Dr. William Wierda discusses the rapidly expanding role cell therapy is playing in cancer treatment while delving into clinical efficacy, cost effectiveness, and potential future growth.
Back to Symposium Page » Hi, everyone. Welcome back. I hope you have enjoyed the morning session thus far. I would like Thio take a moment to introduce our next speaker. It's my honor to introduce my Steve colleague, Dr William Weirdo, who I had the wonderful opportunity to work with when I was the director of inpatient leukemia services at M. D. Anderson Doctor were to move to Houston as an assistant professor of medicine department of leukemia at M. D. Anderson. He was promoted to associate professor in 2007 In 2012, he was promoted to professor professor and continues his focus and clinical and translational research in CLL. Dr Weirder outpatient clinical activities are more than 90% dedicated to treat treating patients with CLL attendee Anderson. Dr Weirdo has been a P I CO p I and a collaborator on numerous clinical trials and conducts translational research in CLL. He has published many peer reviewed articles on various clinical and translational aspects of C, M. C. L. L and Drug development. His focus research in CLL is prognostic factors and development and developing prognostic models in cll immune and gene therapies for patients with CLL. Today, Doctor, we will share with us his expertise regarding car t therapy. And we welcome Dr Weird. Uh, thank you, Patty. It's It's a pleasure to be here on day. It's a pleasure to see you, Patty. Um, e don't get to see you as much as as I used to. So, um, and thank you for the kind words assed Patty said I have been here in MD Anderson for several years since 2000, and one Onda have worked in CLL that whole time. Um and also more recently over the last several years have been focused on car t cell therapy for patients not only with CLL, but I also am the p I for Carty trials in l. L. So other of the leukemias that we deal with, um, I have coordinated the clinical trials for those for those diagnoses. Um, this there is quite a bit of information on car t cell therapy for cll. Um, and my understanding is that the audience is predominantly nurses and physician assistants. Eso I will sort of orient my discussion and review of the data. Um, in that regard on DLA in terms of the laboratory and scientific aspect, Andi, hopefully give you a good understanding of car T cell therapy and how that relates to CLL. Let's see if I can get these sides. Okay, These air, my disclosures. Okay, so I'm going to start with some background and then we'll get into the data for chronic lymphocytic leukemia. If you look on the left side of this slide, you see how T cells normal T cells interact with other cells. Those other cells may be normal cells or viral infected cells. And this cartoon it's a tumor cell on the T cells will recognize, um, antigens or proteins on the surface of, uh, tumor cells on day. Do that through the T cell receptor. When that T cell receptor gets triggered in the in the T cell that activates the T cell, and it will then divide, activate, make side of kinds and expand. And it also, um, may be triggered to kill the tumor cell. Um, and eso this technology and the strategy takes advantage of the fact that these T cells are professional immune cells that ordinarily react to a particular, um, particular protein or peptide. Um, and um, that mechanism is, um, sort of hijacked with a, uh, gene that's inserted in the T cells that retrain the T cells to recognize a different protein that is potentially on the surface of, um, of of a tumor cell. So, um, a gene for a chimeric antigen receptor is placed in the T cell. Um, and it's expressed then on the surface of the T cell in the strategy and that allows the T cell, then Thio engage. Interact with a tumor cell, become activated. Andi ultimately kill the tumor cell. The's T cells still express the T cell receptor on their surface, but, um, they are able to recognize the target Auntie Gin here in red through that expressed King American crime. Eric androgen receptor. There are various forms of the crime Eric Energon receptor that have been developed over the years. Andi, they're referred to as first generation, second generation and third generation. Um, all of those generations have on the surface of the cell the energon binding sites. So that's reflected in these, um, blue boxes. This portion of the chimeric antigen receptor or car is what recognizes that tumor. Auntie Jen Andi. It's made from an antibody genetically engineered from an antibody on gets a single what's called a single chain variable domain, and it allows the car to bind to the particular an agent in the in the examples that I'll go through for CLL that Auntie Jen, um, has been CD 19. Um, other antigens are have been studied, are under investigation. Um, so there's the external binding domain of the car. There's a trans membrane portion that spans the membrane and then inside the cell are signaling proteins or signaling domains. In the first generation, that's just the 503 Zeta. So that is the internal portion of the car that will activate the T cells when the T cell the car binds to CD 19. In this example, that single, um, activation signal that comes from CD three, um, was was not enough in the clinical investigations and the laboratory investigations that were conducted early on, Um, and what was needed was a second signal in addition to the C D three zeta signal. Um, and that is the reason why