(Guest Lecture): March 2024 - T-Cell Re-Direction Therapy

Thank you very much. I know many of you, most of you, and I just want to start by mentioning a couple of things first. One is Anu and Ajay gave great presentations. I have to say, and I think part of the rest of the day is going to be spent sort of discussing the data that's been presented, and that's mostly what I'm going to focus on because I actually came here thinking I was going to be talking about CAR-Ts as well, so many of my slides overlap with Ajay's. And I'm not going to be able to be here this afternoon for the question and answer period, so I'm going to leave a little bit of time at the end of my talk to handle some questions and answers because I've got a hard stop at one o'clock to get back home. So we're going to talk about T cell redirection therapy. And I don't know why this doesn't show it, but okay. T cell redirection therapy simply means taking the T cell that Ajay spoke about and redirecting its function. So instead of it fighting an infection, you're going to take it and have it fight a specific cancer. One of the problems in developing these T cell directing therapy is whether it's redirecting a CAR-T cell or redirecting an antibody to fight the cancer is finding the target. It's not that easy because every cell has thousands, maybe millions of targets, potential targets, and you have to find a target that works to kill that cell but doesn't damage other cells in the body. You can't find a target that kills a myeloma cell but also might destroy a liver. So finding that target is difficult. And one of the questions I always get asked is why leukemia lymphoma have been doing so well with their CAR-Ts and myeloma, we're still looking for a cure. They got lucky in finding a target that really works well for some leukemias and some lymphomas. And we have a couple of targets now. We're going to be talking about BCMA or B cell maturation antigen, which is our most common target that most of the CAR-Ts, the two approved CAR-Ts are directed at BCMA. And in the bispecifics, we do have another target, GPRC5D, but most of our targets are still BCMA. We at UCSF are developing more targets. Our program at UCSF ranges from bench research where we're looking for new targets, new ways of engineering the T cell, to clinical research that many of the studies that Ajay presented we are participating in, to managing patients like you all from diagnosis all the way through CAR-Ts cell therapies where we're not siloed. Many institutions have a separate transplant program, a separate CAR-Ts program, a separate myeloma program. We pride ourselves on being able to manage patients from start to finish. And that includes bench research that we will be bringing to the patients over the next few years. So that's what T cell redirection is. Why am I jumping? Anyway, Ajay skipped over this initially, but I want to go back a little bit and talk about a little bit of the history of development of myeloma therapies because I was indeed there at the beginning. And as you can see here, whoops, I thought that was a laser and I turned it off. Is there a laser on here? Got it. So Ajay mentioned starting here, this is a survival curve. So back in the 60s, these are decades, back in the 60s half the patients were dead within two years. And all we had back then was steroids, prednisone, and then later alkylating agents, some of which we're still using, cytokine or cyclophosphamide, and melphalan, which many of you who had a transplant got melphalan as part of your therapy. And melphalan, actually its generic name is phenylalanine mustard. It's related to mustard gas from World War I. And all those early alkylators, whether it's cyclophosphamide or melphalan, are related to World War I mustard. But that's all we had in the 60s. In the 70s, we put them together when I was at UCSF, one of the physicians there, Sid Salmon was one of the first people to combine steroids and alkylators. And for many years all we had was melphalan and prednisone. And then for a couple of decades not much happened. And in the 80s, we developed autologous stem cell transplant, which is what many of you have had, using your own cells. And that helped us jump the overall survival. And you can see in the 90s, we went maybe to three years or four years. What happened after that was that we discovered maintenance therapy, where we continued therapy afterward with generally lenalidomide or Revlimid. And these days with perhaps two or three drugs as maintenance. And again, we improved. And what you're seeing here in the last decade is the newer immunotherapies, whether it's by specific or CAR T cells. And of course, the anti-CD38 antibodies that have been talked about, daratumab, isotuximab. So we're making tremendous progress here. And our hope, in fact, more than our hope, we know that many patients, especially those who get deep remissions, and at UCSF we're very committed to measuring minimal residual disease or MRD. Those who get to MRD0 do quite well. And many of them are going out 10, 15, 20 years now, hopefully to a time when we'll have a cure. And I'm sticking around till we do that. This is one of Ajay's slides, which I love. It actually gives you an idea of all the categories of drugs that we have. And you can see how the immunologic approaches are just exploding here. But as I said, I want to talk a little bit about dexamethasone. I'm taking this stand here to be able to spin out some other stories, because I don't have as many slides having edited them after Ajay's talk. I want to talk about dexamethasone for a moment, because how many of you have had dexamethasone? Every one of you. So in