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Amelia Langston, MD: Hello. I'm Dr Amelia Langston, and welcome to Medscape's InDiscussion series on chimeric antigen receptor (CAR) T-cell therapy. Today we're going to talk about CAR T-cell therapy for lymphomas, primarily B-cell lymphomas, with Dr Loretta Nastoupil. Dr Nastoupil is an associate professor and the deputy chair of the Department of Lymphoma-Myeloma in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center. In previous episodes, we've talked about CAR T-cell therapy as a way to reprogram a patient's own T cells to become targeted killers aimed at tumor cell-specific surface antigens. Today we're going to focus on the applicability of these therapies specifically to lymphomas, primarily B-cell disease. Dr Nastoupil, let's start with the target. All of the approved CAR T-cell products to date are directed against CD19. Talk a little bit about CD19 and the consequences of killing CD19-positive cells.
Loretta J. Nastoupil, MD: Thanks, Dr Langston. I think that's a great place to start because we know that T cells can be quite effective at eradicating any cell that they can effectively see. CD19 is a great target for B-cell lymphoma because it's present on the vast majority of those lymphomas. It's on the surface of the cell. It's something that an extracellular target could potentially see, and it's present on mature B cells. For instance, if you eradicate all of the mature B cells in a patient, though that might increase their risk for certain types of infections, it doesn't result in significant harm to the patient. It's a fantastic target because it's accessible, it's ubiquitously expressed on the tumor, and people could potentially live without the normal cells that are going to be eradicated in this process.
Langston: We do have some other potential B-cell targets that are under study, both in the setting of monoclonal antibodies and bispecific antibodies, CD22, CD20. There's also interest in potentially mixing and matching, so that a T cell might be reprogramed for more than one target. Do you have any studies at your institution looking at those kinds of issues?
Nastoupil: We know that rituximab — which is a monoclonal antibody that targets CD20, another commonly expressed tumor antigen on B-cell lymphomas — has changed the natural history of the disease for many patients over the past two decades. The challenge there, though, is that because many of these patients will have multiple courses of CD20-targeting therapy, it is nice to have a bit of heterogeneity in terms of the tumor target. We also know CD19 is early in the development of that mature B cell. It should be ubiquitously expressed until we start to potentially target it, or we have some therapeutic pressure that's going to lead to clonal evolution where you're selecting out for those CD19-negative clones. We do know that for lymphoma specifically, about a third of patients who have CD19 targeting will start to lose that antigen. Either it will be internalized into the cell where it's not as easily accessible from an extracellular source, or you lose the antigen expression altogether. That is why there is value in either dual-antigen targeting or sequencing that target. At our center, for instance, we have a CD19/CD20 dual CAR, and we have a CD20 alone CAR. At other centers, there have been CD19/CD22 dual-targeting CARs. I think that's the next wave, because we do see some selective pressure for tumors to either internalize or lose that antigen as one mechanism of resistance.
Langston: You pointed out appropriately that we can live without B cells, but there's a subset of these patients who do develop prolonged B-cell aplasia, and some of them never have their B cells recovered and need intravenous immune globulin (IVIG). I think we have to remember that point as we send patients back to their referring doctors and as we counsel them about their behaviors and about the potential for prolonged need for IVIG because there are late infectious complications that can occur, particularly in those people who have prolonged B-cell aplasia. Dr Nastoupil, the first FDA approvals for CAR T-cell therapy in the lymphoma space were in multiply relapsed, diffuse large B-cell lymphoma (DLBCL) patients. Can you talk about those studies that established CAR T-cell therapy as potentially curative therapy in these patients who are particularly difficult to treat?
Nastoupil: I think you nailed it. They were particularly difficult patients. If we look backwards over time prior to CAR T's entry into the treatment landscape, we saw that the median survival for patients who had failed at least two prior lines of therapy, never achieved chemosensitive disease, or progressed within a year of high-dose therapy or autologous stem cell transplant was 6 months. That was including patients at centers like ours — at MD Anderson, Mayo, large European consortiums — where they potentially had access to novel therapies on clinical trial. We saw very poor outcomes for this population of patients. There were three single-arm phase 2 trials that targeted that population, given there was such an unmet need. The ZUMA-1 study looked at axicabtagene ciloleucel (axi-cel), which is a CD19-directed autologous CAR with a CD28 co-stimulatory molecule. The JULIET study looked at tisagenlecleucel, yet another CD19 but 4-1BB co-stimulatory autologous CAR. The TRANSCEND study looked at lisocabtagene maraleucel (liso-cel). [These studies] were different in terms of the populations they targeted. Also, there are differences among the studies in the construct, how the CARs are manufactured, and the time it takes from collection of those patient cells until you have available product. As a result, you can't really compare across these trials. In general, in this high-risk patient population, about 40% of the patients enrolled on these single-arm phase 2 trials had meaningful remissions, meaning it was a definitive therapy. It changed the natural history of that disease. That is evident by the fact that we see response rates ranging from 60% to 80%, whereas previously a 20% response rate was expected for novel therapies. The complete response rates are in the range of 50% to 60%, and we see durable complete remissions in that 40-percentage range. The overall survival is now dramatically better than 6 months. As a result of these single-arm phase 2 studies, we have three FDA-approved autologous CD19-directed CARs. I would argue it's the most effective therapy we've seen in this high-risk population.