a second domain was, um, spliced onto the receptor. Um, in this example, it's either CD, CD, 28 or for one BB. Andi. What happens then? with the second generation is that the binding domain will bind to C D 19, and it triggers activation and signaling through CD three Zeta and then a second signal from either for one B B or C D. 28 eyes provided, and that is a better way to activate the T cells. They become more fully activated. There's a more robust expansion of the cells. I'll describe a little bit of information about the difference between for one BB versus 128. Um, but with this construct with the second generation, the T cells were much more. Um uh, much were much better and more effective at, um AT T cell activation and expansion. The third generation There's very little data clinical data on the third generation construct. The third generation construct will have two of these, um, other activating domain spliced on. In addition, Thio CD three Zeta. So this the third generation has three activation signals to of the co stimulatory molecules. In addition to city three Zeta. This may this construct may over activate the T cells because one of the challenges we have with the car T cell therapy is the side effects and toxicity is that we see with it, um, things like cited kind release syndrome and neurotoxic city on DWI. See those with the second generation construct with the third generation construct, we worry about those being more severe and being a bigger challenge on We'll talk a little bit more about, um, the features of those Sadiq Khan release syndrome and neurotoxic city and things that strategies that we're working on to get rid of thumb. This animation just illustrates signal one and signal to that is seen with the binding of CD 19. In this example, Um, cll cells are B cells. They're malignant B cells. There are other diseases that are the result of, um, and a malignant B cell. Um, this cartoon shows B cell development. On the left is a very early, immature B cell. On the far right is the plasma cell, which is the most, um, mature type of the so So you can have B cell malignancies arising at any of these steps. Um, and as a result, some of the markers that we see on B cells are expressed on these various B cell malignancies for cll, which you can see here in the middle of the of the slide. Um, those cells, um, expressed CD 19. They also expressed CD 20 as well as other B cell malignancies. Um, and that's the reason why CD 19 was selected as the target for the Carty because SETI Nineteens expressed in these malignant cells, CD 19 is not expressed in normal tissue, so you don't run the risk of reacting against normal tissue and having an autoimmune problem. Um um and um, the one challenge with the strategy is that C D 19 is expressed on normal B cells. So we worry about elimination of normal B cells and immune deficiencies being caused by this treatment strategy. Because if the's T cells that air expressing the car doing what they're supposed to do, they should be getting rid of not only the leukemia or the malignant B cells. They also will get rid of the, um of the normal B cells. Now, fortunately, CD 19 is not expressed on this far left. Sell the stem cell so that your bone marrow can make new B cells, even if the, um, the car T cells eliminate the more mature normal B cells um, but it is immuno suppressive. Potentially. Um, this slide summarizes the different constructs that have been used in clinical trials. Um, there are are three main constructs that have been used in clinical trials that have been further developed by commercial, uh, entities companies. So the first one on the left is the one that's been developed by Kite Pharma and is commercially available. That all three of these buying two CD 19 The This Kite construct has a CD 28 signaling domain. They also have a construct that has a 41 b be signaling domain. The middle one is the one that Novartis has developed and is commercially available. That is a 41 BB ended domain, and then on the far right is Juno's construct, also with a 41 B B, um, and the domain. And again, uh, this slide illustrates what may what? You may see a difference between the end of domains. Thes slides show you expansion in a patient and their hypothetical, but show you expansion of these car T cells once there, um, transfused or infused into a patient. So on the left, this is a CD 28. Um, unexamined of a CD 28 car where you see a rapid and high peak of these, um, car T cells after their infused in the patient, and then they taper off over a month to two months. Um, and that's in contrast to the pattern you see with the 41 BB. Where you don't see is rapid arise, and you don't see us high a peak. But you see these cells lasting longer. And that's important because we think that those cells need to persist in patients for some period of time in order to do all of the work that they need to do to get rid of, um, the critical number of cancer cells in order to potentially cure patients of their disease. Um, eso where both of these constructs have been in clinical development and are commercially available. There are differences in terms of, um, what we see for expansion, activation and expansion of these Carty's as well as persistence. And we think persistence is is important, particularly to give a long term response on day. Keep the tumor away, whether that's BC, uh, diffuse large B cell lymphoma or CLL in this example, so there's a process behind how this works. Patients with leukemia