the 90s, 80s actually, a fellow in Arkansas, who many of us know, Bart Barlogi, started giving incredible doses of dexamethasone. Imagine 40 milligrams a day for four days every week. 40 a day every day for four days every week. And it took us about 20 years, and it worked. It was the only thing we had in the 90s was this high dose dexamethasone. We did a number of studies in the first decade of 2010, comparing the very, very high doses of dexamethasone to what we called low-dose dexamethasone, 40 milligrams a week, which I'm sure none of you believe is low dose, given all the side effects. And there we sort of stopped until recently, when we all looked at each other and said, maybe we can go lower. And that's what Anu talked about earlier, that so many of the toxicities we see are with dexamethasone and maybe not these other drugs. So what we are looking at, especially at UCSF, is can we get away with less? After a period of time, can we reduce the dose? Can we even stop it, as Ajay mentioned, in some of the maintenance trials? Because we know that it's not enough to just treat the disease and get control, but also to control the side effects. So these are the alkylators I mentioned in the second column here. The IMIDs, the proteasome inhibitors, and now all the new immunologic approaches. And then the studies that have been done with the CAR-Ts and the bispecifics often require patients to have had three class exposures. And those three classes that Ajay mentioned are IMIDs, proteasome inhibitors, and the daratumumab, or acetuximab, the anti-CD38s. More specifically, they may ask for penta-drug exposure, as Ajay mentioned, Revlimid and POM, borotesimib, carfilosimib, dira, or acetuximab. The newer trials, what we've discovered with using the bispecifics or the CAR-Ts in patients like this is that they do well, but maybe they'll do well if we do them earlier. And earlier means maybe just one line of therapy or two lines of therapy or three lines of therapy. Sort of four lines of therapy in patients who are penta-refractory. I'll skip a few of these. The three categories of immunotherapies that are more recent are antibody-drug combinations. Again, Dr. Chari mentioned Blendrep or Blendtuzumab. This is a drug that is a BCMA target that also has a toxin attached to it. So when it's administered, the target attacks the myeloma cell and the toxin is injected into the cell to kill the cell. Again, as Dr. Chari mentioned, it has its problems. One is the keratopathy or corneal damage that it can do after two or three doses. So we use this very limited. We use it in a limited way because one of the toxicities, which can occur after two or three doses, but also because, again, as Ajay mentioned, you don't want to use too many BCMA-directed therapies before you go for, say, a BCMA CAR-T cell because it could lower the response rate, it could lower the progression for survival. CAR-T cells are cells that have been engineered. We talk about it as though it's a once and done, meaning you come in the hospital, you get some chemotherapy, you get the cells, and after a period of time where you may get side effects like cytokine release syndrome, which is fever and maybe some confusion, you go home and you're done and you have years of control. As we're discovering, that's not necessarily true. That is, we're seeing later complications, and Ajay went into that, the complications of seeing late neurotoxicities, especially the single nerve problems, or the Parkinson's disease syndromes, which are getting much more attention from us because they're so serious. So it's not necessarily once and done. That is, there's still toxicities and there are infections that come later, too. So I'm going to point this out in the later slide, but these kind of therapies can only be done at high end institutions like UCSF. So there are late complications like infections that we're seeing with the CAR-T cells. We're especially seeing it with the bispecifics. Now bispecifics are antibodies that don't have one arm, like a typical antibody, but have two arms. That's why they're called bi. One arm would grab a myeloma cell and the other one would grab a killer cell, a CD3 positive T cell, bring them together to kill. What we mean by off the shelf is that we don't have to collect the cells, send them off for six to eight weeks, wait for them to come back while the patient may be progressing, but we can just write an order for it and it's taken off the shelf and given to you subcutaneously. But again, it has its issues. One is that it's a huge commitment because you'd have to keep coming back every week, every two weeks, maybe every four weeks for many, many months or years. So it's cumbersome versus the CAR-T cell. It also has many infections that we can see later, mostly viral infections, COVID especially during the COVID epidemic, but other infections like metanumavirus and pneumonias and CMV infections and flu. So these are not once and done and they're not simple. This was one of Ajay's slides. Again the process of the CAR-T is a little bit like a transplant. It looks alike from the outside. That is you get on a pharesis machine, blood comes out of your arm instead of collecting cells, which we then give back to you to help rescue you from the melphalan chemotherapy. Those cells are sent off to a company that will engineer them to recognize the BCMA, let's say, on your cancer cell. They may come back six weeks later, eight weeks later, at which time you get the therapy. You get three days of chemotherapy to make room to suppress your immune system so that you don't reject these cells. Then you get the cells, so it looks like a transplant. Then you're