Langston: One of the things that strikes me is how different the constructs are, how different the studies were, yet they came to pretty similar long-term results with somewhere between 30% and 40% of patients appearing to be cured by this therapy. That is a big breakthrough for this heavily pretreated population of patients. More recently, we've had several studies supporting the use of CAR T-cell therapy earlier in the course of DLBCL, specifically in the second-line setting. Let's talk about the studies in this space and some remaining controversies in patients with first relapse.
Nastoupil: Another lesson that we can learn by looking backwards over time is that in the rituximab era, the ability for us to successfully salvage patients with platinum-based chemotherapy and high-dose therapy autologous transplant in the setting of chemosensitive disease was not quite as great for patients who progressed, particularly within a year of rituximab and anthracycline-containing front-line therapy. So, that sets the stage for an unmet need. Because CAR T was so effective in that third-line or later space among high-risk patients, there were three randomized studies that set out to see if we could do better than what we're currently able to achieve with standard-of-care second line for those early relapsed large cell lymphoma patients. It is the first time that these individual products were studied and compared in the same population. As I mentioned, there was quite a bit of heterogeneity in terms of how the initial phase 2 study trials were conducted. But now, we all agreed on what was the unmet need or the high-risk population. It's those early, relapsed, large cell lymphoma patients. There were differences in how the trials were conducted, though. Once patients were enrolled and randomized in ZUMA-7, for instance, they were randomized to the experimental arm of axi-cel in second line. No bridging other than corticosteroids was allowed, and there was no crossover in that study; the arms were quite well balanced. When we consider the TRANSFORM study, which looked at liso-cel vs second line for early relapse patients, they were actually collected upfront during the screening process, then randomized because there was an allowed crossover given the longer time to manufacture for patients on the experimental CAR T arm. They could have one cycle of platinum-based salvage chemotherapy as a bridging strategy while awaiting manufacturing. Contrast that to the third study, which was the BELINDA trial. They were randomized and collected upfront because crossover was allowed from the control arm to the CAR T arm. Patients in the CAR T arm could have multiple cycles of platinum-based chemo because there was a longer time lapse from enrollment to cell infusion with an average of about 54 days. Patients on the control arm could have more than one attempt at achieving chemosensitive disease, meaning you could alter your platinum-based salvage if you didn't have a deep enough response. I highlight all these differences because we do have two studies that are clearly positive: ZUMA-7, which looked axi-cel in second line, and TRANSFORM, which looked at liso-cel in second line resulting in significant improvements in event-free survival over platinum-based chemo in that second-line setting. We just heard that there's an overall survival statistically significant benefit in the ZUMA-7 study for patients who got axi-cel in second line. But how do we reconcile that with the third study being completely negative? There was no difference between tisa-cel in second line vs platinum-based chemotherapy in second line. I can't help but think of some of the ways the trials were conducted. The delay from enrollment to cell infusion on the CAR T arm with BELINDA probably had an impact. We also start to look at the efficacy of the various agents and have questions. Maybe there is a difference between how well axi-cel and liso-cel works vs tisa-cel. The important thing to remember is this was conducted in patients who not only relapsed early but also were appropriate candidates for intensive therapy. The other questions we now have after these studies are done: What do we do for a later relapse? How do we approach a patient who's a little bit frailer and maybe would not have qualified for these studies? Let me throw that one back to you. How are you fielding those questions right now?
