It gives me great pleasure to introduce the last speaker, Doctor Poo was one of the reasons why I decided to come to Buffalo. Actually, it was his wife. Wait, that sounds wrong. His wife makes an unbelievably delicious duck. And when I came to interview, I was, had the fortune of spending time in his home and enjoying his wife's cooking. Igor is the, is the head and in two degree, a pioneer of the early phase program that we have um at at Roswell Park. So 23 years guys, it'll happen at, at, at Roswell Park. Uh in part because I knew that he was a linchpin to, to, to my success if I came to uh to Roswell, um he has uh led, guided and mentored a lot of our junior faculty. I knew just by her presentation, you could see his, his mentorship qualities is, is, is the latest that, that will benefit from his mentorship. Um I I enjoy his mentorship as well and he will talk about till cell therapy and clinical trials and data summary. I should point out that this is the tip of the iceberg for Igor who is involved in all aspects, in many different technologies in the early phase. And he's an to the institution and Igor. All right. So you can't go either. No. So thank you Rene and uh thank you for inviting me to speak. Uh You know, now the expectation is high, I can only disappoint. So that's perfect. Uh I got here in uh 2016 from Nashville, from Vanderbilt. I spent 14 years there, you know, trained and uh then did uh phase one and uh kidney cancer and Melanoma drug development. I was part fortunate to be part of all the immunology phase ones, including the uh we miss the actually, but then pembrolizumab Zuma T VAC and, and then multiple other combinations targeted therapies such as uh the uh kidney cancer drugs such as uh and, and uh I finished my renal cancer career with the first combination of the targeted and immuno, which was uh at the time. Uh and uh and then I got here because I actually wanted to do something else, then, then do trials. I wanted to learn how to actually organize uh phase one team and uh and uh and with help of uh Doctor Johnson and uh now Reier before that, you know, uh mark, er, you, you remember him? Um he always fondly thinks about waffle. I think we are succeeding and uh it's a real joy to be here. I actually like the weather being from Czechoslovakia originally Czech Republic because we have four uh seasons and this is like perfect. So, uh, the weather is the best, you know, I was at Nashville before in Dallas. You know, this is the best weather, don't let anybody tell you otherwise. So, a actually gave us a really good overview, you know, how we got here with solid tumors. Uh, and, uh, you know, the reason we don't yet have car T cells for solid tumors, not the end is the problem that solid tumors are more heterogeneous, you know, than uh liquid tumors. And um while you can kill all the B cells, as a bystander effect is hard to, you know, kill, you know, all the liver cell, let's say, as a standard effect of treating liver cancer. So the question is how to find good targets for car T cells in uh solid tumors. So the tills are already there. You know, like that's what Anna was trying to stress that you have already cells in the tumor. They are their T cells, they should be killing, but they are not killing because they are somewhat shaken. You know, they are depleted of nutrition, they are blocked, you know, you are trying to get them out, you know, rejuvenate them and then you put them back, you know, as you beautifully. So the um the the timelines and how, how it's actually practically done. And uh you know, the first trial was done by Doctor Steve Rosenberg. He's a genius if you ever met him. Um He is not big in stature, but he's like big, bigger as life, bigger than life. And uh he did it in 1988 and that was his idea uh at N C I and he did it for years and years, you know, where he typically resected the tumor. He is a surgeon by training, you know, then doing the till production, you know, you know, of course, with modifications, we got smarter over the years, we have more cytokines. He was mostly using interleukin two and then he was using the infusion. And then of course, uh the I L two infusions and all and that got modified over the years. And you can see that even in his first attempt, he had actually 11 patients responding with one complete response and 10 partial responses. And that was exciting. Of course, the one thing he never told you is that in order to get these 20 patients, he was looking probably at at least 200 patients because the doctor Rosenberg never believed in the analysis of the patient data by intention to treat, but only by the patients who finished his protocol. So, you know, he always presented 23 days, you know, then responded. But then he didn't talk about the 500 others, you know, who didn't qualify at some shape or form, you know, throughout the there. But there are responses, you know, it's exciting. So, you know, then you have other trials, you know, it didn't actually limp for depletion, you know, I 02 treatment, you can see there are some side effects that are mostly dictated by the chemo and by the inner in two, you know, I will stress out the hypertension with interleukin two, I will stress out, you know, the, you know, some of the diarrhea aura, you know, that of course, goes with the hypertension. These are typically reversible. You stop the inner two people recover. Sometimes you have to, you know, support them. And if you overdo it as some of us know who did high dose I 02, sometimes they have to stay in the intensive unit and I have treated patients with high dose I 02 at Vanderbilt over 350 