(Guest Lecture): November 2022 - CAR-T: Ready for Prime Time?

All right. So obviously you've heard a lot of the Cartes, but you know everyone's kind of excited. So I'm a little simple, so I get the simplest topic because it's just one thing, right? I don't have to go through all these things that Dr. Chari showed you in the tables and all that. So so excellent. So we're in Southern California, right? So you thought you knew cars. I'm going to be basic because I know everyone is at different levels. So we've been talking about Cartes and some of you really know all of these details, but some of you maybe are still wondering what is a Cartes. So this is not the car we're talking about. This is the car we're talking about. So CAR stands for Chimeric Antigen Receptors. And so basically what this means is that these T cells now are getting a new CAR. And this new CAR is a new receptor on their surface that allows them to go and not have to wait for the usual ways the immune system kills cancer. Now they have their own antenna that directs them directly to the cancer cell. Okay. So that's what a Chimeric Antigen Receptor means. So how does this work? So usually we use a virus to introduce DNA into the T cell. And then the T cells now can express their CAR on their surface. This CAR then allows the cell, the T cell to recognize, for example, BCMA on the myeloma cell, which is the target. And then once it does, once it engages, these CAR T cells multiply, they release cytokines, and they kill the myeloma cell. Okay. So that's sort of the idea behind a CAR T. So there are two approved CAR Ts in myeloma. One is BCMA, used to be called, or Aticaps gymificlu cell. And the other one is CAR-VCT. Both are approved for the exact same indication in the United States. So relapse refractory myeloma after at least four prior lines of therapy. And you have had to have had the treatments that Dr. Chary showed you, the proteasome inhibitors, like Velcade, for example, an imid, like Revlimid, and an anti-CD38 antibody like Darcelax. So CARMA is a study that got Abecma approved. And so Abecma is a second generation CAR T. So you see the cartoon there. And basically, it's binding, the CAR is binding to BCMA. Okay. And BCMA is a very important protein in myeloma, and it's basically expressed in all myeloma cells. And so this is the study that was done, and basically patients were treated with three doses, 150, 300, and 450 million CAR T cells. And these were patients that were very refractory. They had seen basically everything, and had had at least six, median six prior lines of therapy. So again, patients that had gone through almost all the therapies that Dr. Chary and Dr. Patel showed you. So this is the response. So if you look all the way to the right, that's everybody. So when patients are at this, we talked about this a little bit. The expectation is that only about 25 to 30% of patients will actually have a response to a new therapy. So we're seeing much higher responses here. So we're talking about 73% of patients, and we're seeing complete remissions. So that was unheard of before these kind of therapies. So when we're talking about the 20, 30%, there were usually partial remissions. It was like less than 1% or 1% of complete remissions. And now with CAR T's, we're actually seeing a significant percentage of patients getting complete remissions. And so that's why there's all this excitement. But when you actually look on the left, you see that the first one's 150, 300, and 450. And the people that got 450 actually seem to be doing better. So there's higher responses with the higher dose of the CAR T. And if you look at the patients just at 450, those patients also stayed in remission longer, for about a year or so. So when you get a Beckma commercially, that is the dose that we're trying to give you. It's around 450 million CAR T cells. What about CARVICTI? So CARVICTI was approved based on the CARTITUDE 1 study. And one of the salient features of this CAR T that is different is that you see, I think I have a pointer. No. Oops. I don't know what it is. Ah. Ah. So CARVICTI actually has two binding sites for BCMA, not just one. And so we think that because of that, perhaps it actually more avidly binds to the myeloma cells. And so, again, this was a, about 100 patients were enrolled. And here they only gave one dose. So they didn't have that dose escalation that we saw with the other trial. The patients also heavily pretreated median six prior lines of therapy. And these are the responses. Quite impressive, right? So basically, almost all patients responded and a lot of patients were in complete remission or better, 80%. And so the latest time we looked, it's been 27 months since the study started, and we have not reached the median, meaning that more than half the patients are still in remission and obviously alive. So it's looking quite good. So that's what got this CAR T approved. So with new therapies, we get new toxicities, right? So these two I put up here are sort of the main toxicities that we worry about with CAR T's. And also you may have heard about I was doing questions. I didn't get to see Dr. Patel's talk, but she may have talked about these toxicities with the bispecifics. But if she didn't, we'll talk now. So we're talking about cytokine release syndrome and neurotoxicity. So any time you engage