CLL, for example. They undergo a process called a fairy sis, where, which is similar to dialysis, where a needle is placed Onda A machine pulls off the white cells, which are enriched for T cells. Normal T cells, those air then, um, in a placed in a bag and transported to a laboratory where they are infected with a virus that carries that car. Gene, um, they're expanded in the laboratory. They're tested to make sure that there of sufficient quality, too put back into a patient, and also that they don't have any bacterial, infectious agents or anything. And once they're cleared, their released for infusion into a patient. Um, so this is the These are the steps for production of the car. T um, the process for these patients is illustrated in this cartoon. I just showed you the look of Charissis and the Luca freezes is the process of removing the T cells for transaction. They go to the laboratory for um, production. Once we have a product that's ready to be given to a patient, patients receive what's called Lin Foh depleting chemotherapy or conditioning chemotherapy. This is a lower dose of chemo that prepares the bone marrow and the body for these T cells and makes for an environment that, um promotes expansion and growth and activation of these car T cells. Um, you don't see that expansion if you don't give the Olympic depleting or the conditioning chemotherapy. So this this chemotherapy step is important, and it helps with expansion and growth of these cells so limpid of pleading chemotherapy. Air conditioning chemotherapy has given a few days before the the Carty's are given. The Carty's are generated in a laboratory, and then usually they're frozen and then shipped to the treating center on Ben, either at the bedside or inthe E cell processing. Um, laboratory there, thought and infused into the patient. And then we just wait. We mon weight and monitor patients for side effects and toxicities, and during this waiting period, the T cells, the car T cells come in contact with C D 19. They become activated. They grow and expand and make all of the chemical messengers, Um um and um are trained to react and eliminate the tumor, the cancer, the CLL in this case, and then in a month, two months, three months. We do response assessments to show that patients have responded to treatment. This figure summarizes, um, some of the chemical messengers that are made by these Carty's when they become activated and other cells of the immune system. Um, and it's the production of these different chemical messengers that are the reason why these patients can develop the side effects and toxicity profile that they do. So on this figure, you can see the conditioning period. Carty Cell infusion here is shown in red, and, um, during this conditioning period, the body does make some side of kinds of chemical messengers. Again, I mentioned that the chemo is given that, and it creates an environment that's conducive for expansion of the cells. This environment is because of the production of these satya kinds that you see here. I'll two, I'll seven and I'll 15. And then after the Carty infusion, you get production of other side of kinds. Um, that peaks after a week to 10 days of infusion. And it's during this time that the cells have become activated, their dividing their growing, Um, and it's these side of kinds that are predominantly responsible for the cytokine release syndrome that we see with the car. T Cell therapy cytokine release syndrome is usually, um, results are gives patients symptoms such as fever, low blood pressure, um, low blood blood oxygenation, thes air, the things that give patients a flu like symptoms. But the flu like symptoms can be very severe to the point where patients may be very hypertensive, require medications to keep their blood pressure up, and may also require, um, uh, intubation mechanical ventilation transferred to the I C u etcetera. We've learned a lot more about the cytokine release syndrome. The fever that we see during this is predominantly related to the aisle six. That's made, um, and we have a drug. That counter acts the aisle six that's produced that drug. We have a couple drugs, actually. One of them is called cell Taksim AB. The other is called Tosa. Lose a mob. So Tosa lose a mob is the major drug that we use, um, to counter counter the effects of vile six and we use to treat Sadiq Khan release. This is very effective, usually at reducing the fever. Andi, also helpful for other manifestations of Sadiq Khan release that we see hypertension. Um um etcetera. The other drugs that we use because it does potentially eliminate or kill some of these expanding cells is steroids. So Dixon methods own or so you may draw. We also use if the cytokine release syndrome is very severe. So during this expansion and growth period, we can see Sadiq Khan release. We can also see neuro toxicity. We have less of of ah, complete understanding of the neuro toxicity that than we do with of cytokine release syndrome. Um, the the they can happen independently. They do frequently happen together. Sadiq Khan release and neuro toxicity. Sometimes the neuro toxicity is worsened by the Sadiq Khan release that scene. So if they're occurring together, we always treat both, um particularly with socialism ab um and um frequently, if we get the Sadiq Khan release under control, the neuro toxicity does improve. Now we can see the neuro toxicity in the absence of Sadiq Khan release syndrome and those instances, it's not uncommon for us toe