(Guest Lecture): October 2023 - New Therapies, New Side Effects

So hi everyone. My name is Kara Cicero and I am a clinical assistant professor at the University of Washington at the Fred Hutchinson Cancer Center working with Dr. Cowan and Dr. Banerjee who you just heard from. So I want to thank you all for coming here today and thank Health Tree for having me speak. So after Dr. Cowan and Dr. Banerjee just set the stage, I'll talk a little bit about some of these specific side effects that is now seen with T-cell directed therapies. So new therapies, new side effects as it relates to multiple myeloma. And so these are my disclosures. And so first, I'll give a very broad overview of T-cells and how they normally function within our bodies just for some context of why we're getting some of these specific side effects that we are with these T-cell directed therapies. And then I'll go into some of the clinical trials for those products that are currently approved and available. So we'll go into the CAR T-cells and those side effects seen there in those clinical trials, followed by the T-cell engaging by specific antibodies. So talking about T-cells. So as Dr. Cowan and Dr. Banerjee has already talked about, T-cells are part of our adaptive immune system. And what this means is that our bodies create many, many, many different types of T-cells, each with the unique ability to recognize one specific type of foreign body, something that's not supposed to be there. So something like a virus like influenza. And when a T-cell sees this virus, sees the influenza, then that specific T-cell that is designed to recognize this virus is activated by itself. And once it's activated, it creates a whole stream of downstream effects. So it releases what we call as cytokines or inflammatory signals. And all these inflammatory signals are released and with the eventual end goal of killing the infected cell, targeting the virus, et cetera. And so when someone is sick with, let's say, the flu, a lot of those manifestations of feeling sick, those physical manifestations of fever, chills, muscle aches, et cetera, are really due to our body's own response, our body's own inflammatory response as it is fighting that infection. And so Drs. Banerjee and Cowan already talked about this. But when we think about CAR T-cells, what it actually is functioning as is a patient has their own blood taken out and then those T-cells are isolated, re-engineered to rather than targeting the viruses or other foreign products, they're re-engineered to find the myeloma cells. So in the cases of the currently approved CAR T-cells, they're both looking at BCMI or B cell maturation antigen. And so it's not surprising that if the CAR T-cells are doing its job, then we will have a lot of those same manifestations that one might have when they are sick with something like the flu. And so we'll talk a little bit about that more when we get to the specific trials, but just some idea that maybe this is why we're seeing some of the side effects of what we are, because the CAR T-cells are acting as they should be. They're targeting the myeloma cells just like our normal T-cells are targeting viruses like the flu. And so then when we think about bispecific antibodies, as Dr. Banerjee has already talked about, this is a very, very oversimplified way of thinking about it. But we have all of our normal T-cells that are circulating throughout our body and then there's also the myeloma cells. And so what bispecific antibodies are now doing is it's taking on one hand targeting the T-cells and it's bringing closer to the myeloma cells on the other hand. And by bringing the T-cells to the myeloma cells, it's activating those T-cells in a similar way that the CAR T-cells are activated, in a similar way that our normal immune system is activating T-cells, and having those same kind of downstream effects, inflammation with the ultimate goal of targeting the myeloma cells. And so, again, it's understandable why sometimes we might feel the manifestations that one might feel when one is sick with something like the flu. So now talking about CAR T-cells specifically. So, Cephalocell and Idacell are the ones that are currently approved. And so CARMA 3 was a randomized study that was looking at Idacell, which is a CAR T-cell that is targeting BCMI, or B-cell maturation antigen. And it was comparing the Idacell to standard of care for relapse refractory multiple myeloma due to two to four prior lines of therapy. And when we're looking at the toxicities, what we can see is that almost every person had some sort of toxicity. So any grade was 99% of people with Idacell, but then standard of care was also quite toxic, with 98% of people having some sort of adverse event. And then you could see grade three or four, the more severe toxicities were also seen in a large percentage of people with both standard of care as well as Idacell. Hematologic toxicities were very common. This is something that we see with pretty much all kinds of myeloma therapies, as you can see from the standard of care regimens. And so you might see decreased blood counts with decreased neutrophils that are normally fighting against