You guys get first dibs any questions for our speakers. So I'll, I'll start, I have a couple of questions. Fantastic presentation. Uh Great. Other thing you said did strike me. Um uh We still don't have a cure for myeloma. So chemotherapies targeted therapies. Now, parties all have had their shot at this. Is this due to an adaptive resistant technique or is this a myeloma stem cell? What is your thought in terms of why we're not there and how can we get there? Yeah. Trust me. I've thought about that a lot. Um And still thinking about it, I think it's all of the above. I think we, we have data and there's a lot of data out there that the immune system is compromised starting in the stage. So once we come to relapse myeloma, the immune system is so exhausted, beat up that it's just not really. And I mean, most of our treatments including cart but also immunes and antibodies, they all need an immune system to fight the cancer. And I think that's one big issue, another one, the myeloma stem cells. I mean, if you have a room full of myeloma experts who will have about 50% saying there is 1 50%. There's none. I'm not sure if I would call it stem cell because what we see when we do these biopsies in different areas, even at first diagnosis, their differences. So I'm not sure if there's this one stem cell, but I think there's a, an event that leads to the development of the myeloma which then leads to the, to the compromise of the immune system. And I think this combination with just not solved yet. My hope is that if we do as we have done in some studies already do car t cells earlier, because I strongly believe that the immune system can overcome this potential stem cell or whatever reason there is that we cannot kill this last myeloma cell because the immune system can adapt as we just learned, right? The immune system can adapt, meal, just kills something, right? That's there. Um But the immune system can adapt and kill hopefully this last cell. And that, that's my hope that if you do that earlier, have still a kind of functional immune system that this will work long answer. Sorry. One other question for. So um with the, one of the biggest things we've always kind of dealt with in my is when is the appropriate time for patient to get because it's a couple month process like collection production tills I'm imagining is very, very similar. So when is the best time for a patient to get referred to you for a consideration of like when it gets approved. Eventually, I would say that after, you know, they are failing the front line of checkpoint inhibitor because, you know, like, uh you know, at that point, you know, you know, it's unlikely to cure because, you know, even if you know, these days, we are more and more combination checkpoint inhibitor, you know, when you look what happens, if you progress on nothing good happens after you progressed on. Uh if you progress on, you know, uh or you know, nothing good happens, you know, there is a hint of data that actually these two seem to be almost mutually exclusive, you know, like you get one and you don't respond to the next one and vice versa. We are going to do the sequential trial to confirm. But there was a new England Journal of Medicine, a letter to the editor by Menzies and the Australian group who did a lot of the, you know, the development and they said that in their hands, you know, after the progression that didn't work that well, you know, it's a one group but they had a lot of patients and uh and uh you know, you can salvage a little bit with the the targeted therapies for sure, but it's not gonna be forever, especially if they progressed all immuno therapy within six months like a primary resistance. Those patients all are dead within 14 months, we wrote a paper on that when I was in Vanderbilt. And, uh, basically the breath mutated, you know, progressor on Checkpoint inhibitor front line, you know, if they progress within six months they are old. And remember, you know, there's a short window to do it and it takes the logistics referral, uh, surgery, somebody needs to schedule that, you know, kind of, uh, then it goes to company, you know, they say, oh, it takes us 22 days, but then you have to get a bed in the hospital, you know, for the prep. Uh, and then, uh, you know, they stay about a week and all that, you know, it really is like a six week process. You know, from when you say, you know, this patient should get pills to actually get the tills. So if, uh, you know, it's like the thought when the patient walks in there is a second progressive, uh you know, second progressive uh C T scan, it's not gonna happen, you know, especially if at that time, you know, they have performance status, you know, three or two go into three, you know, in six weeks, they will be so bad, you know, that, uh, you know, nothing will happen. So it has to, that, that intellectual thought that has to happen when uh people are kind of failing the front line when you see that, you know, sometimes it can be pseudo progression. But usually, you know, that because pseudo progression usually feel good, you know, but if they don't feel good and there is some progression, it's probably a Hallmark of something bad coming down the pike, you know, most of the time, not all the time, but most of the time and, uh, I'll be happy to talk, you know, talk is cheap as I like to say. And, uh, and, uh, and then we can kind of figure out, you know, but think about it early because late it's not gonna happen, may ask something about that. Um, would it make sense to collect these tills as we think about in my Loma earlier? Like the first surgery who will pay for it. So the, the problem is, you know, that would be ideal, you know, like we do something and you collect the tills and you leave them. But the problem is, you know, the preparation of tills is costly. You know, there is a surgery, there is a send out, you know, company gets paid, you know, when they make them, they can freeze them, but I already did their job. So they want their money and, uh, if you are not gonna use them, who's gonna actually pay for those tills. So, you know, if I was independently wealthy, I would say, hey, you know, like I have Melanoma, you know, and why don't you collect my tills? You know, if I don't do it front line, I wanna collect them and have them frozen. But uh and I pay for it. But uh, if I'm insurance, I probably would be reluctant to just pay for it. Willy nilly if you're never gonna use it, you know. So that's the problem. We have a question. So, really great presentation. I'm really excited to know that this is in our um and it's also nice to put a face too. Um Getting back to this question, why are, why are we using this sooner? Multiple myeloma, a patient of mine that you're seeing next week? High risk? I actually mentioned it to him. I didn't know if you guys. Yeah. Yeah. Um We, we would love to uh obviously and we, we had a trial open but this is fully enrolled, the patients that we're on and that's just anecdotal. It's not scientific, but even the science shows these patients do really, really well. I have this one patient. He is independently rich. I think he's just planning literally two. He had early relapse. So really bad prognosis. 