(Guest Lecture): November 2023 - Using CAR T Earlier, Late and Future Advances

All right. Well thank you so much Jenny for that wonderful introduction. And I did start my faculty about nine years ago now. So Jenny met me when I was brand new and you know and I met Dr. Fonseca around that time too. So they've helped me in my career as well. So I appreciate that. And again thank you guys for making it out here on a Saturday. I actually saw one of my patients here. I didn't expect that in Arizona but I saw somebody which is great. And I told Dr. Fonseca that just yesterday I told him today that in July I came to Phoenix last. Yes in July thinking that as a Houstonian I'd be fine. And it's for my bachelorette party and unfortunately two people did get dehydrated despite all this being from Houston. Your heat is just very different. But today is amazing. Today's weather is fantastic. So I think I'm going to start coming in the fall and the spring instead. Okay so car tease. So this is something I've been working on since I was a fellow. So it really is a passion of mine in terms of cell therapy. And how can we use our own immune cells to kill myeloma. And I will tell you when I was a fellow, 2012, I was meeting with my executive committee talking to them about what I thought, what I wanted to do for my research. And when I told them that I thought T cells were really cool, because I didn't know what they really were and what we could do with them. Until I became a fellow in sarcoma and other cancers, melanoma is what I learned where we were using T cells already. Everybody in that committee looked at me and they said, well myeloma, you can't really, can't use T cells against it because it's not immunogenic. Meaning your immune system can't recognize it. How would you ever be able to do this? And I was actually told that maybe I shouldn't go down that road. And I think where from then to now even just in ten years where we've come, to me it always made sense. If your myeloma is a plasma cell, right? It's a plasma cell that went wrong. That's a white blood cell. So why can't we use other white blood cells to kill it? They're in the same place. They grew up together. So how can we not do that? So again, I think that the field is changing. We're learning so much and we've gone so far so quickly. But there's still a lot of questions that we're all trying to answer. Okay, so with that, so what are chimeric antigen receptor or CAR T cells? So this is what I like to tell my patients. And I know all of you are, probably have heard about this, but at different levels. So I'm gonna try to keep it a little bit more simple and just sort of explaining what the biology is a little bit. All of you have seen your white blood cell, your CBC, right? That tells you what the cells in your bone marrow are doing. And white blood cells, or WBCs, are your immune fighting cells, basically. So the neutrophils help with bacterial infections, the lymphocytes, all different kinds help with viruses usually and fungus sometimes. And then you have other ones that aren't as, you don't have as many of those but they have other functions. So T cells are in that lymphocyte part of it. We always talk about neutrophils, right? If your neutrophils are low, you're at risk for bacterial infections. We might give you GCSF or we might do these things to help prevent infections. But most people don't realize that those lymphocytes are also very important. And again, that's where the T cell comes from. And T cells normally already have receptors on there. So unlike other white blood cells, that sort of just kill based on a little bit more rudimentary way. T cells have something that when they were made in our body, they were made specifically to kill a pathogen. It could be a fungus, it could be a virus. They help kill certain cancer cells already. We all have cancer cells in our body that our T cells are supposed to get rid of. So they have this night vision that they know what their role is to go after. And what a chimeric antigen receptor is, is something that we can genetically make, genetically modify to go after a specific target that's only or mostly only on the cancer we're going after. So in myeloma, we have a couple, but the one I'll talk most about is BCMA or B cell maturation antigen. And this is a flag that's on the myeloma cells, it's on the outside. And it's just, for whatever reason, it's involved in the way the myeloma progresses and proliferates. So it's a flag on top that we can use to recognize that myeloma cell and get whatever treatment we're trying to get to that myeloma cell instead of everywhere in your body and hope something works, right? So it's very targeted. So we put this receptor inside that cell. And basically, this is just a depiction of this. This was an MMRF patient education that's online. It's a little bit older, but it kind of gives you the idea that what we do initially, number one is collect cells. So patients who have had a stem cell transplant know what aphoresis is, right? This is a little different. So stem cells, for stem cell transplant, we're trying to get from your bone marrow. They're not usually in your blood. So this is why people get those four days of shots first to get the stem cells out. Then we do collection for four to ten days, depending on how long it takes to collect. CAR T is different. Remember I told you the T cells are part of the lymphocytes. They're already in your blood. They're hanging out in there. And so anyone that knows what dialysis is, if they don't know what aphoresis, dialysis