patients in my 14 years there. And we never lost a patient, you know, but we had a toxic cities, you know, you know, all that. But if you have a well trained team and a good supportive colleagues, you can actually do it. But you have to have that if you don't have it, I always tell people don't do it. That goes for car cells that goes for tills, you know, the same situation. I always give that analogy. If you have Lamborghini and you take it to the fourth shop, they will be excited because they have never seen it. You know, they want to work on that Lamborghini, but they shouldn't because Lamborghini belongs to the Lamborghini shop and, and you know, and that's the team which is actually doing this on a regular basis. They get a skill, not any different than surgeon who gets better, the more surgeries they actually do. And uh and you can see more trials over the time now actually and then flu and again, response rate, about 50% of patients of the ones who were able to finish, you know, so they are more fit patients for you, but they are highly treated because in order to actually to get to these programs, you know, in the old days and you can see the day there, uh you had to actually have high dose I L two before you even were considered, you know, by these groups, you know, by Dr Rosenberg. And uh the negative, there was also that in order to get these skills, you had to be able to travel. So the patient had to travel to N C I and they paid for the travel and they paid for the state. That was good. But how many patients do you know who can actually travel at the time when they had a 23 lines for Melanoma treatment? You know, there are not that many. And so that was the hindrance. So there was always a big promise but it couldn't translate to something bigger because you just simply were unable to do it, this is just another modification, you know, looking at what they call a young ta you know, kind of because one of the worry was that if you use, you know, they already are in the tumor, they will be a little bit senescent, you know, they will be a little bit weakened, you know, by just like being there fully mature. So it was an idea to find these earlier, you know, less mature cells and make them into tails to give them the necessary longevity. And uh and as you can see, again and again, your overall survival is actually pretty promising, especially when you take what we had, you know, in those times like 2013 and where the typical tail was like 34%. And again, you can see the typical side effects, you know, hypertension renal failure from the hypertension, pulmonary congestion. That's a vascular leak syndrome. That's a little different than C R S, you know, C R S is I six driven. You give for this, you actually basically just support the patient and make sure you don't overload them with fluids. The guidelines actually how to do it. And I was lucky enough to write some of them. And uh and this is not what changed, you know, in the last couple of years, you know, and believe me, I initially, I was not a big believer because I was thinking, well, that's Dr Rosenberg, he's doing it for the last 20 years, you know, that's not that exciting. So what they did actually, they said look, you know, I'm doing it at N C I and uh and it doesn't amount to, to, to, you know, I cannot spread it, you know, elsewhere. So he got together with uh with uh technology people, uh you know, other people and they started, you know, um uh an outfit which basically was working on how to make these uh tumors and travel. So that's the secret sauce. You know, the secret sauce, it's not new, but the secret sauce is that you can harvest the tumor. You know, where the patient is, send it to the company, you know, do something in the, in the, in between and you know what it is, you know, depends. For example, if a patient is Melanoma patient and they have breath mutation, you give them a front line, they progress and you are, you know, you are in trouble, the patient is in trouble. You can actually harvest the tumor, send it, you know, for the tills, you know, if and when it's available and uh then give me, you know, in between and as soon as the tills are back, you can start the process. You know, if patient is breath non mutant, it's a little bit trickier because, you know, you need to do something and a patient who is, you know, progressing quickly may actually miss that mark, you know, So the key is to think about it at the beginning. And also I would stress that uh if you are seeing the patient, you know, in the office, that's kind of like a high dose I L two patient, you know, in the old days when people look and uh they called me and they said, you know, I think this patient should do high dose I two earlier because you can always go back to something later. But uh if you miss that initially, when they are really fit, you missed it. You know, there's no going back, you know, nobody in a wheelchair gonna get, you know, tail therapy or, you know, in the old days, high dose I 02 therapy. This is what they did. You know, the cryo preserve is the key, you know, these are the tails isolated from the patient. Uh in order to actually do it, you need to have at least 1.5 centimeter tumor, you know, removed, you know, so that's the key 1.5 centimeter tumor. You know, if it can be a little bigger, it's actually better. But at least that. So 0.5 centimeter. No, you cannot do that. And uh you know, patients were heavily pretreated as you can see. And uh a lot of them actually had elevated the L DH with uh we know that those patients have a poor prognosis and they were both breath mutant as well as