Biomarkers Predict Outcomes of CAR T-Cell Therapy in Patients with Diffuse Large B-Cell Lymphoma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I program and co-director of sarcoma care at Cleveland Clinic. Today, I'm happy to be joined by Dr. Brian Hill, Director of the Lymphoid Malignancies Program and the Cleveland Clinic Taussig Cancer Institute. He's here today to talk to us about research from the recent American Society of Hematology meeting on biomarkers predicting outcomes of CAR T-cell therapy and patients with diverse large B-Cell lymphoma. So welcome, Brian.

Brian Hill, MD, PhD: Thank you. Thank you for having me.

Dale Shepard, MD, PhD: Absolutely. So maybe to start, tell us a little bit about what you do here at Cleveland Clinic.

Brian Hill, MD, PhD: Yeah. So my role here, as you pointed out, is the Director of Lymphoid Malignancies. So I'm a physician who sees patients with lymphoma, chronic lymphocytic leukemia and related conditions. So I see and treat patients and also perform clinical and translational research in those diseases.

Dale Shepard, MD, PhD: Excellent. So we're going to talk today about the research that you presented at the recent ASH meeting, looking at biomarkers and CAR T-cell therapy. So tell us a little bit about the background and what was the question you were trying to answer?

Brian Hill, MD, PhD: Yeah, so for the most common lymphoma that we see, which is called diffuse large B-cell lymphoma, this actually represents not a single disease, but probably multiple different sort of subtypes that we've learned based on advanced molecular profiling over the past several years.

The treatment for diffuse large B-cell lymphoma in 2022 remains the same treatment that we've had for the past 20 years or so, which is a cocktail of chemotherapy drugs and an antibody that, combined together, is called R-CHOP. And that hasn't changed for a long time despite multiple attempts to improve upon the outcomes. What has changed in the management of diffuse large B-cell lymphoma is how we treat or manage patients who relapse. So we probably cure about 70% of patients with the diffuse large B-cell lymphoma with R-CHOP, which means another 30% or so are not going to be cured.

And in that scenario, there's a few different approaches to management, including high-dose chemotherapy and autologous stem cell transplant historically or, more recently, CAR T-cell therapy. If you haven't heard of CAR T-cell therapy yet, this refers to chimeric antigen receptors that are conferred upon the patient's own T-cells in a laboratory. So T-cells are collected by leukapheresis and, ex vivo, in the lab, are manipulated with a lentiviral vector to encode a gene that recognizes a B-cell target. In this case, CD19.

Those cells are then reinfused to the patient after lymphodepleting chemotherapy and this redirects the patient's own T-cells to recognize and destroy B-cell malignant cells. And even though it sort of sounds a little bit like science fiction, this is now pretty standard of care for third line and eventually probably will become second line treatment for DLBCL.

Dale Shepard, MD, PhD: So your particular trial was looking at biomarkers related to this treatment. So tell us a little bit about that.

Brian Hill, MD, PhD: So what we notice with CAR T-cell treatment is it works very well in many patients, but like many cancer therapies, it doesn't work in everyone. And there are probably many reasons for the failure of CAR T-cell treatment to work.

One of the reasons it may not work may be just simply that the lymph nodes and the tumor bulk is too big or other reasons may be the T-cells that were collected were not very healthy at the time that the CAR T-cells were manufactured and so forth.

But what hasn't really been extensively investigated is the role of the actual tumor biology in resistance or sensitivity to CAR T-cell therapy. So our project that I worked closely with a collaborator at Duke University, Dr. Sandeep Dave, involved the collection of clinical specimens from biopsies of over a hundred patients with diffuse large B-cell lymphoma that had relapsed and then undergone subsequent treatment with CAR T-cell therapy.

And we subjected the specimens to whole exome sequencing, gene expression profiling, chromosome copy number alteration. And what we learned from this is that the subgroups of patients with diffuse large B-cell lymphoma that are seen in the sort of frontline and have different outcomes with R-CHOP have various representations in the relapse setting.