other types of infections, decreased red blood cells. So you might be anemic, have symptoms of fatigue, lightheadedness, palpitation, shortness of breath if it gets pretty bad. Thrombocytopenia, so that's decreased platelets, so you might have symptoms of bruising or bleeding if that gets quite low. So these are symptoms that are seen with most standard of care myeloma treatments, but also with CAR T cells. GI effects were something that was seen with both CAR T as well as standard of care. But if you look at the grade three or four side effects, these aren't very common. Most of them were not as severe. And then other adverse events when we look at what we want to pay attention to is really infections. So because these T cell directed therapies are targeting the plasma cells, which are the myeloma cells, there's also a risk. Plasma cells normally create antibodies to fight against all different types of infections. And so there's a risk of when we decrease normal plasma cells, there's also a risk of having more infections. So whether it's standard of care or the CAR T cells, it's not surprising that there's always going to be this risk of infection. Cartitude four was looking at CILTA cell, which is another CAR T cell therapy directed at BCMA. And this was CILTA cell compared to standard of care for one to three prior lines of therapy for multiple myeloma. And here again, every single participant in this trial had some sort of adverse event. Hematologic events were, again, quite common, whether or not one got CAR T cell or whether or not one just had normal standard of care with decreased blood counts. Infection, as we just discussed, was quite common. And then a whole range of other adverse events, whether GI or not, that were seen in more than 15 percent of those participants. But really what I want to focus on are the T cell directed specific side effects. And so what we see is something called cytokine release syndrome and then neurotoxicity. And I'll go into each of these a bit more now. So cytokine release syndrome. So Dr. Banerjee kind of touched on this. And initially this was actually a term that was coined in the 1990s when an anti T cell antibody was created for solid organ transplant. And what they found was that, you know, there was a systemic inflammatory response when giving T cell directed therapy. And so when we think about back to how T cells normally act in infection. So when one has the flu, then T cells are simulated. They're doing their job and they're they're releasing a bunch of these inflammatory markers causing this cytokine storm. And therefore, based on all these inflammatory markers that are fighting against infection, that you have the manifestations of severe infection. You have manifestations of sometimes sepsis. And so this is mimicked by when we're giving T cell directed therapy. So when the treatment is something like when you're being treated with something like car T, then T cells are similarly being stimulated. Similarly, there's a cytokine storm. And so when these inflammatory signals are being activated, then you have similar manifestations of flu like illness. So initially, fever is seen pretty much universally with CRS or cytokine release syndrome. And fevers, it could be muscle aches, cough, joint pain. And then if it gets more severe, it could actually involve other organs and pretty much any organ system can be involved. So there can be decreased blood pressure leading to shock. There can be kidney involvement. There can be lung involvement in which oxygen is required. And so there could be issues with bleeding and clotting. And so, again, it really is this systemic inflammatory response that's really mimicking what happens when one has a severe infection. And so severe CRS is a risk for concurrent infection. But at the same time, because of the similar pathogenesis between the two, it's really difficult to differentiate between infection and CRS. So in general, very low threshold to treat it like an infection as well as treating the CRS with antibiotics. So in terms of severity of CRS, so there's a couple of predictors of severity. The first is disease burden. And if one has a lot of myeloma cells prior to the infusion of CAR T, then one is more likely to have more severe CRS because, as Dr. Banerjee said, you know, the CAR T cells are kind of inducing this explosion of fighting the myeloma cells. And so typically what is done is that while you're waiting for the CAR T cells to be manufactured, there's also one is getting bridging therapy or in some regards, some either chemotherapy or other types of treatment to debulk the myeloma tumor burden so that the risk of not only for disease control, but also for the risk of CRS to be lessened. Strength of T cell activation and the degree of T cell expansion also predict for CRS severity. And this is pretty much dictated by the actual CAR constructs themselves. So how strong the CARs are binding to the myeloma cells and expanding within your body will dictate the severity of CRS. And then not surprisingly, when one does not have a great response to CAR T cells, CRS might be more mild or absent. The reason being that if the CAR T's are doing