(Guest Lecture): October 2023 - Immunotherapy's Evolution

I'm Dr. Banerjee, one of the other oncologists in the myeloma group under Dr. Cowen's leadership here. So I'll be kind of dovetailing on what he discussed talking about immunotherapy a little bit more on that paper by Dr. Till and Dr. Press in terms of how it's evolved really in the last decade. Here are my disclosures. And so all of you on this audience have seen or been or heard of these drugs, most of you have been on them before. It's worth noting, right, that myeloma therapy is complicated. It's, you know, many different types of drugs being used in many different combinations. Big picture. When I use the word chemotherapy with my patients, I'm referring to drugs that kill rapidly dividing cells that cause nausea, that cause hair loss, etc. And so, you know, melphalan, which is used in transplant is one of them. Cyclophosphamide, cytoxan, pills, many of you are familiar with. That's in that category. Then if you skip over the middle for a second at the bottom, you have all sorts of targeted therapies that attack cells from the inside. You know, so proteasome inhibitors, Dr. Cowen alluded to, imids, Revlim, and all of you are quite familiar with lenalidomide. And then in the middle there, there's all these tools that basically attack the myeloma cells from the outside and or help your immune system to attack them. Myeloma is unlike solid cancers. Many of you know this quite well because people often ask, you know, in solid tumors and breast cancer, lung cancer, prostate cancer, the cancer cells are hiding from the immune system. The immune cells can't get in there. In myeloma, the cells aren't hiding. They're sitting there in your bone marrow saying, come and get me to the immune system and the immune system isn't able to get them as well as it can without the help of these drugs. So what these drugs do is they kind of level out the playing field. They let our immune systems realize this is an intruder, let's get rid of it. Many options here, monoclonal antibodies attack myeloma cells from the outside, what we call naked antibodies that just attack it and let the immune system go from there. CAR-T therapy, Dr. Cowen alluded to, I'll go more into it. So there we engineer your own T-patients' own T cells to allow them to actually fight the myeloma, kind of forced unrecognized myeloma. And a bispecific antibody that we'll briefly talk about, then my colleague Dr. Cicero will go into it more. Basically it forces your T cells, so remember that your immune cells normally are each immune cell is destined to bind to one particular protein for the rest of its life. A bispecific antibody tells it, forget what you're doing, go attack this myeloma cell instead. So really cool things that are in the field here of immunotherapies that are helping the immune system fight myeloma better. Dr. Cowen briefly touched on this, but to go into more detail here from, is this a laser pointer? Well I'll try not to use a pointer because I know this will be recorded afterwards. In terms of how CAR-T cells work for the cells, we'll talk about the cells first, then we'll talk about the patient, which is much more important. The cells here, you can see a kind of a clockwise circle happening here. At the bottom left, we collect T cells from the patient. We genetically modify them to basically say, hey, whatever this T cell was destined to do with this life, forget that destiny. We have a more important destiny for you. Put on this chimeric receptor that forces it to recognize the myeloma that Dr. Cowen alluded to. That's actually pretty easy to do. The hard part actually is then taking it, growing those T cells. T cells are very finicky, so getting them to grow and grow and grow into millions of them and giving them back to the patient. From the patient perspective, this time a counterclockwise circle just to make sure you guys are paying attention. At the top left, you can see aphoresis. That is the word for collection of the T cells from the patient. Many of you know this. It might seem similar to stem cell collection, but again, we're collecting a different kind of cell entirely with different medications beforehand. We manufacture the T cells into CAR T cells. We have trials of new CAR T therapies open at Fred Hutch where that manufacturing interval is as short as two days. Right now for commercial CAR T therapies, typically several weeks, sometimes a month or two. Once the cells are ready to be infused back into the patient, we use something called lymphodepletion, low dose chemotherapy, not transplant, not malaflux. It's a small dose of chemo that's designed to basically make your body hungry for these T cells to make it welcoming of the new T cells when they come back in again. Then at the top, we infuse everything back. CAR T therapy currently, as of October 2023, is approved for patients who have had at least four prior lines of therapy, including at least one imid, that's lanolidomide, revlimid, or pomalidomide, pomelist, at least one proteasome inhibitor, that's bortezomib, velcade, or carfilizomib, kiprolis, and either daratumumab, darzalex, or esotoxamab, sarclisa. People ask me this all the time. What is a line of therapy? I'm not going to quiz you, but if I were to do multiple choice here, is it A, a relic of our past? Yes. B, is it an unplanned substitution or escalation of treatment? Yes. Or does it mean both of the above? In brief, in myeloma, counting doesn't make sense. As all of you know, one plus one does not equal two. If you got induction therapy and then got a transplant, even though it's two very different things, it's one line of therapy. It's a