Langston: I would say my bar for appropriateness for CAR T-cell therapy is similar to my frailty bar for undergoing an autologous transplant. Certainly, the chemotherapy part of CAR T-cell therapy is not nearly as intensive as the high-dose therapy we use for transplant. But, on the other hand, you take a patient who is frail, and you give them cytokine release syndrome or neurotoxicity, and that could be a rough situation. I think you have to have some degree of robustness in order for a patient to be a candidate for CAR T-cell therapy. We are still transplanting patients as second-line therapy if they have a longer first remission. I see patients all the time who had a 2- or 3-year remission who do very well. I agree that autotransplant is not terribly effective in rituximab-exposed patients who are either primary refractory or relapse within a year. We are offering those patients CAR T therapy if we can get them in and get them collected and manufactured. That brings us to some of the logistical hurdles that come up. I think there's a lack of appreciation on the part of referring physicians and patients about the different steps involved between the time the patient comes in and the time that the patient gets treated with CAR T-cell therapy. They have to be apheresed, then that product needs to be sent off and manufactured. That can be a long time period. How were you at your center approaching the question of bridging therapy?
Nastoupil: That's a critical question. I think the BELINDA study shed some light on how critical time is, because the longer it takes for us to consider a patient for CAR until we actually infuse those cells probably does have an impact on outcome. We talk about this regularly, and we're not perfect by any sense, but we're constantly reevaluating and improving our workflow. Even things like getting that first patient appointment. Everybody is really backed up right now, and I think COVID did have an impact on that. Our next available appointments are much further out than we would like them to be. How can we improve flagging these patients who are considered for CAR where we might triage them a little bit differently? Can we prioritize giving them an appointment and overbooking a slot if necessary to get them in? I think the sooner we can get them in our hands, the better. There's going to be a delay from the time we deem them to be an appropriate candidate until we can actually proceed with leukapheresis because of the insurance issues that we face, at least in our center. Medicare patients are probably one of the fastest in terms of approval. If a patient is privately insured, it's going to take longer. All those things factor in to patient outcomes. Bridging generally implies that I've collected their cells, and I need to stabilize their lymphoma while we're manufacturing a product. Depending on how long it takes to even get to leukapheresis, that's going to impact how and when I choose to bridge. In our center, led by Chelsea Pinnix, MD, PhD, who is a fantastic radiation oncologist, we've started using quite a bit of bridging radiation for a couple reasons. You can use lower dose — even for our aggressive lymphomas, we use 12 Gy. For our low-grade lymphoma, which is not that common that you need to bridge those patients, we've been using 4 Gy. The idea is that we're going to target the largest mass that will be the highest risk in terms of organ compromise, or maybe it's a mass that we're concerned we're not going be able to get those cells to traffic in as well. I do like radiation if it can be done safely, and it's going to control the disease well enough to get them through those 3-4 weeks of manufacturing. If radiation is not an option, then I think any systemic therapy can be considered. What we learn from our outcomes is the more intensive chemo you give, particularly in these patients who are more heavily pretreated, the more likely you're going to have a potential infectious complication that might then delay that CAR. If I need a systemic option, I tend to try to use things like polatuzumab and rituximab as opposed to more intensive chemo.
Langston: Now, switching gears, we've now had more recent approval of CD19-directed CAR T-cell therapy for B-cell lymphomas other than DLBCL. We've got mantle cell now and follicular lymphomas. Can you talk about the data that led to those approvals?
Nastoupil: I'll start with mantle cell, because it's a little bit easier to define a patient who would be appropriate for CAR T with mantle cell lymphoma (MCL). The ZUMA-2 study was a single-arm phase 2 study. The enrolled patients were in the relapsed setting. They had to have had prior exposure to Bruton tyrosine kinase (BTK) inhibitors. They didn't have to fail BTK, but they had to have 100% of the patients having prior BTK inhibitor therapy, and the majority — about 60% — had actually progressed or failed to respond to BTK inhibitors. That identifies the population. It's usually in that second or third line after a BTK inhibitor. It's a slightly different manufacturing process because MCL can be extra nodal, including in the peripheral blood. The leukapheresis product is purged of CD19-expressing cells. Because of that extra step, it's called brexucabtagene autoleucel (brexa-cel). It looks a lot like axi-cel in terms of the construct and that it's a CD19/CD28 CAR. These patients have toxicity, in my opinion, that mirrors what we see with large cell lymphoma. About a third get neurotoxicity, or immune effector cell-associated neurotoxicity syndrome (ICANS) that's grade 3 or higher, and we tend to see cytokine release syndrome in the similar rates that we would see with large cell lymphoma, but