2.5 years after he got his car T cell, he's planning an eight month cruise around the world and asking me where in the world he can make stops in my Loma center. So that's an anecdote, of course, but I think it does make a lot of sense to do it. Earlier on the other hand, we still struggle with side effects and then you have a second line patient who has maybe had, you know what we do. There are R V D but they have not had curs with all these things where we know how they work. We know the toxicities. The patient has to really want to do that and take this risk. But also hopefully get the reward that they might get. RJ. You had a question. You, it's like your third question, Marco. I mean, do you think that might lead to an earlier in? That's the expectation. Yeah, most people think that 2nd, 2nd or third line, we don't have it yet, but are you, are you OK, Marco? OK. So my question of domination therapies, OK. 8 902 plus plus. Uh uh So I'll take the Tills. So actually, uh U U P MC, U P MC actually did a single uh nine patient trial with Pembroke and Tills, you know, front line uncontrolled, you know, just single arm study. They had seven patients, you know, with uh either deep uh pr or C R. And there is a plan to do a phase three confirmatory trial in the front line actually tills versus uh I think it's a P D one uh therapies, it's in plans, you know, so there is actually data, front line look good, but it's uncontrolled. And remember the, the selection bias may bias you, you know that there is definitely plan checkpoint plus. Yeah, if I could just chime in, I think I can um you know, this idea of combining with, with, with uh checkpoint inhibition. If you ever run into uh doctor, he will lament that he came up with that idea and deserves a Nobel Prize, no doubt for it. Um Back in the, in, in, in probably for 2010 and the the reviewers of the grant roundly uh besmirched it. So there are logical combinations. I think that, that, that a a unfortunately one of the obstacles um that you face is you have different companies making different drugs and then getting them to work together to provide drugs to do this in a clinical trial. Despite the fact that it makes intuitive sense um is sometimes uh what the problem is. And I think uh Marco alluded to this, um look, when you start in this new technology, you have patients that have gotten anywhere from 4 to 8 different prior therapies. So if it works there, my God, let's imagine what it would be in the front line or the second line setting. And so I think that that will be the first part of the trend is to move some of these cell therapies to earlier lines of setting. In part, especially if you're taking the immune cells out of the patient. I mean, the more that those immune cells get exposed to toxic chemotherapies, the less likely they're going to be robust. Um And so um already second line and, and there are a bunch of first line high risk patients for relapse where car T cells have moved forward. And I think that, that uh uh uh Igor alluded to uh trials where, where, where tills and, and other modalities. So it's, it's, it's unfortunate that it's going to take time because you'd like to do this in rapid succession so that you find the sweet spot. But, but if it were that simple, but it's, it's, it's cost, it's, it's, it's, it's interest, it's, it's licensed technology that makes it difficult to do these combination trials in space. I, I actually read an article about and they were talking about, you know how there is like this BC MA and that BC MA and which one looks better and then one discussant actually said it doesn't matter because if you are looking for BC MA to go to your vein, you know, that uh you cannot find a space, you know, there is not enough beds, you know, I think that's why actually our uh foray into like really invest into cell therapies including like expand, you know, the space for uh patient uh beds and such is important because, you know, it opened my eyes that, you know, we talk about science and which data looks better. But if you are a patient, you are waiting in line to actually get there. And if we go to earlier lines, that's more patients, that's even more beds, you know, like uh, you know, remember the first time you treat like 95% the second line in Melanoma, you treat maybe 50 the third line you may need, you know, 30. So, you know, like if you start to treat in front line, that's a lot of more patients, you know, and, uh, everybody stays a week in the hospital and the longer if they have complications, you know, where are you gonna put them? and where are you gonna find the nurses and uh, and staff? We have time for one more question, I think because we're before we collect and then we have to wait for Melanoma if they are on I O I O combination. Is that a time frame? Is that a wash out or for till or that it is not applicable? Not really, you know, the, the half life is long and, you know, these drugs actually hang around for up to three months. You know, if you were trying to do, you know, like five house lives, you know, you never do it. You know, it is what it is, you know, it gets washed out, you know, as they get messed with, you know, like that's my uh scientific explanation. He good one. All right. So I think we'll wrap it up. Uh I, I don't see, I think there's one question. I, I don't know if this is updating. What are the plans for sequencing trials with so many targets? Is there room to optimize sequences. I mean, in Melanoma, we did the dream seek trial and we did a trial, you know, like targeted therapy and then, or then targeted therapy showing first was better than, you know, targeted therapy first. And then actually, you can get some benefit to really seek progress in patients with a short eight week course of uh you know, uh and followed by, but at the end, the overall survival is dictated by. So we have done that and we plan actually to do uh a s sequencing trial with and uh uh and the, because nobody knows what to use. And as you guys know, they're both approved in front line. And uh and uh you know, which one should you use? I actually personally use because there is longer update and, you know, like a longer uh follow up and everything. But some people actually say, look, you know, you have a better data really technically with because it was planned that way while actually in, you know, if you read like the fine print, the statistical comparison was between A and I and, and, and, but there was not actually planned statistical analysis between and, you know, so you see that little gap there but that like, statistically like it never happened. You know, it's really strange. I think the company didn't want to find out, you know, if it was, you know, really together and uh and then they were like, pleasantly surprised, you know, but uh but uh for the rela actually, there was a planned analysis between and, and so, I don't know, I, I just use that but, you know, I can stand corrected if the sequencing is better the other way, but we need to find out. I think we will stop there. I want to thank our speakers tonight, including myself. Um I think some of our speakers will be around for a little while longer. Thank you so much. Thank you for all of you uh visited us um online. I'm sorry, we couldn't get to more questions, but I knew just kept talking about immunology for so long again, college credits for everyone that, that that attended. Um Thank you very much.
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