relic of our past when some of you, we were diagnosed during this time, all we had was chemotherapy for myeloma. So line of therapy was just how many different kinds of chemotherapy could we use? We've thankfully come a long way since then, but this is confusing. Maybe even sometimes myself and my colleagues would disagree on how many lines of therapy someone has had. Unfortunately, is what we're stuck with in terms of the FDA approval as of right now. But with that in mind, can we move CAR-T to earlier lines? So right now in plain English, CAR-T is only available for patients where we've had to change therapies in an unexpected manner at least four times. Can we move it to earlier? I would love that. Dr. Cowan alluded to that with siltacell, and Dr. Cicero will talk about this too. So if you look here, the writing is kind of small, but this was a study, the CAR-T2-4 study comparing siltacell or CAR-VCT-CART-T versus what they call standard of care. So some therapies that could be used that were not CAR-T. And so siltacell clearly beats standard of care in that study. But you can see here in the blue, the top blue line is patients who receive siltacell after one prior line of therapy. The blue line underneath it is patients who receive CAR-T after two or three lines of therapy. Kaplan-Meier curves are confusing, but they're the bread and butter of what we do as oncologists. In brief, basically, this is the number of patients, the percents on the y-axis, on the x-axis number of months. So you can see, for example, at 18 months, or let's say 24 months, for example, if you look at 24 on the bottom right and move your eye up, you can see that the number of patients you can see that around maybe 75% of the patients who got CAR-T after one prior line of therapy were still in remission. But for the two to three prior lines of therapy, it was only like 55%. Why might that be? If you give CAR-T earlier, obviously the patient is healthier. They haven't been beaten up by as much of the therapy that we've offered them. Their T cells might be healthier, right? Because T cells can also get exhausted, just like human beings can get exhausted. So the earlier we give CAR-T, the more patients we have. So the earlier we give the CAR-T, the T cells might be better equipped to fight the cancer. And then, in general, as with each successive time the mine element comes back, it often comes back more aggressively. Many of you in the audience have lived through this personally. Or it comes back with more extra medullary disease, disease outside of the bones, et cetera. So the earlier we give CAR-T, maybe we can intervene on that cycle. That being said, as a caveat, and I'll get to this next slide as well, again, people, you might look at this and say, oh my God, CAR-T is always better than the standard of care, the green lines. Again, this standard of care is not the US standard of care that we typically would offer for many of you in this scenario today. So Dr. Cowan alluded to this. You know, at this time, next April, the FDA is set to look at whether CAR-T should be moved to earlier lines of therapy. If they do it, let's say they approve everyone after one line of therapy can get CAR-T. Should we do CAR-T for everybody? It's a tricky question. The biggest issue Dr. Cowan alluded to is that CAR-T is very complicated. We have to take T cells and slowly finesse them into cancer-fighting CAR-T cells. That's very resource intensive, both for the patient and for the company and for the lab and for the cancer center. It's a lot for everybody. Even if CAR-T cells grew on trees, even if CAR-T were super easy to make, even if you could make them right here, you know, while you're getting your coffee, it's a lot more to it than that. We need hospital beds. We need our nursing colleagues. We need, you know, the T cells have to be basically taken out of the patient, carefully processed, sent to the company, sent back, carefully thought, brought back to the patient. There's a lot of logistics behind the scene. CAR-T isn't a good fit for everybody. So as I alluded to earlier, right now, typically I tell patients CAR-T takes about one to two months to manufacture. What we call the vein to vein interval from the day that the T cells are taken out to the day the CAR-T cells are put back in again, I would say six to eight weeks. Sometimes four to six, often six to eight. We have a trial open right now where that is down to three weeks, which is awesome. Hopefully we can get it on to one week in due time, but we're not there yet. For some patients, waiting six to eight weeks is just not practical for them. And for those patients, CAR-T is not a good idea. As all of you know, you know, as of right now, CAR-T is only available in the state of Washington in Seattle. And so that's not perfect for everybody. Someone who lives in Montana, someone who lives in Alaska, someone who lives even on this side of the path and it's that time of year where you can't get over, this might not be the best therapy for them. And the other thing, again, I'll allude to on the previous slide. I typically for my patients in second and third relapse use a CD38 monoclonal antibody like Dera-2-mimab, Darzalex, or Isotexamab, Sarkliza with Carp-Caiprolis, Carfilizomib. And that kind of a control was not an option in this particular trial. And those regimens do quite well in lines two and three. And those patients might be able to do what they're doing for years without requiring CAR-T therapy. On the flip side, the C word, not cancer, but cure, right? The word that all of us, you know, all the oncologists here are always nervous about saying this word to our patients with