Have Sadiq Khan release fever, hypertension. We treat that those things resolve and then, a day or a few days later, the patients can have the neuro toxicity really the predominant, um, treatment for the neuro toxicity. And that situation is the steroids to eliminate or reduce the number of these activated Carty's, um, as as treatment for the neuro toxicity. But both of these air very manageable. Andi. And have been a challenge in development of this treatment. Um, having trouble going forward? Mhm. Mhm. Okay, All right. So that's that's the basics of car t cell therapy. Um and so I'm gonna go relatively quickly through CLL, and I'll highlight a few of the clinical trials for CLL and where we're at with regard to CLL. So CLL is the most common type of leukemia. Um, and there are features of the c l l that are unique and unlike other leukemias that we deal with, some patients don't need treatment. We only treat when patients have active disease. And there are features that we evaluate for patients that tell us ah, lot about the prognosis of the disease and those air summarized here and we need to know these prior to starting treatment. Now, car T cell therapy for CLL has really been limited. Thio re lapsed disease patients who have been treated with the standard treatments. Onda failed those standard treatments. Um, then become eligible for Carty Cell therapy. Um, but we look for chromosome abnormalities. We look for gene mutations. Um, and we also looked for mutations in genes that are used for targeted therapy, for example, B t. K Um, But the important point here is that we do have factors that we evaluate and we can use. Those factors toe identify high risk patients with, particularly in the relapse, refractory setting and those air the patients that we've put on clinical trials with Carty cells. I'm going to skip over these slides because they review standard first line therapy. My comments on re lapsed treatment for l are summarized here. When patients have relapse disease, that means that they've had the standard treatments. Andi Previously that was chemotherapy. Now it's sometimes chemotherapy. Um, but usually targeted therapy on DWI have targeted therapy against a protein called B d K um, and that those targeted therapy those the drugs that fall in that category are I Britain Ebb and a calibrated nib. Um, And then there's targeted therapy against another protein called BCL two Onda drug that targets. BCL two is called Veneta Clacks. Um, and so the landscape for relapse cll has changed a lot because previously was limited predominantly to patients who had failed chemotherapy. Now they have a lot of treatment options. And so the patients who are going on Carty self trials tend to be ones who failed. Um, not just one prior standard treatment, but multiple. And it's becoming less and less chemotherapy as a prior treatment but and mawr towards targeted therapy on the right, you see treatment options for relapse patients. And really, the goal of treatment for these patients is long term control of their disease, which we can really effectively do with the targeted therapy. However, patients do are developed resistance. And as I mentioned, there are some features, like 17 p deletion and mutated TP 53 that are those patients are at high risk for developing resistance to all of these treatments and have, um, shorter survival and and poorer outcome. We don't use chemotherapy so much in the re lapsed setting. Um, okay, so let's go through some of the car T cell data for CLL. Andi. I think it's important to put it in perspective with other be some malignancy. SOCAR T cells have been developed for patients with acute lymphoblastic leukemia. There's a Carty product approved for pediatric l l. There's a Carty product, and that's targeting CD 19. There's a product, and I'm not going to talk about it. But there's a product also more than one product approved for diffuse large B cell lymphoma. We don't yet have a product that's approved for CLL. Andi. These trials really are directed towards having, AH, product that's approved for patients with SEAL. We evaluate response to treatment in terms of the remission for l for l. L. We focus on complete remission as an important endpoint where we're going to get a much longer period of disease. Control of patients achieve a complete remission than if they just achieve a partial remission or they don't get a remission from the treatment. The thing toe highlight here is that if you look at the data for the trials with for Al L with the Car T Cell CD 19 Carty and there's a fair number of patients, and as I mentioned, we have products that are approved, the CR rate, the complete remission, Aidas Hyatt's 80% or higher on those studies. If you look at the bottom part of this slide, Um, although they're much fewer patients, it's a more limited experience with either the CD 28 or the 41 BB product. We see a much lower, complete remission rate and and we're still working on trying to figure that out. We think it's because the immune system is dis regulated, including these T cells that we get from patients with CLL. But this regulated and don't work. Aziz well, as as the T cells from patients with other B cell malignancies like yellow and diffuse large B cell. So the early reports reported about a 25% complete remission rate, which is low for car T cell therapy in patients with CLL. This slide shows you mawr trials and predominantly. Among the the experience at this time was mawr with the 41 BB construct. But