the efficacy looks good. We see about 60% of patients maintaining their complete response. We don't see the same curve shape that we see with large cell lymphoma, where we see this drop off but then plateauing — if you're in a complete response at month 3, you're going to be in a complete response at 12 months or 2 years out. It's a little bit different. We're optimistic about the outcomes with CAR T and mantle cell and follicular lymphomas. At this point, I don't know if it's as curative or a definitive therapy as I'm confident saying in large cell, but I do use it for patients. I use it in that second- or third-line space, if they've already had a BTK inhibitor and are progressing, and particularly for those high-risk patients like 17p/TP53 or complex cytogenetics. For follicular lymphoma, we have two products, both axi-cel and tisa-cel based off of single-arm phase 2 studies. It's a little bit harder to define which patients should be considered for CAR, but at least in my practice, it's generally patients who are progressing quickly through effective therapy. So, those progression of disease within 2 years (POD24) patients. They progressed within 24 months of chemoimmunotherapy, and they've had two rounds of chemo or chemo and lenalidomide/rituximab, for instance, and they're just not responding like I would have anticipated. It looks a lot like transformed disease, meaning they have a lot of symptoms: lactate dehydrogenase (LDH) is rising quickly and standardized uptake values (SUVs) on positron emission tomography (PET) may be high. I biopsy them, and I'm surprised to see it's still follicular lymphoma. Those are the patients I'm going to consider for CAR because the efficacy both in ZUMA-5 and ELARA look really good in terms of what I would expect for those higher-risk patients. It's a smaller population in indolent lymphoma for whom we consider CAR, given all the other available options to them.
Langston: With the last few minutes, where do you see the CAR T story going? What are the things that you think are most exciting?
Nastoupil: I'm really excited about the overall survival advantage we're seeing right now with axi-cel in second line for early relapse, large cell lymphomas. To me, that's the sweet spot. That's where I am going to use it every chance I have opportunity. For the indolent lymphomas, I think it's going to be a little bit harder to carve out who the high-risk patients are where it's going to be more mainstay. I think it will be in a smaller cohort of patients who are high enough risk that it's warranted. What I'm not sure about is if we're going to ever move it into front line for something like TP53-mutated mantle cell, or whether you can define a large cell lymphoma that's high enough risk that you would forego an anthracycline-containing front-line chemoimmunotherapy. We have a few studies where that's being asked right now, particularly ZUMA-23, where you take patients who have high-grade B-cell lymphoma (HGBL), double-hit features, and an International Prognostic Index (IPI) that's quite high. They get two cycles of rituximab and anthracycline, and then they're randomized to CAR vs continuing chemotherapy. If that's a positive study, I might move it even earlier into the treatment course for those high-risk large cell lymphoma patients. I think the challenge is going to be what happens for patients who fail, particularly if we move it into earlier lines. Can we optimize patients, meaning can we reduce the financial burden by identifying patients most likely to benefit and less likely to have toxicity? I think we need more time and experience to get better at that.
Langston: I think the idea of being able to have an off-the-shelf product is interesting, whether it's a T-cell product or an NK/T-cell product. We're not there yet, but certainly those things are being studied and that would greatly reduce the cost as well as that time lag that we struggle with so much. What about T-cell lymphomas and Hodgkin's?
Nastoupil: It's a good question. Clearly, CD30 targeting in Hodgkin's and some T-cell lymphomas has been important. There are CD30-directed CARs that are under exploration. In T-cell lymphoma, where you have a more traditional T-cell target, you have to be careful. You don't want to eradicate your CARs. There has to be more engineering or identifying of a target where you are hoping to use a T cell to target a malignant T cell and not just eradicate your CARs as a bystander effect. Those are some of the challenges that we're facing. The durability of response in these diseases is another challenge. With Hodgkin's lymphoma, we know that the microenvironment is so much more inflamed and pro tumor, and there might be other challenges in terms of that T cell getting in there and not getting exhausted. It's a different biology, so it's a different strategy in terms of the antigen you're targeting. I'm still optimistic that we'll figure those things out.
Langston: This has been a really great discussion, Dr Nastoupil. Thank you for talking with me today, and thanks to the audience for joining us. This is Dr Amelia Langston signing off for InDiscussion.
Resources
Axicabtagene Ciloleucel CAR T-cell Therapy in Refractory Large B-cell Lymphoma
Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma
Axicabtagene Ciloleucel as Second-line Therapy for Large B-cell Lymphoma
Second-line Tisagenlecleucel or Standard Care in Aggressive B-cell Lymphoma
KTE-X19 CAR T-cell Therapy in Relapsed or Refractory Mantle-cell Lymphoma
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Cite this: CAR T-Cell Therapy for B-Cell Lymphomas - Medscape - Jul 11, 2023.
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