myeloma because people ask, you know, am I cured? I don't know. I say remission. I say complete response. I say durable remission. Why won't I use the C word, cure? I'll admit it. I think I'm happy to say that I think we are curing some of our patients. We just don't know who those patients are in advance. That's the tricky part. In some other cancers, you can reliably say that if you give them this therapy, over 60% of them will never have this cancer ever come back. We're not there in myeloma. This is probably the closest we've come. So in silt-to-cell carvicti, which is one of the, you know, one of the CAR-T products, the earliest study that was done in China that led to this eventual drug being approved, 18% of patients were actually alive and disease-free, totally in remission five years out. No therapy for cancer, just completely just in remission. And so you can see the Kaplan-Meier curve here. And again, you can see at the very right there, there's one patient there, 78, that's six years out on this study, who remains in remission. So it's possible we just don't know who those patients are. That's the biggest challenge that all of us are working on in our research and so forth. How do we make this rate, this cure rate, higher? So the flip side of that, well, why does CAR-T stop working? So a couple things that can happen. So now we'll go into the details. As I alluded to earlier, this is a lot of information. So, you know, we'll keep kind of processing this. I'm, hopefully this slide will be out of date in the next year, which I'll be happy about. We're learning much more about this. I would say there are three reasons why CAR-T therapy might fail a patient. Either the myeloma cell does something funny, the CAR-T cell does something funny, or the TME, the tumor microenvironment, everything else around the myeloma and the bone marrow does something funny. In terms of the myeloma cell, so myeloma cells are wily and we know that. And that's why, you know, all of your testimony to the fact that, you know, with the patient ingenuity, patients, patients, and a lot of our scientific advances, we can get around that. But this is a problem. What can happen? Myeloma cells can lose BCMA. B-cell maturation antigen is for all commercially approved CAR-T therapies right now, the target of all of them. They look for this one protein of myeloma cells. If the myeloma cells don't express that protein anymore, they become invisible once again to the immune cells. They can stop producing BCMA altogether or they can mutate it in a way that the T-cell can no longer see it. There are all sorts of things that, you know, I'm not that old, but when I was in medical school, I'd never heard of any of these words. Tragocytosis is where the myeloma cell gives its BCMA back to the CAR-T cell and the CAR-T cell takes the BCMA and kills itself, what we call T-cell fratricide. Sounds like something out of Shakespeare, but that's the T-cells killing each other. Weird things can happen and thanks to innovations at Fred Hutch and other places, we're trying to figure out how to get around this. So how do we get around it? Some of the work here at Fred Hutch, actually most of the work here at Fred Hutch internationally has been happening here. Gamma-secretase inhibitors. So again, if the myeloma cell is going to try to shed the BCMA and become invisible again, you can give a drug that prevents it from doing that, forces it to express BCMA at very high level so the T-cell can attack it. We can attack two different proteins at once to make it harder for a myeloma cell to squirm away or we can target something besides BCMA entirely and Dr. Sitter will talk about that. That's a myeloma cell. What about the CAR-T cell? So CAR-T cells I alluded to earlier, you know, are T-cells and you know, T-cells can get exhausted. They can't and that's actually the clinical word we use for it. It's not just me humanizing them. T-cells get exhausted meaning that they're just not able to activate and proliferate and do their job the way that they used to do. That's the biggest issue we run into. It is also possible that the body can treat these CAR-T cells as foreign and try to reject them. But the T-cell exhaustion is a big issue for us. So how do we get around that? The immune system is a constant network of checks and balances, you know, autoimmune disorders are a good example of where the checks and balances go awry and the body starts attacking itself. Well, maybe we can, you know, it's not a yes or no, right? Everything with the immune system is nuanced and if we can use some quote-unquote checkpoint inhibitors to just tell the T-cell to take, take your foot off the brake for a little bit longer, maybe that can help. A lot of that work, Dr. Cowan actually is the principal investigator, the leader of one of this big study that we're presenting at our big ASH meeting later this year. Dr. State-Rutman was also on the study. We can change how the CAR-T cells are made. We can try to make the CAR-T cells healthier, rejuvenate them, invigorate them, whatever verb you want to use to make them healthy. We're working on that. There are many studies of technologies to make the T-cells healthier. The idea being if they are healthier, stick around for longer. And if this is the issue, the issue, the issue with the issue is we can't tell if this is the problem. If this is the problem, then I would say, well, if your T-cells are a problem, let's give you some new T-cells or use something different. Right now when BCMA CAR-T therapy stops working for a patient, I don't have a good way of telling why, but if it's this, that's something that we can definitely work