the immune system, you're going to get side effects. So when you get the flu, right, you get fevers, you get achy, you feel kind of crappy. That's actually not the virus. That's your immune system fighting the virus that is causing those symptoms. If you get a really bad infection, you can get this condition called sepsis, right? Where it's very dangerous, where the immune system is so wrapped up that you start sort of getting fluid in your lungs and your blood pressure drops. You end up in an intensive care unit. Again, that is not necessarily the infection. It's the immune system that is so active trying to get rid of this bad infection that is kind of leading collateral damage. And that's what cytokine release syndrome is. So when you give the CAR T's, the CAR T's are expanding and as they're expanding, they're sending all these cytokines that are leading to these side effects. Luckily for most of these therapies, we're talking about more like flu-like symptoms than true sepsis. And luckily, we also have medicines that can reverse the process. We just need to recognize it and intervene right away. Okay. So that's cytokine release. Neurotoxicity is a little bit similar, although we don't understand it as well. But when all these cytokines get released, you also end up sort of affecting the blood-brain barrier. And so you start getting sort of the cells that go in there and causing inflammation. And so neurotoxicity or ICANS can be as simple as perhaps some mild confusion, maybe some mild word finding, like you can't quite find the word to say, kind of like doing now. Right. So you can't find that word and you notice sort of some off things, but then it goes away. But it could also be severe where you can actually get stroke-like symptoms, seizures, and even go into a full coma. So it can be very dangerous. And so those are called grades of toxicity. Luckily with CAR-Ts, for the most part, they tend to be, again, the low grade. And as long as we intervene early, we can stop the process and it doesn't become any worse. But obviously, these are if left untreated or if they progress beyond the treatments, they are life threatening. So when we talk about the cytokine release and the neurotoxicity, for the most part, we're thinking early on. So the first couple of weeks after the CAR-T. But one of the things that I think we don't talk enough about that we actually mentioned several times in the panels was this cytopenia. So when people have get CAR-Ts, your blood counts drop like when you get chemotherapy. And it's especially true when your bone marrow is has a lot of myeloma cells. So the CAR-Ts are so powerful, they go in there and they kill the myeloma cells in the bone marrow that they actually cause a lot of damage. And the bone marrow takes a long time to recover. And so that's often when we see these sort of prolongs at opinions. Also, before the CAR-T, you get chemotherapy that also can cause sort of your blood counts to come low. So it's a combination of two things that happen. And so it's very common to get like low neutrophils and low platelets and often require transfusions. But in about a third of patients, this continues into later beyond the month, sometimes even three months later, people still have low blood counts. And so that's when we're talking about maybe giving stem cells to try and restore that. But that luckily that is rare. Most people eventually do recover their blood counts. But because of this, one of the important things that we need to watch out for is infections. So not only are your blood counts low. We gave you chemotherapy to tamp down your T cells. We gave you CAR-Ts that engage your T cells and thus the part of your immune system that protects you from viruses and things like that. So those will be low. The CAR-Ts are going after your plasma cells and those are the cells that make your antibodies. So you got rid of those two. So now you have basically no B cells and you have low T cells. So infections and infection prevention is incredibly important after CAR-Ts. All right. So what does it mean to go through CAR-Ts? So the CAR-Ts that we're talking about that are approved are what we call autologous CAR-Ts, meaning that they're made out of T cells from yourself. OK, if you're a patient, of course. And so what does the patient go through? So the patient first has to be collected. So those T cells are collected and through aphoresis, so similar to stem cell collection. And we'll talk about the difference from an autologous transplant in a second. So you collect your T cells and then those T cells have to be manufactured. You have to make the CAR-Ts. Well, you send the T cells and that manufacturing process and by the time you get them back, it could be about four weeks. Here it says 10 to 28 days, but we all know that it can be one to two months before we get them back. So during that time, before you actually get your CAR-Ts, we need to make sure that your myeloma is under control and that it doesn't continue to progress. And so a lot of people will need what we call bridging therapy to keep the myeloma under control before we can get the CAR-Ts. And so once you're ready to get CAR-Ts, then you get this low dose of chemotherapy, which is called lymphodepletion that allows your CAR-Ts to expand. And then you get the infusion of your CAR-Ts. So the process itself