again, you can see here if you look to the far, um, right column a complete remission rate of in the order of 25% lower than for a l l, um, and for D l BCL the future large B cell lymphoma. Um, I was gonna highlight a couple of the of the trials. This was one of the first trials, and you can see when it was reported back in 2011. So Carty work has been ongoing in CLL for many years on get started with the 503 Zeta first generation construct and then subsequently moved into the second generation. Work on dis is a small Siris of patients that Ryner branches from the Memorial Sloan Kettering Group reported on this same group also looked at, um, car T cell therapy early on after chemotherapy for these. So these patients received six cycles of a standard regimen for, uh for their disease with PCR, Penta, statin, cyclophosphamide and rituximab. And then, if they had measurable residual disease, were given car t cell therapy. Um, at the three different doses that you see there and in the limited number of patients treated on this study, you can see there were patients who responded by converting from partial remission after chemo to a complete remission after the Carty and those responses, um, were durable, but again somewhat limited in terms of the response rate. Uh, compute eso the three main groups that have done the early work with Carty were the Memorial Sloan Kettering Group that was the Rainier Branches and Jay Park data I just showed. The second group is the U Penn Group. That's the group that has been led by Carl June. Um, and, um, David Porter has reported their data from U Penn. And then the third group has been the Seattle group at the University of Washington, led by David Moloney. So this is the second generation Carty, um cohort with a 41 BB construct, 14 patients treated. All of these patients had relapse refractory disease. I've highlighted the patients who achieved a complete remission in the yellow, and you can see four of these patients achieving complete remission on does responses were relatively long lasting. Andi In these trials, the singer Single Center Trials work has been done, uh, in the laboratory to try to get a better idea around how these work, who's likely to respond on DWhite does the response. What are the characteristics in patients who respond? So one of the things that was reported and learned is that patients who have a better expansion of the car t cells after their administered are more likely to get a complete remission. And that's illustrated in this, um, in this figure, eso um you can see the patients who fall into the responding category. Complete or partial responses have a higher percentage of Carty, uh, cells measured in their blood after infusion and also there longer lasting. So the top row here that I've highlighted in the red box are patients who achieved complete remission. And you can see the car t cells being, uh, persistent in the blood. Um, in the longer follow up among these patients, compared to the patients below them achieve a partial remission or who don't achieve response. Um, where the car t cell count goes down during the follow up period. Expansion also correlated with toxicity. So we see a higher toxicity in patients who have, ah, greater expansion. Um, but persistence is important for response and durability of the response. Um, uh, there has been less data supporting selection of a dose. Um, but we do tend to see higher toxicity in those patients who receive a higher dose of the car T cells. This is a trial that was done by the U Penn Group. Patients were randomized to receive one of two different doses. Ah, high dose or low dose. And you can see in this cohort of patients the response was relatively low. 2022% complete, um, remission. Overall response was 35% and this trial didn't really show any difference. Um, in terms of toxicity or in terms of response, Um, but the numbers of these patients is relatively limited. It's, um and then this is data from the from the University of Washington group. I think I'll go through these slides quickly. Um, there's a lot of information in here, but again, it highlights the responses correlating with expansion of T cells and the quality of T cells, car T cells that air given and how long those T cells last in patients. Um, and there are data that show, uh, persisting responses and durable responses In the early data, we talked about a plateau on the curve where patients went into remission and their disease did not come back in longer. Follow up. Those data are relatively limited. We're still looking for plateau in the long term. Follow up from these data, um, and most of the work that's been re then most of the work that's been published so far has been work that's come out of single centers. Um, there is one trial that I'm going to show you. That is a multi center trial that was sponsored by Juno Andi. It's actually the first large sponsored study that has data available that's being reported. Um, there has been some work, and I'm not going to go in detail. Over this has been some work that gives insight into the fact that T cells from patients with C L L don't work well. And they produce a inferior product, um, in the lab compared to normal donors, um, and compared to patients with other B cell malignancies. And they have been studying this and trying to figure out why, that is. What is it about patients with CLL that disrupts their T cell function and makes their T's tells, not work as well. We don't have a good grasp