um What strategies are available to deal with the, the main problem with transplant now, uh relapse if, if gvhd is less of a problem. Yeah. Good question. So, can you hear me? I think the mics on, oh, there we go. Ok, cool. So, yeah. Um, right now there's actually several things are being done off label. Uh, people are using Veneta and azaCITIDine or H MA, either alone or with, then, um, there's actually a clinical trial ongoing right now. Um, looking at that, I think it's randomized between placebo versus Veneta clock and, uh, H MA, uh, in addition to that, we're looking at car T, so that's where the CD A three car um would have value. Um But tho those are kind of the things we're looking at. Even DL I, there's actually people looking at strategies for uh planned a back of donor lym infusion, uh whether they're T cells or even natural killer cells. I think in Minnesota they're working with uh NKS a lot too. I'll have a kind of, I have a follow up to that. Do you have any particular um agent H MA that you think that data look better for uh for um uh post allo maintenance? I don't know about better but convenience. Uh oral H MA is probably, you know, nice thing to think about. Uh sometimes patients don't mind sub Q though and that's something you can do. And uh there might be a little bit more uh dosing uh fine tuning you can do with uh sub Q or even IV, especially if you're gonna combine it with uh something like Mela where you're, you're may be a little concerned about uh my suppression. Uh One thing to kind of as a caution, you know, when you're using PT SI, there's a couple of different ways to use it. You can use it with tacrolimus. And mmf uh ideally, patients would be off immune suppression before you start using maintenance therapy. So you don't run into uh concurrent toxicities. Uh Sometimes pe people are combining sinus with PT SI and that can be a little more mild suppressive. So you gotta be a little careful when you're thinking about maintenance therapy there because it might be harder to give because uh neutropenia, right? I think this uh question is for, for Doctor Molly, the Excell gene therapy. What? Oh, happy birthday. Doctor Marley. You didn't tell me it was your birthday. Um The XSL gene therapy uh for non malignant um hemoglobinopathy. What toxicities are associated with it. So it's actually mostly um the toxicity associated with new. Do you get the, you know, uh phyto some um nausea, vomiting? They have just um a couple, there were like two cases out of all the patients where they developed like an HLH type cytokine storm um during the infusion of the Excel. But again, that was out of the 70 patients at all, I'm not going to. So the majority of the toxicities really are just associated with VLO bladed mu. So I actually have a, a follow up question to that because it reminds me of the, um, the Bluebird Bio uh gene therapy clinical trial where there are some patients that developed MD F afterwards, have anything like that been seen in these patients with the so far. But the follow up for those patients right now, um, on the Thalia 30 it's like 46 months and then for the sample. So it's on the 40 months. So we still have that long. Just take a little insight on the blue bio because I've also um chatted with them before. So of the three cases of M DS that they had in the sickle cell patients, um one was thought to be solely due to the self and conditioning because there was no vector found um in that particular M DS AM L case. So the other two, there were evidence of vector and actually it used to um off site uh integration of the life. And then similarly just I know we did talk about it today, but there's a gene therapy group of bio for um Adreno with a dystrophy which uses a different promoter and they also similarly against some antiviral waste vector. Um and they've had three cases of M BS again, related more to the gene therapy. So I think the CRISPR nine, like with, with this editing immune system, it does seem like there'll be less target editing. Hopefully there's some data still looking at that. We do need to do the work I'm just saying that it's not hard as well. Uncle Dinosaurs. Um I think this is a question best for the medical students. What cost Iy Domain is used in Tiso like Lucy CD 28 or 41 BB. Tik Tok Tik Tok, Tik Tok Tik Tok. Oh I like that. Good. Correct. Um III I used that question just because of our, our host, the, this generally Glu Krya. I'm I am a CD 28 person. So I was behind some of the technology that used uh the CD 28 coast in military domains. Uh But I wanted to, to be, you know, acknowledge our grateful host for, for tonight. Um Doctor Mali, a question for you. What are, what clinical trials do you have