in the hospital, not necessarily with a lot of side effects, with nausea, vomiting, diarrhea like you have with transplant, but with the risk of cytokine release syndrome and the neurological complications that come early. So that if you are in the middle of the night, it's two in the morning and you have fever and chills and getting confused. When the nurse comes in, calls the doc, you get the antidote, which is tocilizumab, and almost immediately those symptoms go away. So it's not something you can go home and wait at home and then deal with it in the middle of the night. And again, it has to be done in an institution that not only has a lot of experience, but has been approved by the accreditation societies. The antibodies, again as Dr. Chary showed you, have two arms. One arm attaches to the myeloma cell, one to a T cell, and kills the, to kill the myeloma cell. This is again a slide that Ajay put together that I'm going to borrow because it shows you what a tremendous improvement we've made with the CAR T cells in patients who are relapsed refractory. I mean, many of you have had two, three, four, five lines of therapy. Maybe you can show of hands. Many lines of therapy. For the moment, those are the data that you see for people like you who have had many lines of therapy. What I'm going to show you next are the data just from this December of using these CAR T cells earlier, like after one line of therapy, two lines of therapy, three lines of therapy. And our hope that this year the FDA will approve it for that so that we don't have to wait too long and maybe earlier therapy will be better therapy. I guess I'll stop on this before I go to those slides. What would be the reason to use a Bi-Specific? Well, let's say you've had four lines of therapy and your myeloma is exploding. You have new bone lesions. The bone marrow is packed. You're more anemic. And you can't wait the two months for those cells to come back. Well, having a drug that's right on the shelf that we can write a prescription for and start that day is very helpful. So that's where you might think of a Bi-Specific. Maybe as in the past, we've had trouble getting enough CAR T slots to have those cells engineered so that these days it's getting easier and hopefully it'll keep getting easier. But sometimes we just don't have a slot and we need to wait a month or two to get that slot so maybe you need the Bi-Specific earlier. Why would you want to use a CAR T? Well, maybe your disease is slower growing where you can wait one or two months. Sometimes you're in the middle and we collect the cells and give you what we call bridging therapy. We give you some additional chemotherapy to hold the line on the disease for a couple months. But what if you live really far away? What if you're in Alaska? What if you're in the middle of Nevada? How are you going to come in every week for a shot of Ticlystumab or Tilquetumab? So in that case, getting a CAR T might make sense. Ajay again mentioned this. It turns out that age has been a problem with bone marrow transplant or stem cell transplant. When I was first doing transplants, I was 30 years old and we wouldn't transplant anyone over age 40. And as we, the transplanters, got older, we kept moving that up. And now I'm 77 and I don't think that's too old to get a transplant. Ajay says I'm still eligible at the higher dose of Melphalan. But we are transplanting people in their 70s. We're actually doing CAR T cells in the 80s because it's a lot more tolerable than a transplant as it turns out. And there are toxicities, but a lot of people breeze right through it even in their 80s. You have to have the support at home. And how long can we wait for the CAR T engineering? What about the site? Well, a site like UCSF has the entire spectrum of what you're going to need, which means our unit is devoted to things like transplant and CAR T. We have nurses who know what they're doing and know when they see a problem and call us. We have pharmacists who work side by side with us who get the antidote to you guys. And we have the consultants that we need. We have neurologists who are now focusing their research on the neurological complications. We have ICU specialists who manage our pneumonias. We have infectious disease experts who know these viruses. And then in terms of sequences, Ajay mentioned, you probably don't want to use a BCMA therapy before you go to a CAR T or a bispecific. You may over time lose those BCMA targets on the cell so that there's no target for the therapy you're giving. The more therapies you have, the more possibility that the T cells are aged or are more fatigued or not as capable. So earlier therapy would be better. I'm going to jump a little bit and then leave room for targets for talk. IVIG is a therapy that really is important. Plasma cells make immunoglobulins called IgG or IgM or IgA. You can imagine if a cohort of your plasma cells becomes malignant, that cohort grows. It suppresses the good guys, the good guys that make immunoglobulins that protect you from infection. So many of you know that if you look at your IgG myeloma, you look at your IgG, it might be high, your IgM, your IgA may be low. And that's because you're not making enough of those good guys. It turns out that from the diagnosis, everybody with myeloma is immunocompromised. You're at risk of infections. That's why so many of you are wearing masks. IVIG can correct some of that problem. And in this study you can see that in terms of infections, those patients who got IVIG or intravenous immunoglobulin had many fewer infections than those who didn't get it, including grade 3 and 5 infections, bacterial infections, say, pneumonia