breath non mutant. And interestingly half of them uh actually had, you know, half of them. So they were like your typical patient. You see it today because we use more or maybe in. But, you know, people usually see that before they even consider clinical trial. And uh as you can see the safer it was reasonable, um you know, the uh uh people of course develop the typical chills, Pyrex, you know, fever utopia from the chemo hypertension, you know, diarrhea, that's usually either the chemo or the I L two. And uh and when you look, you know, the neutropenia, thrombocytopenia, leukopenia, that's actually more related to the prep regimen than the high dose I L two. Interestingly, people will say, hey, you have high dose I two. Is it all all the rage? You know the high dose I two and tills do nothing. So you can actually get away with just two doses of I L two. It really is just to feed the cells. It's not like the typical high dose I 02 where you get 14 doses or up to 14 doses, then you go home for a week and up to 14 doses again. So uh you know, here you can see the summary uh the cohort two cohort four were a little different cohort four was more pretreated and had more L DH you know elevation. And when you put it together, these are patients who progressed, you know, on uh uh, as I said, multiple lines, you know, P D one was the minimum, but most of them had either or they had a breath, you know, breath, 31% responses, you know, C R about 6% 25% pr So, actually, it's very much in line with the previous experiences from the N C I and these are less selected patients again because, uh, you know how the trial was done. So it's not just like one person doing it. And uh and uh it's a and this is your uh response, you know, the typical waterfall plot looks, looks great. There is no control. Of course, you can argue, you know, there is no control, you know, you can do whatever. Um when you look at the uh uh different disease characteristics, you know, pretty much everybody, you know, seems to be uh you know, benefiting and uh you can see the disease and therapy characteristics there. And I will point to you that even the patients with a prior uh P D one anti C T L A four actually benefited. And that's exciting because we don't have much for them. Um And uh that's good duration of response. So, well, you know, about 50% of the responses are actually very durable. Um You know, as you can see that median duration is 8.3 months, you know, but then there is just a little, you know, patients down and then you go up to, you know, four years, you know, so, you know, people made a big deal that it's 8.3 months. But when you actually look, I think the difference was if there was a three patients more, you would have actually longer. But so there is the, there is a tale what you wanna see tail with, uh with these therapies, you know, survival, you know, is actually, you know, hard to tell because it's a single arm study, you know, can be biased, you know, by patient selection. Uh But uh but it's promising because, you know, those are heavily treated patient and the media is about 14 months, give or take, you know, what actually is really made the till therapy to kick in a bigger gear. Is this John Hanen study, you know, John Hanen, good friend of mine from uh of course, uh Netherlands, you know, so, you know, there you go, Dutch, you know, like what's gonna go wrong in? We actually work on a trial together with the cancer vaccine and uh and other, you know, really good people and what they did, they actually make their own tails in the Netherlands Cancer Institute. So this is not the same thing I showed you before. This is like a old school Rosenberg, you know, we make your tails, you know, at home. But what was different, they actually randomized people. Finally, first trial of Tills, second line after P D one progression, just P D one, not P D one. And they compared to why they compare to because that's a standard in Europe. And uh again, typical randomization stratification, uh they, you know, they harvest the tails, they make them, they shoot them back and uh and look what happens uh what they did actually, but Rosenberg never did. They actually showed us that most of the patients were actually able to get to the tills, like the 84 were assigned to the till treatment, intention to treat and 80 receive infusion of till. So that's really good. You know, that's not like 20 out of 500. That's actually they wanted to do it and they actually did it and that's important, you know, here and then you see the baseline characteristics, these are less pretreated patients because that's how it's designed just P D one progression and you go and uh but you, you still see a good number, 20% you know, having elevation of uh of um uh L DH, but it's not more than two, you know, and really where people start being sick is more than two. So these are kind of lighter, lighter patients, you know, they are not your, you know, patients who come uh with uh bone mats and, you know, liver meds and, you know, just in trouble. And uh and this is what happened, you know, the tills were better than, you know, it's randomized. It's with the P value. You can see that, you know, it's a progression free survival. Um You know, there is a tale again with the tills and there is no tail, you know, really with and uh there you go and uh all the uh subgroups, you know, pretty much benefit or there is a big spread, you know, remember these are hypothesis generating data because they are uh a post doc analysis. And uh you can see the response rate, you know, complete response 20% for seven, for 28 partial 14. You know, I