we use to help clean the blood. Here, we use the same type of machine, but we take the T cells out, our blood cells out. And then the number three, we actually send them out to a lab that makes these CAR T. So again, putting that new receptor in there that can recognize the myeloma and overtake whatever receptor was already in that T cell that it was programmed for naturally. The other thing that's a little different for CAR T cells compared to any other T cell therapies we're going to talk about later is we actually multiply them. We grow them. So not only is it the quality, because now it knows where to go to kill, we actually increase the number. So you get a lot more soldiers going in when we give them back. So number four, injection. So the one thing that's missing here is, unfortunately, if we give these cells back to you without any kind of chemo, your own immune system, even though these are your own cells, right? They will recognize that little receptor as something different and kill them off. And we've tried studies to say, what if we don't give any chemo, we just give the cells? And they can't get to the myeloma because your immune system works against you. So this is why we give those three days of chemotherapy usually. It's low dose. It's not like transplant chemo, like the high dose melphalan. It's similar in the way it works, but it's much, much lower dose. So most people don't get the GI symptoms or the hair loss or all those things that my patients usually are worried about. But those are outpatient chemo days for most patients. And then you get two days of rest where you're not getting anything. You might get preventative antibacterials or things like that, but no other actual treatment. And then you get the T cells. And these are infused, usually, small bag, but there's millions of cells in there. So it's not like the big transplant bags, but these cells go in. It usually takes 15, 20 minutes. And depending on the type of CAR T it is, they could start working right away and you start getting fevers that first or second day. So again, T cells are biologic. So unlike transplant or some of the other chemos that we use to treat, these are live cells going in. So just as if you had an infection, like the flu or a viral infection, when the T cells are attacking that, just like when they attack the myeloma, they'll actually start causing a lot of cytokines, which I'll show on the next slide, that then lead to fevers and some inflammatory symptoms. So patients, if they have symptoms for the most part, feel feverish. They might have myalgias or muscle aches, that type of symptom, unlike most of the other therapies we use for CAR T. And this is similar to the bispecifics that I think you get to hear about in a little bit as well. So for most patients, this is an involved process. It's great that we have the ability to do this, but it takes about four weeks to make the cells, four to eight weeks, depending on how good your T cells were, the product we're trying to make, etc. So during that four to eight week, once you've had the cells between basically one and four, labs making your cells. But for us, we might be giving you something called bridging therapy. So if your myeloma is still kind of coming up and it's gonna take us four to six weeks to be able to get these cells back before we can actually start treatment. We might give you a different treatment that will hopefully help bring the myeloma down or at least keep it from expanding. Because that part we've learned is really, really important. We wanna make sure that you have myeloma that's either coming down or at least stable, so that you have less of those side effects. If you think about it, the more myeloma there is, the more those T cells have to go and kill, and there's more inflammation that's gonna happen. So those side effects we're gonna talk about are more likely to happen if you have a lot of myeloma coming in. And so that's where either you're getting treatment with us or you're going back to your local oncologist and we're working with them to make sure you have the right treatment during that time. And then when you come back, we wanna make sure you're not having any infections or anything like that, because again, those are the biggest side effects that we can get. Okay, so then the question is when should you get CAR T? And again, there's two products right now that have been FDA approved. So IdaCell and Silt-A-Cell, and both of them are approved in fifth line. So lines of therapy, most of us as physicians don't like lines of therapy anymore. We just wanna know what types of therapies you've had and your myelomas come back. Because we know that once we've used certain treatments and they're not working anymore, we need to use something different and new like CAR T sort of by specifics. But unfortunately, this is how it's been approved in the FDA and until it changes, this is what it is. So that means you have to have failed four other lines of therapy. Either you've relapsed with four different types of therapies or something was intolerable. So you had a side effect and we can't use that anymore and we had to change. And what most people don't realize is that when you're newly diagnosed and you get a treatment, that initial treatment, and if you have a transplant or not, the transplant plus the maintenance you get is actually all considered one line of therapy. That's your front line therapy. So again, most people have to relapse multiple times. And the other problem is that not everybody can make it through all these