of this. There is a drug that may correct this in part, and that is a Britain it and so there's been data that's been published that has shown a better product that is made from patients who are on I brutes and when they're t cells have been collected. Andi used for production compared to patients with CLL who have not been on I brutes and in prior Thio harvest Um, a fairy sis and harvest eso. This is data that just shows you normal donor T cells expand beyond activate mawr efficiently and readily than T cells from patients with cll. Um and that's also illustrated here and then there. These are data that show that patients who have been on my brutes in it, which is a drug that's used to treat cll um T cells that are collected from patients who are on i brutes and make for a better, more potent product. Um, car T cell product, when they're used for production, compared toa T cells from patients who are not on a routine hib that has translated into clinical trials. Um, that have been reported two of them, in fact, one from the U Penn Group and one from the University of Washington group. Um, now it's one of the University of Washington group did make a comparison, um, based on their historic response rates and outcome um, and and I'll show you that data. But it's not totally clear that patients do do better with Britain if they're on my Britain. And when they get their Carty's eso that's still in area of clinical trial and investigation. Um, this slide just summarizes again the fact that the response rates are higher NLL compared to CLL that's illustrated here at the top on the left for L L. And on the on the top on the right for CLL. And this figure in the middle shows you the persistence and the potentially the plateau with long term, non relapsing patients who have long term remission and don't relapse after their car. T cell therapy. So, as I mentioned to, groups have looked in limited numbers of patients at car T cell therapy in the presence of a brutal nib on DSO. This is one of the data sets on, but it's about 20 patients who were treated. They were all relapse patients, Um, and the other thing it relates to toxicity and its better illustrated in the University of Washington trial, which I'll show you in a second. But certainly there isn't certainly the car T cells work in patients who are on a routine if they continue their I brew tinted. So we see responses. Perhaps the response rates a bit higher on bats again illustrated here in a limited number of patients. So six complete responders out of 14 at three months, Um, but again, it's limited numbers of patients, and it's hard to be definitive about, um, whether or not the response rates higher. Um, and we do see persistence among those patients who received the Carty and continue on their A brute nib. And the persistence is shown here. The light blue curves are the Carty numbers in the blood after treatment, the dark purple are normal B cells on dso, you can see, um, a reduction in the normal B cell count. So if you take if you take the first upper left hand corner, uh, figure you see, with treatment, the number of normal B cells goes down. It stays down as the Carty's um, expand. But then the car T cell number goes down and is undetectable for long term follow up, and at that point, the normal B cell count goes up. That's different than the figure below it which is in the middle on the left, where you see a reduction in the normal B cell counts as the Carty goes up and the car T cells persist, and while they persist, your normal B cells stay down. And we think this is probably, um, or ideal scenario where you have some persistence. You still have these car T cells working on getting rid of any residual, um, leukemia cells, Um, in in long term. And when patients relapse, it's usually in a situation where their car T cell count goes down to zero and you can detect, um, not only normal B cells, but also malignant cells. Okay, so that's the U Penn data. This is the University of Washington data, and I'm just going to skip through to the responses. These were all previously treated patients and as I mentioned, they compared Carty plus I Britain eb with um no, I brought in ibra Carty alone, 19 patients in the combination versus 24 the in the mono Carty. Only on day they made a statement that the characteristics of the patients were similar. They didn't see any toxicities that were concerning when they added i Britain ib Um and they did see a trend, as you can see here for improved responses. So 83% versus 65%. But it wasn't statistically significant. And 85% Mardi or minimal residual disease free, with the combination versus 50%. So a trend toward improved efficacy but not statistically significant but at least worthy of further study on day did show also data on expansion of the Carty's being more favorable when, when the Carty's were given with a brutal Neb, which is in the red, you can see a higher level of Carty here compared toa No, I brought in it, which is the blue both for CD force and CD eights a minute. And then the other important feature from this study is toxicity. So this is side of kind release syndrome. Um, and you can see if you look at the on the on the far right 25% of Grade three or higher side a kind release with no i Britain IB, which went down to zero among 19 patients when patients were treated with Britain s. So perhaps there's an improvement and effectiveness. Andi also perhaps there is a reduction in, um, in toxicity and severity of toxicity when you