actually is very similar to an autologous stem cell transplant in sort of the logistics, but with very special differences, right? So when you do an autologous stem cell transplant, you first have to collect your stem cells. And so we talked about that process where you have to stimulate the stem cells to leave the bone marrow to start circulating. And then you go through the leukophoresis where your blood goes through the machine and we collect the stem cells and put them away and freeze them. Once you collect though, it's only about a week or two weeks or less, you come in and actually get your transplant. And the transplant really is just giving you high doses of melphalan. It's the chemotherapy that is the treatment. And then you get the stem cells just to rescue you from the chemotherapy. And so the toxicities that you then experience are from the chemotherapy, not from the cells, right? So then once your blood counts recover, you can leave the hospital. If you're in the hospital, you get to kind of leave the local area. With CAR-Ts, you go through that collection again, but you don't have to stimulate the T cells. The T cells are already circulating your bloodstream. So you don't have to go through all that mobilization. So it's a much faster process, an easier process. So you collect T cells, but then you have to send them away to manufacture the CAR-Ts. And we talked about how that takes a long time. During that time, you might need bridging therapy to help control your CAR-Ts because, again, a very important distinction here is when we do a stem cell transplant, you're in remission, right? You've gotten your induction chemo and you're under control and you get your transplant. With the CAR-Ts right now, what we're giving them, you're progressing. The disease is progressing. So we need to kind of keep that from becoming an issue before we give you your CAR-Ts, right? Because if your myeloma progresses, it could hurt your kidneys and make you ineligible for the CAR-Ts. So you need to get bridging therapy. And then once you're actually ready to get the CAR-Ts, you get this low dose of chemotherapy. And the purpose of the chemotherapy is not to treat your myeloma, is to basically sort of tone down your normal T cells so when the CAR-Ts come in, they can expand and go after your myeloma. But it's the CAR-Ts that are the treatment here, not the chemotherapy. And so the toxicity is not from the chemotherapy necessarily, although it adds a little bit. It's from the CAR-Ts. So similar in process, but very different in terms of the actual treatment. All right. I was asked to predict the future. So before I can predict the future, I'm going to talk about sort of what are the shortcomings right now with CAR-Ts, right? So the first part is improving the efficacy. So you're probably saying, well, you know, 100% response is pretty efficacious, right? So how can we improve on that? But the truth is that the majority of patients are still relapsing after CAR-Ts. So unfortunately, CAR-Ts don't seem to be curative the way we're giving them right now. So obviously, that needs to change. So we need to understand why. Oh, here I go again. There we go. We need to understand why that's happening. And so there's a lot of studies going on and trying to figure out the mechanisms of resistance to CAR-Ts. And then the question is, will they work better earlier? Right. Dr. Chary sort of brought it up in his talk about should we be giving CAR-Ts even in the frontline setting? And so those studies are ongoing at this point. And then, you know, right now, the nice thing about CAR-Ts is that it's a one and done, right? So those of you who may have had a CAR-T, that's probably what you enjoy the most, that you're not in a maintenance therapy of any sort and you're going to gain a break. But do we need to give maintenance perhaps in some patients to maintain that remission? And again, some of those studies are ongoing. Hopefully not, or at least not for a long time. We'll see. Can we do anything to improve the quality of those T cells? Right. So we know that the effectiveness of the CAR-T depends on the substrate. So the T cells we collect are now don't work very well. The CAR-Ts are not going to work very well either. So is there something we can do to actually help them out? And can we go after different targets? We need to make them safer. So we need to sort of identify why some patients get high grade cytokine release and neurotoxicity and why others don't. We know that, for example, when you come in with bulky disease, you're more likely to have higher grade of symptoms. And so now we're getting better at maybe controlling or kind of tamping down your disease so that those toxicities are not as great. There are some CAR-Ts that have safety switches. So that if things get out of hand, you can actually go in and actually they commit, you basically commit suicide and they go away. So things like that hopefully will make this an easier, more safer treatment because that's what's going to be required if we're going to be looking at giving it in the, at the very beginning, right, when people can live for so many years with myeloma, you don't want to give something that could potentially harm you. So. And then access. So I don't know who's actually gotten commercial CAR-Ts, but it can be a difficult process, right? There's