lines of therapy and still be in great shape. Sometimes patients will get older, that if we could have done it earlier, they would have been able to get it. And let's say someone has something else that happens. As we get older, we all get medical problems. And for the most part, I will say CAR T is probably easier than stem cell transplant. So even if someone couldn't get a stem cell transplant, that doesn't mean I can't do CAR T. But we still want you to have the best outcome long term. And so really, the healthiest you are that we can take you, the better it is. So again, it's great that we have these. In fifth line, we have actually the trials. I don't have a lot of the data up here, but most therapies, so things like daratumumab, pomalidomide, all those drugs, when they were first tested, they're always tested in patients who don't have other options left that have had multiple lines of therapy. And the response rate, meaning how many patients actually responded to this treatment, was around 30%. So a third of patients would respond, and then they would get FDA approved. And then they would do combinations, or they would bring them up earlier, so in first line or second line, and then patients did better. With CAR T, I think I have it on the next slide, but the response rates are anywhere from 85% to 100%. These are patients that already had all these therapies like DERA and POM and CD38 ESA and Bortezomib and Carfilzomib, right? So again, this is why it's such a big deal in terms of efficacy. It's something that we've never seen before for patients that have had so many different treatments and they did so well. And then how long it lasts, I'll go over to in the next slide. But again, getting everybody to fourth, fifth line is not the easiest. And keeping your myeloma control during that time is also not necessarily the easiest. So the good news is that just recently, for the last few years, we've done a lot of trials to say, can we now bring CAR T earlier? Since we had these amazing responses when patients were very relapsed or factory, can we do it earlier and get maybe better responses? And so those trials have been done. So for IDA cell, it's the CARMA 3 study and Celtosilic Heart Institute 4 study. Both of these have been presented at big conferences this last summer and spring. And they were actually looked at, what we call randomized studies. So people either got the CAR T or they got a standard of care. This was in earlier lines of therapy. The trials are different. They're different populations of patients, so I don't like comparing them. But it was still for patients who were either second line, fourth line, or third line, fourth line, fifth line. So earlier than the fifth, sixth line. And basically, they were randomized to getting either the CAR T when they go in on trial or a standard of care therapy. So something like Dara Palm Dex or a carfilzomib based therapy. So we got to pick based on what was available. And both of them beat the standard of care by a lot. I mean, to the point where we actually haven't seen those types of differences between the treatment that we're looking at versus the standard of care. So that tells us that this is better than our standard of care for our patients even earlier lines. So now the FDA is evaluating that data. And I'm hoping, it sounds like that by the spring of 2024, we'll actually be able to get it in second or third line. Which again, will improve access to our patients. And then hopefully go in with disease that's a little bit more treatable. And so hopefully actually get better responses for longer. And so then again, when should you get it? So once we have this in second or third line, when is the best time to go? And really as I think Dr. Fonseca talked about it before, it's risk benefit for each patient and what's available. So for patients who have high risk disease, those are the patients that I really can't get to fifth line to make sure that they can actually wait for four to six weeks to have the CAR Ts made, to be able to give it to them. And so for our clinical trials, some of our trials have had a lot of patients with high risk on there because we didn't have other available therapies that they were gonna respond to. For standard risk patients, I think it's still an amazing therapy, cuz it did still work better than our standard of care. But some of those trials didn't have all our standard of care on there. And it really depends on what other potential side effects you might get, right? So as I go into the potential complications that can happen, if someone has a lot of other comorbidities, let's say if they're on dialysis, and it could be from the myeloma, it could be from something else. Then I wanna make sure it's still safe and the right thing to do when we have other treatments that we can use safely for patients with dialysis. So still, I mean, I think this is really, really exciting. But we're gonna learn over the next few years which patients should really go right when we can get it. Versus maybe there's some patients we should wait and try other therapies first. My conflict of interest, I tell everybody, is I love CAR T cells. And so I try to get everybody CAR T's as early as I can. But again, there really is this discussion we have with every patient to make sure it's the right time for you. So then the other question that we don't know yet, because we don't have, so these trials, again, were done in the last few years and we just got the initial results. But we don't know that means that patients are gonna have longer