give the Carty's with a brutal nib for these patients. So the commercial try Alehouse has with Juno has moved forward with a cohort of, um, I Britain. Plus Jake are 17, which is the product I'm gonna finish up here in the next few minutes with Commercial Trial, which is Lissa Cell or Jake Car 17. This has been reported at a few meetings. It's going to be updated at Ash. There's two cohorts. There's a monotherapy cohort, and then there's a combination cohort. I'll be presenting the combination cohort for the first time at Ash in a few weeks, a couple weeks. But the mono therapy has been reported on going to go through that data. Uh, here again, it's the same strategy of, um, Linford Depletion a fairy sis, then Linford depletion than treatment and monitoring for follow up this try a Len Rolled patients who were previously treated and um had failed B t k inhibitor, which is a standard treatment that we have for CLL now. Um, and um, it studied two different dose levels of Carty, um, to evaluate tolerable ity toxicity and effectiveness on do you conceive for 23 patients, nine were assigned to the low dose level and 14 to the higher dose level. Um, all of these patients again were previously treated. These were just the patient characteristics. And they are a high risk group because of their prior treatment and failure of prior treatment thes air the toxicities that were reported, um, including cida kind released. So you can see 74% of the patients had any satya kind release. 9% of them had great three or higher. Um, which is a reasonable amount, um, of Saida kind, severe cytokine release among these patients. And relatively Well, um, tolerated. Um, we also reported on neurologic toxicity, um, which is shown down lower here. Um, on the figure, the the incidents of the neuro toxicity was a bit higher than the sight of kind release. Um, and then those air also summarized here. So again, Sadiq Khan, release grade 39%. 22% for grade three or higher. Um, neurotoxic city. And then these air the responses. So we evaluate for complete remission, partial remission or non response, and those were shown over here on the left and you can see, um, 45% or 40 45.5% of the patients treated here chief to complete remission. That's a bit higher than had been reported in the single center studies. This transcends study is a multi center commercial, um, commercial supported study. So there are many different investigators at different sites that participated in this study. 36% partial responses. Onda. We did see responses in patients who had failed the standard prior treatments, and we also evaluate for minimal residual disease. Weaken, evaluate in the blood and we can evaluate in the bone marrow. The dark bars here are blood. The light blue bars are the bone marrow, and you can see a high percentage of patients achieving undetectable M. R. De Onda. That really reflects the depth of remission, how deep a remission these patients are getting, and those remissions are durable. And that's reflected here in the in the swimmers plot eso you. You can see patients with the arrow at the end Here the swimmers plot our patients who continued to respond. Now there are some patients who do have progressive disease. There were several patients so far who have had progressive disease with what's called Richter's transformation or conversion to, um or aggressive form. But, um, the follow up thus far has been relatively short. But we do see durable responses for these patients, and that's important, I think, because these patients have failed standard treatments. Usually their responses are not very long, but we are with this treatment seeing longer responses. And Thea update for this data will will be presented again it ash blonde again with longer follow up. So we'll have a better idea of how long those responses are lasting. This is my final side and just summarizes the concepts around car t cell therapy. Andi, where we're going, um, we're trying to figure out how to make it more effective in sale. It's very expensive treatment eso for l l. And for diffuse large B cell lymphoma, A product can and treatment can cost between 300,000 and $500,000 for for a patient, um, for a treatment that Onley achieves a 25 to 30% complete remission rate, that seems very expensive to me. So we need to bring the cost down. We need to make it more effective in patients with CLL. There are strategies that air directed at doing that. Um, it is relatively well tolerated in in CLL. We have less, um, challenges in CLL with Sata kind release syndrome and neuro toxicity than we do for patients with a little getting this treatment for sure. Um, and we're working towards strategies of what's called off the shelf product. Because Aziz you saw with this data the product was generated from a patient after a ferry sis, and that production time usually takes 3 to 4 weeks. Sometimes patients don't have that timeto wait for a product because their diseases so aggressive and needs to be treated, um, with something that's effective to get control of it. And they patients can progress during that production time, Um, if they have very refractory disease. So there are a number of efforts that we're working on, and, um, and strategies. It's a very promising treatment, but as you can see and as I think, you can probably tell, we have a lot more work to dio eso. With that, I'll be, um, I'll be happy to take questions and thank you for your attention. Thank you, Dr Weirdo. That was very interesting. And, uh, I