don't have to convince you clinical benefit, 70% versus 40. And uh here you have the waterfall plants and overall survival is not mature. And also it's too preliminary to tell. And uh and uh and we have to wait and again, very similar to what I showed you. Um you know, they were able to manage them and over overall quality of life, you know, that's actually always good because, you know, patient asked, you know, how is my quality of life? The blue light is actually I and the red line is the tails and the red line is above the blue line. It's not higher, it's not that higher, but it's not that lower, you know, so that's an important part. So in summary, actually, we now have a randomized phase three trial of tails and then we have, you know, that long term till data, you know, from the single arm study. And when you compare actually data in a second line, advanced Melanoma, like what you can give people in second line, I will point to you, you know, just, you know, looking at the overall response rate and, you know, is, of course there, you know, because if you have, you know, like that's a good saver, but it's not forever, it's not very, you know, it's not completely durable and you can see actually the tills, you know, are there and really almost compatible to the, to the, you know, and the breath ma after you progressed on P D one is not going to save the day except for, you know, individual cases. So it's good to actually start thinking about tills if your patient progress do not, you know, checkpoint inhibitor in some shape or form. And, you know, just to show it's not just for Melanoma, there is now some preliminary data in lung cancer. It's not as impressive, you know, not surprising in lung cancer is more difficult and people have more toxicities. And uh uh there is actually really nice data which MS zero is one of the leaders, you know, at the, you know, again, similar, you know, kind of design, you do tails and uh and you see actually the response rate are, you know, really good, you know, it's a preliminary small data set but cervical cancer. So, you know, not just 11 trick pony but maybe other other tumors may respond. And of course, you know, we have trials, you know, which targeted in ovarian cancer, you know, which were done when was here. So as Ranier said, there was some work done. But yo, you know, I will say it because he won't, you know, is maybe not the best target, you know, but I think, you know, we kind of agree and there is multiple trials ongoing with tall in different centers. And one thing I will tell you, there is a lot of trials. It's hard to get patients on it because, you know, it's one off, you know, you know, people, people have to get in line. I tried to get patients until at the memorial when they had the expanded access program for the it was good but that closed. So right now, you know, it's really hard to get until therapy we are hoping, you know, that eventually FDA will look at the data and render some decision. I'm thinking third or fourth quarter of this year. And if that happens, you know, in a positive way, then at we are ready to roll because we already have all the teams, all the instruments, all the things lined up and it will be a pleasure to work with all of you because you know, if you see somebody, you know me, I give everybody my cell phone, you text me, I call you back and if that patient is interested and if you are interested in having that patient, look at you, look at them and we get them in and uh and we will collaborate, figure out who does what, you know, who does the surgery, who sends what you know. And I would really caution, you know, saying like it's like cart cells, you know, if you are doing car t cells in your institution, you can do tails, you know, but if you are not doing cart cells, then I think it's better to do that one off, you know, with us as a collaboration, I have done it at Vanderbilt successfully for, you know, really 14 years where, you know, if patient needed he aisle two, they came to me and if they didn't need idols, aisle two, they went back home and if they lived, you know, in Knoxville where I had a lot of patients from and needed like a suit and you know, they were going to Knoxville, get their suit and, and I saw them clinical trial or something specialized and there is more trials, you know, then you can put your head around, you know, and how are we gonna finish all these trials? I don't know because these patients are pretty selected. And if you ask me, if you look at the publication of the, which came out at J C O, it took like three or four years to get these 55 patients. So when people get excited that there is like a new one, a new one, a new one, you know, we don't have enough patients actually to do all that. You know, we need to get something smarter, you know, in terms of how we do these clinical trials because some technologies may die because they simply don't find the champion. And uh and that's my summary here. And uh you can see that uh the filter trials in Melanoma confirmed, you know, the importance of the lympho the patient. They, well, we can limit I 02 doses to reduce the incidence of a it's effective and uh they are now active and all in patients. And we are waiting basically decision on Melanoma and two other cancers, you know, as they are kind of rolling to see if it's applicable in cervical, non small cell lung cancer. I didn't mention ovarian and I didn't mention head and egg, but there is a lot of trials ongoing in those in vacations and that's all I had for you. So, thank you very much.
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