remission. So compared to fifth line therapy, sixth line, where we have some data I'm gonna go over. If you get it earlier, will you get longer before you'll need treatment again? Or will it cure people to the point that we don't need any treatment? And that definition of cure is very different for different people. For my patients and I, it's I want you off all therapy and never needing treatment for myeloma again, right? But in most trials, it's at five years, how many patients are still in remission without any therapy? And so again, I think it's gonna increase that, hopefully, but we don't know that, we don't have that long term data yet. So the big question is, are there some patients that are gonna do just as well if they do it later than if they do it earlier? Now I will say, the biggest thing is quality of life as well. So most of my patients who go on to CAR T have had therapy their entire diagnosis. They might have stopped maintenance if they were doing really well for a little while. But after that, it's really hard to come off all therapy and have a break. And this has been one of the other big things for CAR T is that my patients are not on any therapy. We do have to give at least the first six months, we still give anti preventive medications for infections and other things. So it's not that you're just gone and never seeing me again, we still have to make sure everything's okay. But again, you're not coming into the chemo suites, you're not having to take pills specifically for the myeloma. So there's been quality of life studies that have been done that show that patients really get their functionality back, they're feeling well, they're not having major side effects for potentially many years. And so that's the other reason I think this is such a big deal for my patients to have access to. And then again, are some patients likely not going to be candidates later, so we really should get it earlier. And again, some of my high risk patients, I can't get them to fifth line. So this is gonna be really big for them to be able to do something very novel and different than the things we already have where we know they work for a little bit, but maybe not as long. And will that change our outcomes for these patients? Something else that Dr. Fonseca brought up was overall survival. So CAR T is when one of those things that we actually see patients living longer, even when they get it in fifth line. And so the question really scientifically for me is if my patient gets CAR T and then their myeloma comes back, can I treat it better now? Is it less resistant? Is their immune system better? And a lot of us have noticed that our patients who get CAR T, all of a sudden it's like their myeloma got reset. They might be coming in with disease everywhere and we had nothing else left. And then all of a sudden after CAR T, even though it's not a cure for them as of yet, when it comes back, we're able to treat with some of the things they already had or again, the phenomenon of now we have new therapies that are available that they weren't gonna have before. And so again, for multiple reasons, the overall survival is even higher. So if I can get that to my high risk patients earlier, will that hopefully change it to where they do just as well as our standard risk patients then? So again, just lots of questions still to answer, but a lot of hope. So then it comes again, as I said, that one on one discussion with my patients. So efficacy versus toxicity. So again, response rates for these different products have been between 84 and there's another trial where this is 100% response rate. So again, baseline was 30% for FDA approval for most other drugs out there. The bi-specifics are still great, but they're about 60 to 70%. So median progression free survival, meaning once you get the drug or once you get the T cells, how long do you really get before you need treatment again that the myeloma starts coming up? And again, different trials, different patient populations, but anything from a year to 34 months for patients that have had six lines of therapy. So those initial trials for CAR T, those are the final responses we got finally in the last year. That came out just summer for the 34 months. And again, the other thing, the one and done. So you get this prolonged break from therapy, which again we know improves quality of life. So with all those great things, this is my one figure that I have that's a little complicated, but this is what's happening in your body when you're getting the CAR T. So when you're first getting the CAR T, so remember you come back to the hospital, you get the three days of chemo, you get a break for two days, and then you get the cells. As those T cells are going in, remember they have night vision for that BCMA now to find those myeloma cells. And the faster they find the myeloma cells and start trying to kill, they actually recruit other white blood cells to come. So all those other white blood cells I told you about, they also come. So macrophages, NK cells, all these cells are coming to help fight because the T cells as they're killing the myeloma will send out these signals called cytokines that then tell other cells to come and they're recruited there. And white blood cells, they cause inflammation, right? So if you get a cut or if you get an infection, there's inflammation and it's the same thing that's happening here. So the two big side effects that we worry about in the initial part, usually in the first week or two, are CRS, cytokine release syndrome. Meaning that as these