would agree of ever evolving field that we have a lot to learn. We have a few questions for you. Uh, first question, Is there a standard conditioning chemotherapy regimen? Um, seeing through their opinion, cyclophosphamide being done pre Carty. So there isn't one particular standard in terms of dose. We have worked on various lin foh depleting, um, regiments. We have used cyclophosphamide by itself. We've used flu. Tara Bean. We've used Benham. Houston. Um, I think the consensus is that you need both food Arab in and cyclophosphamide. So currently, most people are using both cyclophosphamide and flood Arab in, um, not really. Anything else. And the doses for those will vary by the clinical trial that's being done. So yes, they're standard is is, um, cyclophosphamide. Flood era being doses will will vary. We're not really using anything else for Linford depletion. Thank you. Next question is, does the aisle six or steroids decreased efficacy. So that's a great question. That's something that we have worried and worried and worried and worried about. We worried Maura about steroids, Thantos, Alou's Ahmadiyah, and, um uh and I'll six. So Tosa lose a mob? No, um way did to a trial in a little while we were looking at Prophylactic Tosa. Lose a mob, um, giving patients Tosa lose a mob before they got side of kind release as a way thio reduce the incidents in toxicity with treatment that was not a, um, positive study. So we don't do Tosa lose a map prophylactically. We just give it if patients are having, um, having having side a kind release that needs to be treated steroids We worry more about, um, being a problem with effectiveness, although with lymphoma they have done analyses and have not shown and have not shown any compromised of effectiveness by use of steroids and patients who are getting it for side of kind release. So there isn't any data that so far has been been generated that shows compromise of effectiveness with the use of steroids. But we still worry about about it and are cautious about using steroids. Okay, uh, next question is do tumor cells down, regulate and ch that make them more difficult for T cells to see if that's the case to the car able to overcome this. Some tumors as the mechanism to evade the immune system, do down regulate MHC. So MHC is what's used for normal T cell recognizing tumor cells or normal cells. So you need MHC Class one Class two for the T cell receptor to engage and react. The Carty gets around that mechanism, so if you have a car that's expressed on a T cell they don't need on, they don't use the MHC. They don't require MHC toe, engage and activate and react against it. So that's the beauty of the Carty. It's a way that you sort of hijacked the immune system and hijacked the T cells to react against against the tumor cell. And it would work ends Tumors that lose MHC because that is a mechanism by some tumors to evade the immune system. Eso. The next question is we have complete response in um El El in 25 CLL. What is the C, R and B cell and be so like lymphoma? It's 40 to 50%. If you look at the diffuse large B cell lymphoma experience, I believe it's about 50% of the patients get a complete remission and those complete remissions are durable, complete remissions. Is there any influence of the microbiome on cars? I am not aware of any data that has shown that the microbiome effects um the toxicity profile or the effectiveness of Cartier in Carty treated patients. Are there any biomarkers that can predict response that can predict toxicity in aisle six? Um, there s o prior to treatment. There really aren't any predictors of response or side effect profile or uh or toxicities that patient experience. Um, once patients are treated, we do look at things like ferret tin and C reactive protein and I'll six level And those things will change as patients develop side of kind release so you can monitor them in patients who gets out of kind release. But they're not really predictive because they go up as you're having the that side effect or complication. What would be ideal is if we had some test or measure that would say before treatment. Yes, this patient is highly likely Thio have bad side of kind release or have neuro toxicity and those if we could identify those patients at risk before they get treatment, then we might be able to manage them a bit differently. But right now that we're not, we don't have those tools great. With the 25 to 30% minimal survival rate in the cost, um, being so much, what's the percentage? And how's the performance status of the patient chosen to continue treatment? Yes, eso. If patients have severe cytokine release syndrome or significant neuro toxicity, they can become very de conditioned and can be hospitalized for long periods of time, particularly the neuro toxicity. Um, so it that really is a case by case patient by patient um, issue. Some patients have no problems. Some patients will have fever and fatigue, and you can manage them with Tosa. Lose a map and they do great and they leave the hospital and they're back to their regular self. Others will have have sighted kind release or we'll have neuro toxicity and become debilitated. They spend a week or two weeks in bed. They're very D condition. They can require an extended period of time of rehab and the ones who get bad Neuro toxicity can also require an extended period of rehab and e mean their quality of life. If they have, those can be compromised for sure and require a long period of time for recovery.