on. And then finally, the TME, the tumor microenvironment, that's everything else in the bone marrow where these cells are hiding. The myeloma cells are sitting in the bone marrow, but it's not just them. They're surrounded by all sorts of other immune cells that they've twisted to kind of, you know, follow what they're asking them to do. And those other cells in the tumor microenvironment, they make it harder for the T-cells to get in. And so issues that can happen. So, you know, CAR-T cell does work against extra medullary disease, against plasma cytomas, but it's sometimes going to be trickier because the T-cells actually have to swim their way through all these hostile cells to get in there. Or there can be other cells in the area. There are something called regulatory T-cells that are going to shut these T-cells down. So how do we get around that? You know, ever since that first paper that Dr. Kahn alluded to his talk, there's been a whole army of puns around the word CAR. Right, CAR is chimeric emigen receptor. That's what we actually do with an automobile. But, you know, we like making jokes with ourselves over trying to help cure our patients. So we say, well, why not have a car when we can have an armored car? And the armored car basically can get its way through this hostile tumor microenvironment. There are also such a thing as instead of a car, T-cells redirected for universal cytokine based killing, which sounds like the craziest acronym ever until you see that that spells truck. So we're not there to curing our patients yet, but we have good, when that day comes, we'll have a good acronym for what we're calling these things. But so armored cars and trucks can possibly either get through the tumor microenvironment or actually secrete chemicals to help motivate themselves to keep going, going, going. Don't let that regulatory T-cell slow you down. Keep going. Kill that myeloma cell. The other thing that we can do is not keep all of our eggs in one basket. So everything I've discussed to so far, both commercially available CAR T therapies, target the same protein called BCMA, B-cell maturation antibody. You can see a lot of the drugs we target, target BCMA. So both CAR T's, teclistomab, l-rinatumab. We have a rapid infusion car, rapid manufacturing car. T open here, for example. It makes sense. BCMA is found in myeloma cells. In the CAR TUT4 study, which is the one I looked at earlier, of 176 patients who got CILTA cell CAR T therapy, 175 of them saw their blood numbers improve by 50%, if not more. And so it definitely works. It doesn't work forever. Unfortunately, there are some cons with BCMA. So BCMA is found on normal immune cells. And so that means that these patients who get these therapies are at risk of infections, as many of you are well aware. Other things, GPRC5D, that's a mouthful, but that is another, is what's called an orphan receptor. We don't know why it's on the myeloma cells, but it's there. So let's target it. We do have an FDA approved bispecific antibody called talcquetumab that attacks it. Dr. Cicero will talk about that more in her talk. Interestingly, this one doesn't seem to be found on normal immune cells as much. So patients possibly aren't that high of a risk of infection with these. But for reasons that I don't fully understand, GPRC5D is found on myeloma cells, on tongue cells, and skin cells. Kind of a strange combination of things here. But patients getting talcquetumab can be at risk of tongue issues, for example dysgousia, which changes their taste, or skin and nail issues. We also have other proteins in the works. Sovastumab is not yet FDA approved, but just as an example of something targeting another product, another antigen as a bispecific antibody. And then CD38. Some of you may be familiar with this word. Anyone who's received daratumumab or esatuxumab, so Darzalex or sarclisa, that's what's being attacked by it. And we have others. We have a trial about to open here at Fred Hutch of a different CD38 attacker. Basically, it will work even in patients where the darzalex or the esatuxumab stops working. So let's briefly go into bispecific. Dr. Cicero will talk about this a bit more in her section right after mine. So bispecific antibodies, also called BITES, that's a trademark, so I won't use that word that term again. But bispecific antibodies, you can see a good example here, is an antibody that has two arms and it pulls these two cells together. It pulls a T cell together and a myeloma cell together. Again, so what's actually happening here? The T cell normally, every one of our T cells is normally destined to only attack one thing in its life, if it ever finds it. Otherwise, it just goes around looking for its quote-unquote soulmate, whatever is destined to attack. Bispecific antibody, basically, whatever word you want to use, distracts it, disorients it, hijacks it, whatever word you want to use that says, you know, whatever you thought you were going to do, forget that. Let's do this instead. Let's kill this stupid myeloma cell. And that's exactly what it does. There are many. So the ones that are starred here, FDA approved, the Csosanab was approved like 51 weeks ago. It was this year. It was a Tuesday. It was in clinic. I know, I think 50 weeks ago, it was approved a year ago. L-Renatum and Tocutum are both approved two months ago in August. So this is a lot of advancement happening very quickly. And there's a lot of other drugs here, Limosultumab, Alnuctumab, ABV383. Forimptomig targets GPRC5D, again, that other protein. Savosum targets another protein. So there's a lot of cool advances happening here. And so I was asked in my slide deck to say, you