cytokines are going, if a lot of white blood cells are fighting, people can get really high fever sometimes. Now the good thing, most patients, that's all they get is fevers. And we usually just support you through with Tylenol and maybe fluids or just keeping you from having chills. But if the inflammation gets bad enough, people's oxygen can drop a little bit, where they're needing oxygen, their blood pressure can drop or you need to get blood pressure medicine. So just like sepsis if you think about with infection where it can get worse. And that's where we have medications to help decrease that, something called tosalluzumab, and it works. But these are the reasons why patients have to come to a center and actually stay nearby so that we can keep an eye on you or even be hospitalized. So most of my patients are hospitalized for CAR T, but we're starting to do it outpatient as well, as we learn more and more of how to maybe prevent some of these things. But the other big one is ICANN. So ICANN is a type of neurotoxicity. And again, for most patients, when we get fevers, I tell everybody it's not necessarily just age. I got H1N1 I think a few years ago, and my fevers were so high, I was talking to the wall. So we can get delirium with really high fevers. And so sometimes it's more of a confusion or delirium you get with fever. But sometimes there really is cytokines and other things can go into the brain space that can cause legitimate issues with your thinking. So we ask these questions every morning and night to make sure we have patients write sentences, cuz if we see that you're not able to write, that might be the earliest sign of this type of neurotoxicity, where we give steroids as the treatment instead. So again, we have great ways of finding these things early, treating it early. But for patients, less than 5%, but some patients can get really high grade CRS or neurotoxicity that, especially if they have a lot of disease or something's going on with their myeloma, that maybe that's not the right time for those patients to go. And we need to get their myeloma down first, cuz again, when we know there's less myeloma, patients tend to do a lot better with less of these side effects. So good news, most patients don't get high grade of any of these. And they recover and we still get them out in time of the hospital and back home. But again, there's certain patients that we might say, you know what, this is gonna cause problems, and we need to be careful. So the other thing that I didn't talk about here is infections. And we talk about infections all the time with most of our myeloma therapies. But specifically, CAR-Ts and bispecifics, we've learned that now we're messing with your T cells too. It's not just your neutrophils and the immunoglobulins where your normal antibodies go down and we might have to give you IVIG. BCMA therapies specifically, they go after good plasma cells and other cells, B cells that make antibodies for you, the IgG. So when we have a good response, it's great, we've killed the bad cells. Now we've killed the good cells too. So that's another reason people are at risk of infection. And then we also, we're knocking out your T cells because we're using them to kill the myeloma. So we use lots of different prophylaxis. So we give patients a lot of IVIG. We might be giving them something for like Bactrim or Pentamidine for PJP pneumonia. The nice thing with CAR-T is it's a one and done. So usually after the first six months to a year, most people we can stop all these other things for and just monitor them. Versus by specifics, the longer you're on it, we still keep going with some of those medicines because you're still at a higher risk of infection. But in this first six months, I tell my patients, just like transplant, you don't have to be in a bubble but be careful. Especially with COVID and flu and RSV right now, those are the things that patients end up with higher risk of pneumonia and more risk of infections right after the CAR-T therapy until everything recovers. Okay, so then what are the strategies to extend CAR-T impact? I have six minutes, I'll spend three minutes on this slide and the next one. But this is really where most of my time is in terms of research. So access, so even though these are amazing therapies and we are getting more and more access, our company partners have been able to make more cells. But remember, it's a biologic, so it's not like I have a drug in the fridge or my shelf that I can just order and give to you. It's a lot of, it's high maintenance. It takes time to actually do all these things. And even for a center like ours, where I have all the A4C machines, I have all the support, it takes a lot of people to get this done. So we really need shorter time for manufacturing. So four to six weeks is a long time. We figure out a way to make it work. But there's a lot of different other, I guess, products that they're looking at. How do we make cells within two days and then get them released by the FDA so we can get it in two weeks instead? And then manufacturing issues. So again, a lot of our patients, they've had a lot of therapy. Someone came up and asked me this question today. Should we be careful what we're giving right before we try to do a CAR T or a Bi-specific? Your T cells are really important. And unfortunately, some of the medicines we use, steroids, dexamethasone, which we use all the time. But Cytoxan, Bendimustine sometimes people are given. Those are medicines that kill your T cells. So if we've killed off your T cells and then