available uh for uh Igus uh monoclonal uh GM of unknown significance. That's a very uh I think nice uh point. Uh Unfortunately, MCO space is or a smoldering myeloma, in fact, uh is a space that nationally we don't have much chemical trials in Swan. Um And I, I like to bring it here is one of the dendritic cell vaccine that uh we wanna try it in M OS Space. Um And hopefully we can get it running here. Uh Other than that, you see MGUS is a pre-cancerous state and I think the vaccine approach it fit very nicely in that space because majority of NGOS are never gonna have myeloma. So at going to chemotherapy and so forth is too much essentially. But vaccine like uh let's say you have vaccine for preventing cervical cancer and so forth. So, with prevention of myeloma in the end, God's uh predisposing condition, I think uh uh that such as the vaccine, that is a cellular therapy, uh it can be, can be crucial. We are working on different targets, including some of those car cells that hopefully we can offer it to M people And it could be very. Now, I have a question for all of the pan uh the panelists. Um since this is kind of an opportunity to have these folks here in Central New York to meet us know about us. I would like the Panelist to each. Share one. Interesting fact to, about themselves. I'm gonna start with doctor bets because I know him the longest and he's got lots of them. So, just, just one, please. Brian. Yeah, just one, just one. I was, I was a DJ for a while before med school. Yeah. Yeah. It was a DJ. He was a college DJ for a while and I'll throw another one that you played drums for. Was it a Latin ska band or Latin jazz and a punk band and a punk band? So he, he's anyone who has an opportunity ever to spend 10 minutes with him, you know, it's, it's always a fun conversation with him. OK, Doctor Matlick, you're next. So the fact should be odd or fine. Anything that's good to know you, you've been here the least. So I need, I actually need to kind of know you appreciate it. So, um I would say one of the things that my friends get surprised when they hear is I, I run barefoot and I started like, um, it could be a problem in Buffalo. I throw that out there. You know, I come from Cleveland, I'm not coming from Florida, So I, I'll send you a tweet. So around 2000, I think 17, I would say I start doing that. And Toland obviously, you know, the, the and so forth. So I wear socks that is not waterproof but keep your coat together. So you don't get frostbite, but I didn't run when we have more than one fee of the snow and so forth. So Buffalo, I think there are higher number of, uh, days. But, um, but it's fun. I mean, you know, I, I ran much faster and easier than before bare and, um, it looks odd but it's fun. I can talk with you personally. I don't wanna go more details at all. I don't want to stop. What's that? Oh, is that right? I don't, that's my estra. I can give you my estra. I will, I will share one other thing that I cannot verify yet. But I hope to soon, Doctor Mali claims to be an ex excellent, uh, meat smoker. Right. Well, that is li, yeah, but my boss Rain is so our boss, Doctor Brinch claims to be an excellent barbecuer. So I've, I've already, you know, laid it to him that there has to be a, a barbecue off and I will be one of the judges. I think. I think he has the quality gears than me. That's important. But I'm happy to compete anytime. All right. Uh, Doctor Molly, anything as interesting as those two. So, um I'm Canadian. I don't know if that's a good, I think so. I don't have a winter coat. Oh, my, go up to Toronto. They, they have a, a goose and they have, I've been to that there. They have a cold room so you can try on this stuff or you can just, you know, be in Buffalo. I need a storm last time around Thanksgiving. So I get that jacket decision. Well, I don't wanna let my kind of colleagues, uh you know, alone in this. So I'll say um uh I am a huge hockey fan. I have uh season tickets to the Sabers and last slide as part of the hockey fights cancer thing. I had dinner with Don Granato, uh the head coach of the Sabers and it was a really kind of amazing evening. If anyone ever wants to talk about cell therapy and go to a hockey game, please let me know. I, I got these two tickets thinking that Brian from Minnesota would love to, to watch hockey with me, but he's not a hockey fan. So I, I can be, I can be all right. Well, I think actually that's all the questions uh that we had. Um So I think everyone should just kind of enjoy their food and I just kind of ask to you all sit and maybe mingle and, and if you want to torture the medical students, torture the medical students off, off camera, off camera. Sounds great. Thanks. Yeah, thank you.