not enough, I don't think the current CAR-Ts are enough for the demand that is out there. And so there's people that have been on waitlists for six plus months and to get these CAR-Ts. So that's a problem. It also takes a long time to get them back. And so, so sort of kind of making CAR-Ts faster, that's going to be an important process. And so perhaps these allogeneic or off-the-shelf CAR-Ts may help with that. And then these are really expensive. So CAR-VIC-T is I think $457,000, just for the actual CAR-T. And so these are pretty expensive therapies. These are all just a list of all the studies that are ongoing in earlier lines. So looking at CAR-Ts sort of beyond that relapse refractory setting and even in the frontline settings. So stay tuned for those. And then I think we have sort of new and improved CAR-Ts that are coming. So we have alternate targets. So the two CAR-Ts that are FDA approved are against BCMA. And then you heard with the BiSpecifx, we have other targets like GPRC5D and CS1. And so those are ongoing. And you'll see some actually some of you here may have already gotten GPRC5D because I know City of Hope has a study with that. And so, you know, should we be doing multi-targeted CAR-Ts? Can we go after different sort of proteins? Kind of like we do that already, right? We do combination treatment in myeloma all the time. So can we do it with just, you know, one T cell going after different things? For example, we talked about off the shelves. So your T cells, if you're a patient, have had a lot of chemotherapy. Maybe they're not working as well anymore. So maybe we should get a donor that doesn't have cancer, hasn't had chemo and use their T cells to do CAR-Ts. And those are those allogeneic CAR-T cells. And then this concept of an armored car. So it's kind of like I think of it as a CAR-T that has its own pit stop crew. So basically, these are CAR-Ts that can secrete cytokines that can help them revitalize and persist. And so basically, they're providing their own fuel and changing their tires, et cetera, to hopefully keep moving longer. So all those things are going on. And so just really quickly, I don't know how much time I have. OK. So I'm not going to go through this trial, but this is the first allogeneic CAR-T. So this is using T cells from a donor that doesn't have cancer or had chemo. And so it's called Allo 715. One of the things is to do that, you have to be more careful because, you know, when you get a transplant using someone else's T cells, you have to match. So those T cells don't cause graft versus host disease. So here, the technology has improved enough that you can actually remove parts of the T cells that usually sort of mediate graft versus host disease so that these cells can't do that to the body. And so far, the allogeneic CAR-Ts have not caused graft versus host disease. So stay tuned. Early data, they look active. Question is, can they persist as long as the autologous CAR-Ts? We now have a new target, GPRC5D. So CAR-T that looks really good against this new target. And so we now have patients who've gone from a CAR-T against BCMA to a CAR-T against GPRC5D with good results. So, again, stay tuned for more of that. There'll be a presentation at ASH this year of a GPRC5D CAR-T as well. And then we have these CAR-Ts called FAST-CAR, which is a dual targeted CAR-T. So it targets, we talked about sort of going after two different sort of proteins. So in this case, BCMA and CD19. And the plus of this is also that they can do very quick manufacturing. So they say next day manufacturing, although because of all the regulatory tests and so forth, it still takes about 10 to 14 days to actually get the cells back. But again, it looks like a very promising CAR-T. So CAR-Ts are powerful, right? They work against myeloma. It's a one time treatment, at least right now. So that's a really nice thing. Clearly very logistical specific issues that we haven't seen with other type of products. So it does limit the access, unfortunately. It may work better if done earlier and that's being tested. And so it is a very exciting therapy. So I guess the question is, you know, what do I see for the future itself? I see the CAR-Ts. I think CAR-Ts will be used much earlier. And I even think it will be in front line. We'll start. We're starting with the high risk patients, but ultimately, I think all patients will be getting potentially CAR-Ts as their front line, unlike what Dr. Chari said. I think we should be using CAR-Ts as consolidation. I don't think we should be giving CAR-Ts when the disease is rampant and growing. I think these are very powerful. We don't need a lot of disease to help them expand. So I see it as somebody getting, for example, induction, getting remission, giving them a CAR-T, just like we do with transplant. And what we've seen and you'll see some data is that when we do that, as much as that can release, there seem to be much safer and they work better, actually. And so I ultimately see that we will be using CAR-Ts, hopefully with some of our other exciting therapies. I anticipate that people will get some kind of induction to control the disease, get the CAR-T like we do transplants consolidation, and then follow with like a six month of a bi-specific and then actually stop. And that's what I see for the future. And that's what I see especially.