we try to T cell therapy, it's not gonna work very well, right? So there's ways that we're trying to figure out what should we be giving before we give T cells or should we take a break before we try to do this? So again, timing will matter on that too. And then there's different companies. We're not there yet, but allogeneic, meaning using someone else's T cells that are already healthy, like a normal donor, so that we don't have to worry about the fact that your T cells might not be working very well. So there is progress that's made. I think there's new trials that are trying to find better ways of doing it. So hopefully we'll hear about that down the road as well. And then the other big thing, people have to be hospitalized. A lot of patients have to be hospitalized, not everybody. But we have a trial to give CAR T outpatient where we can actually measure your temperature so that you know that you have a fever before you have to, checking your, with a thermometer. Because again, CRS is the biggest thing that we see. And if you're outpatient, as soon as you have a fever, we gotta admit you to make sure you don't have an infection. You might need IV antibiotics. Thankfully on average, patients are only in the hospital at three or four days when we do that. But when we admit from the beginning, they can be in the hospital anywhere from seven to 14 days. So it's a big time in the hospital, which again, for access and for patients to have to do that, caregivers, etc. So the prophylaxis, can we give steroids, can we give TOSI ahead of time to decrease those risks of those toxicities? People are doing trials for that. And then I think the resources, again, because this makes you have to come to a center and stay there for 30 days. Really, there's some great resources out there already from the companies, but also LLS and other programs. And then just making sure we're increasing that as much as possible. Okay, so the last three minutes. So what about all the new stuff? So these are great initial therapies and trials that again, have blown us out of the water. We were all really excited to see all these amazing responses. And why I still go to work every day and keep doing all of this, even though, even now I've gotten paged like four times for some of the CAR T patients. But the really cool thing is, okay, we might have some patients that are cured already, right? Again, it's not very many. Most patients do relapse. We have to treat them again. It could take a year, three years. It could take a long time. But about 16% of patients on one of the trials that was originally done in China, about 16% of patients are still over five and a half, six years out, without needing therapy. That's great, but that's still not high enough, right? We want to get better. We want more patients to not have to have therapy. We want more myeloma kill, and we want you to figure out why that is. What happened with those 16% of patients versus everybody else that eventually relapsed? So sometimes it's the target. So BCMA is a great target, but not every myeloma cell will have the same amount of that flag, and not everybody will have that same level of that. And same thing with T cells. Not everybody's T cells are the same. So again, we're coming up with new targets, or what we call antigens, flags on the myeloma to go after. So GPRC5D, everything's alphabets and numbers in our world. But that is another target we found on myeloma, that there's a lot of therapies that we're using now. So now there's combinations with GPRC5D plus BCMA CAR-T. So we're looking at different targets at the same time, either both as CAR-Ts or as a bispecific in a CAR-T. In myeloma, we love to combine things. Our goal still is to give you a break afterwards, so it's not to just keep going with a different therapy like maintenance. But figuring out a way that we can get more people into that best response, that MRD negative, and keeping them MRD negative, so that hopefully they also get more than five, six years. And again, hopefully a true cure for some patients. And then again, the timing. Instead of auto transplant, should we be doing CAR-Ts now? And so there are clinical trials that are looking at that, that patients can either get transplant or CAR-T. So we can't do one or the other yet. We don't have data. And again, it's not just the efficacy, but we wanna make sure the toxicity isn't any worse. With Melphalan, I get it. I used to be a transplant in my first two years. And GI symptoms, the brain fog, all those things that happen. But we've been doing it for decades, right? Almost 40 years now. So we know it really well, and most patients do long term do well with it. We don't see deaths from those types of things with CAR-T or newer. And we really wanna make sure it's just as safe as well. But again, those clinical trials are happening, so we'll see if it beats out transplant. Versus for some of my high risk patients with doing a CAR-T after transplant, if they don't get that best response, can I now consolidate with the CAR-T? And we've had a trial that's already looked at that. Now there's a bigger trial that's gonna look at that. So again, finding a way to put these into earlier lines of therapy to see if we can, again, increase that cure fracture, but also hopefully decrease toxicity and really change the way our outcomes are for myeloma. And with that, I will end. Thank you very much. Nope. Thank you very much. Thank you. R especial thanks to quote p. That was great. Thank you very much. apostate about the fact that Yeah. It was just The shows