their job and fighting against the myeloma cells, then we would expect some sort of inflammatory response and some sort of degree of CRS. So the treatment of CRS is really delineated by the severity of CRS. With mild CRS, which is really just symptoms of mild flu, so fatigue, fevers, muscle aches, really not severe symptoms, you're really treating those symptoms. So you're giving antipyretics like Tylenol. You're giving fluids, whether by orally or by IV, to increase the blood pressure. And then a very low threshold again to give antibiotics just because it's difficult to distinguish a concurrent infection. When it then turns into severe CRS is when there's shock and there's multi-organ failure. And so again, this can be any kind of organ system can be involved, whether it's the lungs, the kidneys, the heart. And in cases of severe CRS, now you're treating the CRS itself. So again, thinking about the pathogenesis of CRS. So the T cells are stimulated when you're giving CAR T or other T cell directed therapies, and they're releasing all these cytokines, these inflammatory signals. And one of these cytokines is called IL-6. That's a big marker for the cytokine storm. And so tocilizumab is an antibody that blocks IL-6. So when someone has severe CRS, tocilizumab is the mainstay of treatment. And so it's supposed to block the downstream effects of CRS. Steroids may or may not be given as well to have a global decrease in cytokines and immunosuppression. And then, you know, more supportive treatments. So oxygen if it's needed, pressures if you need to raise your blood pressure, et cetera. And so although severe CRS can be scary, it is often preventable and often reversible if it's recognized and treated early. So looking at then back to these trials, when we looked at CARMA 3 with IDA cell, we saw that CRS happened in 88 percent of people. But severe CRS only in 4 percent. And there was one person, two people that did unfortunately have fatal CRS. CILTA cell was also seen in 76 percent of people. But more severe CRS, grade 3 or 4, was seen only in 1 percent. So as we become more experienced with CAR T cell, T cell directed therapies in general, we're learning how to manage it. And so we're learning how to recognize, treat appropriately and treat early so that even though CRS in general is very common, actually the severe CRS is not. So switching gears a bit to immune effector cell associated neurotoxicity syndrome. So it's a mouthful and also is called ICANNs. And so this is another T cell directed therapy, unique adverse event. And here what's happening is when the CAR T cells are expanding throughout the body, they're circulating looking for the tumor cells, in this case the plasma cells. They're also crossing the blood brain barrier. And the blood brain barrier is our body's natural physical defense, separating our central nervous system. So encompassing the brain, encompassing our spinal cord from the rest of our body, from the outside world. Because it really should be protected. But when these CAR T cells cross the blood brain barrier, then they disrupt the blood brain barrier. And ICANNs is a little bit less understood than CRS in general, but one of the biggest theories about why one has these neurotoxic effects is because with disruption of the blood brain barrier, these inflammatory signals, the cytokines, are then able to enter the central nervous system space. And so there is able to be some toxic effects on the brain tissue itself. And so symptoms of ICANNs range from mild to more severe. So oftentimes they'll start with mild confusion and it might not be noticeable at all. So maybe some word finding difficulties, changes in handwriting is something that's commonly seen. And then it could switch over to more severe so that people might not be able to comprehend anything or might have difficulty speaking entirely. And in very severe cases could lead to seizures and somnolence. This is also typically self-limited and often reversible without any permanent neurologic damage. And the treatment here is really steroids. So tocilizumab, which was used for CRS, is not really used in this case, perhaps because it doesn't cross the blood brain barrier. But either whatever the reason, it's not effective in ICANNs. So steroids is really the main set of treatment here. And so if we look at the CAR T cell therapy trials, we see that neurotoxic events happened at any grade with 15 percent of people in IDA cell. And ICANN specifically with Cilta cell was 4 percent. Again, the more grade three or four severe adverse events were quite rare in both. Looking at something that was interesting, these movement disorders that was seen in Cilta cell, just want to take a second to talk about this. So this was a case study that was actually published about one patient who developed symptoms like Parkinson's, a hundred days after receiving Cilta cell. And this is this was thought to be due to Cilta cell targets BCMA. And there was BCMA expression on the part of the brain that is typically implicated in Parkinson's. And so this patient ended up having Parkinson's like features a hundred days after probably due to the CAR T cell targeting that same area