with bacteria. So all of our patients who get CAR T cell and specific to a great extent get replacement IVIG every month. And it really prevents a lot of infections. Finally, I'm going to talk about two studies that were presented in December that hopefully will help us move CAR T cells to an earlier therapy, say after one line or two lines or three lines of therapy. And the first one was CAR T4. In this study, CILTA cell was compared to standard of care for first or second or third line therapy. And you can see here that those patients who got the CAR T, the CILTA cell CAR T, did far better than those who just got standard of care. And it turns out that even with the patients who got only one prior line of therapy did better than those who got two or three lines of therapy. So again, earlier is better. And then when you compare it to the very first CAR T1 or phase 1 study, again, giving the therapy earlier resulted in a better progression for survival, a higher curve than those who got it much later. And this is what we're hoping the FDA will be looking at. In terms of the monoclonal antibodies or the bispecific antibodies, a combination of teclistomab, which is a BCMA target, and telquetumab, which is a GPRC5D target, combining those two in these patients who are relapsed and refractory, resulted in a 96% response rate, which is spectacular, with many, many stringent CRs and a median progression for survival here of over 20 months. So that these bispecifics in the future we may be combining them. Okay, so let me leave a little bit of time to answer some questions, because I won't be here this afternoon. Do we have a mic that we can pass around? As you guys know, Jen Doudna at UC Berkeley discovered CRISPR technology, which is the ability to edit DNA, the ability to go in and take a piece of DNA, get rid of it, and replace it with the DNA we want the cell to have. CAR T cells currently are manufactured by taking the cell and introducing a virus that carries with it new DNA. That virus actually can be related to the HIV virus, but it's been edited in a way that it won't cause HIV. That virus will carry into the cell a new DNA product, but it will place it in the DNA randomly. It may place it in some bad places, we talked about possibly causing other cancers, but not specifically. It may not be as effective if it's just randomly placed. We at UCSF are taking Jen's work with some of her students, actually, and people who have become famous in their own right, but sort of the F1 generation after Jen Doudna, who are working with us to use CRISPR technology to make our new CAR T cells at UCSF, in which we know the site where the DNA belongs, and we are now able, in mice, to go in and edit the T cells just to put the DNA in the right place and cure the myeloma in the mice. We're about to enter into human studies later this year. Wow, that's amazing. Maybe we have two more questions, and then you guys will have the opportunity to ask questions twice. There's a question here. I'm not sure I heard you too well, but you were talking about CAR T cell therapy, and you used the phrase, no longer, or it is once and done. Is it? Which is? Yeah, it's referred to as once and done because we only administer the cells once. It's not done. So, it's half of being once and done. It's once, but it's not done because we're seeing late complications we didn't expect before, and we're only learning about them now. So, infections, neurological complications, like, and when we talk about Parkinson's disease, it's serious. It's a little shakiness. It can be loss of mental acuity. That may not be reversible. So, we don't think of it as done. We're still learning about them, but it is once. No, not now. Not that I can imagine the future. We might be giving CAR T cells that have more than one target, or we might be giving CAR T cells that have multiple different CAR Ts that we give all at once, but we won't be giving CAR T every month, for example, like we might do with the BiSpecifics. So, it is once, but don't think of it as done. Another two questions over there, and then I'd be happy to step down. Okay, two, and then that's it. I have to listen to Dr. Wolff. I said one, he said two. I was just wondering if, like you were saying, if you did a BiSpecific that's targeting something different, not BCMA, and then, I mean, would that be fine then to do BiSpecifics first and then still be? Yes. In fact, it's a great question, and we are in many cases buying time, for example, with a BiSpecific that targets GPRC5D, so Telquetamab. We may use that to buy some time and then go to a BCMA-targeted CAR T, yes, but we wouldn't do BCMA followed by BCMA followed by BCMA, any more than we would do lenalidomide followed by lenalidomide followed by lenalidomide. There was another question back there. Yes, so you mentioned using IVIG after CAR T therapies. Does it have any role to play in, like, easing the burden after stem cell transplants as well? Absolutely, and I think everybody at UCSF uses IVIG pretty liberally for patients after transplant or during other therapies if the patient has very low IgG levels, like under 300, or patients who have multiple infections, like one virus infection after another. I have patients who come to me and say, I've had a bad cold every month or the last three, or I was in the hospital with a bad COVID, or I had COVID and then two weeks later I had some other infection. Those people need IVIG, and we use it regularly, not just after CAR T, not just after BiSpecifics, but any time the patient is what we call hypogamma. They have a hypo, meaning low, gamma globulin level, we give IVIG. Thank you so much. Thank you.