know, choosing between CAR-T and bispecifics. And so, you know, I get asked this question by patients. I get asked this question when I'm talking to other doctors all the time. In short, there's no one universal answer. The answer is that it completely depends on the patient, not just clinically, but on the patient's values, on the patient's logistical support network to do different kinds of things and so forth. But in general, so the contenders here, so again, CAR-T, we take out someone's T cells. We genetically modify them permanently to attack myeloma. We infuse them back into them after commercially right now about a one to two month pause. Bispecific antibodies are quote unquote off the shelf. There's no manufacturing and real-time required. But you basically give the patient a bispecific immediately that, again, for as long as it's in their blood, distracts their T cells, disorients their T cells, and forces them to attack the myeloma instead. In general, I would say that if you're talking about safety, bispecifics are probably a little bit safer, just because a little bit of a controlled explosion. What do I mean by that? The biggest side effect of CAR-T therapy, Dr. Sissler is going to talk about this at length, is something called cytokine release syndrome, CRS, where basically all of a sudden the immune system recognizes millions of cancer cells that have been hiding from it for years. And so people, most patients will get high fevers. They can get plenty of other issues Dr. Sissler will talk about. With CAR-T, once those cells are inside of you, they're just growing and growing and growing. They see their autonomy. They attack. They proliferate and so forth. With bispecifics, you can kind of control that expansion a bit more in a careful manner. On the flip side, CAR-T is probably more natural, right? It's a more natural thing for T cells to grow out of their own volition and not be, you know, disoriented by the bispecific every two weeks. So CAR-T cells probably have better efficacy and the trials seem to match that. In terms of logistics before starting, I alluded to this, CAR-T therapies right now typically require one to two months. There are trials of CAR-T that can be done sooner. There are trials of allogeneic CAR-T cells that come from a healthy donor. But we don't really have those yet. So that takes about one to two months versus the bispecific. You know, from the day I see a patient at clinic and say, time to do bispecific, I need to get insurance approval. I need to get a hospital bed and that's it. And I can do that typically in about one to two weeks at the most. On the flip side, once someone gets one of these therapies, CAR-T is way easier. CAR-T, some people call it a one and done. I call it a two and done. The patient has to come in for collection of the T cells, go home, come in for the CAR-T cells, be monitored for 28 days, go home. That's it. There's no maintenance with CAR-T therapy as Lisa's right now, not commercially kind of not the standard of care to give maintenance after CAR-T therapy. And that's it. And again, for example, in the study I mentioned the Legend 2 study, 18% of patients five years later out of CAR-T are alive, doing great, no issues, no relapse, no myeloma therapies whatsoever. Bispecific antibodies on the other hand, again, they work, you can start them right away, but the bispecific antibody only works for as long as it's in the patient's bloodstream to kind of help disorient those T cells. And so by the book, you know, the currently approved bispecific antibodies are given once a week until progression and that can be years of bispecific antibodies once a week. In real life, with one, I should take that back, L-Renatumab, the package that sort of allows us to space out there every two weeks. In real life, for all the bispecifics, we're kind of making them every two weeks or even every four weeks and so forth. So we're kind of, you know, that phrase, building a plane while you fly it or flying a plane as you build it, right? You guys know this analogy. That's what we're trying to do with these bispecifics. They're all approved now. We're trying to figure in real time, how do we make the treatment continue to work while not requiring the patient to have to drive into Seattle every single week and deal with the toxicities that come with continued bispecifics. So again, I think this is my last slide and I have 71 seconds left. Which one should I choose? So again, I've given hour-long lectures just about choosing bispecifics and not CAR T. And here I have two minutes to talk about CAR T and bispecifics together. And brief, there's no right answer. You know, some of you are, I recognize some of you from my own clinic, so I'm happy to talk about this with you guys when I see you next. Otherwise, talk with your physician because every case is very unique. And the last thing I'll say is this might be a false dichotomy. You know, we're like academic oncologists, like us, we love arguing. We love to argue. We love to just debate each other. So we try to make this as artificial CAR T versus bispecifics. In reality, it actually might be both. So there may come a time where we say, look, someone got a CAR T therapy and it worked well, but not longer and it's working at all. So let's give a bispecific instead. Or we may, and we're actually doing this right now for a patient, using a bispecific to help get rid of a lot of her disease before getting her CAR T to lower the risk of side effects from CAR T. So with that, I will stop. This is one of my favorite quotes. I'll let you read it while I stall for seven more seconds. And I'll say thank you all for your time.