of the brain. So very rare, but it has been seen. Switching gears to bispecific antibodies. So Toclistumab is a BCMA targeting bispecific antibody. And similar to the CAR T cells, we see adverse events in pretty much everyone. Same kind of thing. We see decreased blood counts quite commonly. But the real point that I want to make with the bispecific antibodies is this risk of infection. So infection is quite common with bispecific antibodies and can be severe. So 76 percent were seen to have some sort of infection, 45 percent with severe infection. And this is thought to be due to bispecifics are giving continuously. And so your normal plasma cells are being targeted. You don't have the ability to create normal bodies to fight against infections. At the same time, you have decreased blood counts, the white blood, you know, your nutrient bills, your other types of lymphocytes to fight against infection. And as Dr. Banerjee had talked about, there's this idea of T cell exhaustion. So if you're continuously getting this therapy, then there's the risk that your T cells are always fighting against the myeloma cells being exhausted and not really able to fight against the other types of infections out there. Elrinatumab also 100 percent of people had some sort of adverse event, low blood counts. But then infection, again, a big problem that we see. So 70 percent of people had some sort of infection, 40 percent had severe infection, and there were 6.5 percent of people with fatal infections. And then there's telcoidumab. So this is a GPR, GPR C5D, always a mouthful, targeting bispecific antibody. And here we also see, you know, 100 percent have some sort of adverse event. But here the infections, although they're prevalent at any grade, so 34 to 47 percent, depending on how it's dosed, the severe infections are less so. So here the severe infections are really only 7 percent. And so that's important then when we think about, you know, how to prevent certain types of preventative strategies when someone's getting bispecifics. Telcoidumab, too, has some unique toxicities that have been seen. So as Dr. Banerjee had talked about, telcoidumab has been found to have associations with skin changes and nail changes. And so skin and nail changes are quite common, but it can range from many different things, whether it's eczema and dry skin to ulcers and darkening of skin to just itching. There's a lot of different changes that might be seen, mostly because there have been thoughts that GPR C5D is seen in the body. And so this is also thought to be seen in the skin itself or in nail beds. There's also some oral changes, so changes in taste, dry mouth, and this difficulty with swallowing. And this could all lead to some weight loss, which can be problematic. And this is also thought because the same kind of receptor is seen on or the same kind of marker is also seen on the tongue. So this is a study that was published about a more severe case of telcoidumab skin changes. And for this, we're still trying to figure out how best to treat it. But lotion was used, and they were able to stop the itching, but they weren't really able to stop the darkening or the actual physical changes of it. So the bi-specifics, as I said, infection is a pretty big problem because it's giving continuously. And the longer that one receives the bi-specifics, the higher likelihood that one would have infections eventually. And so with the BCMA targeted bi-specifics, infections are more common than the GPR C5D bi-specifics. And so there's different strategies that have been used in order to prevent infections. A lot of supplementary medications like antibiotics are used. Sometimes people will get IVIG specifically for the BCMAs, more so than the GPR C5Ds. And so then going back to the CRS, cytokine release syndrome, we're seeing the same kind of thing with these bi-specifics. So to Clistomab, L-Renatumab, and Telcoidumab all have a high degree of CRS similar to the CAR T8 because, again, they're activating these T cells. ICANNs was less common in bi-specifics, although it can be seen. And the reason here is that bi-specifics aren't really thought to cross the blood-brain barrier to the same degree as CAR T cells. So typically, more of the neurotoxicities are more like headaches rather than the full ICANNs picture. So in conclusion, CRS could be thought of as like flu-like symptoms that range from mild to severe. There are common side effects of both CAR T and bi-specifics. And organ dysfunction is possible, but often preventable or reversible if it's treated early. Then there's ICANNs, which are the neurotoxic symptoms that range from mild to severe. It's more so a side effect of CAR T more so than bi-specifics. And it also is often time-limited and reversible. And then lastly, there are some target-specific unique toxicities. So very rarely there's Parkinsonism features seen with BCMA CAR T's. And then with the GPRC5D bi-specifics, there's skin and nail changes are quite common. And then there's also oral related changes like changes of taste that are quite common as well. And with that, I thank you for your time and I'll be happy to answer any questions later. Thank you.