Interestingly enough, there's about five of these subgroups they call cluster one, two, three, four, five, and there's another nomenclature, but, suffice it to say, that some of the high risk clusters are groups, including a group that's characterized by p53 mutation, actually, which normally has very poor outcomes with standard R-CHOP therapy, had favorable outcomes with CAR T-cell treatment. And so what we sort of conclude from this is that some of the molecular features that confer poor outcomes to treatment with standard chemotherapy are different from the molecular features that confer favorable or unfavorable outcomes with adoptive cellular therapy.

Dale Shepard, MD, PhD: So could this potentially mean that there are patients who should not start with R-CHOP and that maybe people should have this molecular testing upfront and choose therapies based on that?

Brian Hill, MD, PhD: That's a great question that is being actively explored. One of the challenges with doing this sort of sophisticated level of molecular analysis is that it's, right now, mostly a research tool. We don't have clinically available tests that we can order that to give us the subgroup of diffuse large B-cell lymphoma.

We can tell whether it's a germinal center or an activated B-cell subtype with some crude sort of immunohistochemistry stains, but it's not very precise. So I think, going forward, it's very likely that there will be attempts to pick the treatment specific based on the subtype or cluster of the diffuse large B-cell lymphoma and then test this in a perspective fashion. But those type of efforts are going to take time and resources to complete, but such trials are in the development and planning stage already.

Dale Shepard, MD, PhD: And you said that this CAR T-cell therapy is oftentimes a third line therapy. What might make that move earlier into treatment?

Brian Hill, MD, PhD: Yeah, so that's a very, very good question. A lot of excitement came with the FDA approval of multiple different CAR T-cell products for diffuse large B-cell lymphoma and other lymphomas. And as we alluded to, it really has been used for patients who've already gone through an autologous transplant or patients who are not really eligible for an autologous transplant, usually because their disease is not controlled well from... It's not sensitive enough to chemotherapy to justify high-dose chemotherapy.

And so at this year's ASH meeting, we did see actually three clinical trials were reported with each of the three CAR T-cell products. And these were all randomized phase three trials that compared standard of care therapy with CAR T-cell treatment. And actually two of the three studies were positive, published in the New England Journal of Medicine recently and presented at high-profile sessions at the meeting.

And what they showed is that patients with early relapse after standard therapy of with diffuse large B-cell lymphoma had better outcomes judged by event-free survival and probably overall survival if they go straight to CAR T-cell therapy rather than getting what we call second line or salvage treatment with an intent to go to autologous stem cell transplant.

Dale Shepard, MD, PhD: So too often, sort of what people, particularly when they're treating a wide range of diseases or they're not really covering an area, the headline's sort of what people remember. So new drug comes out and we think it's more active than it probably ends up being or in particular CAR T-cell therapies as they were being developed, there was a lot of concern about toxicity. And so can you maybe give us an update on kind of what that toxicity is of CAR T-cells in reality?

Brian Hill, MD, PhD: Yeah, so I think it's not for everyone. Certainly age and performance status, comorbidities, functional age all can play into whether someone can receive CAR T-cell treatment. It frequently requires a hospitalization of 10 to 14 days, which is shorter than a transplant, but there are still significant toxicities depending on the product and the main toxicities include cytokine release syndrome, which is characterized by fever, hypotension, hypoxia, sometimes significant cardiopulmonary instability requiring ICU stay, and the potential for neurotoxicity, which is sort of an encephalopathy confusion aphasia, which is reversible, but still can be very sort of disconcerting to family members particularly.

So some of the newer products have lower rates of cytokine release syndrome and lower rates of neurotoxicity, but they're not zero. What I would say is that there's been a tremendously rapid learning curve from sites like ours that have been doing CAR T-cells for about five years now through clinical trials and standard of care. And I think we're better at patient selection, but also much better at management and much more preemptive with aggregating therapies that can minimize the likelihood of developing high-grade complications such as IL-6 monoclonal antibody Tocilizumab or Siltuximab, and actually glucocorticoids, or just plain old steroids, are very effective at sort of eliminating cytokine release syndrome and treating neurotoxicity.

Dale Shepard, MD, PhD: So the biomarker work that you are sort of developing to select patients is really important because it sounds like these are very, very likely to be active, but then there's also toxicity. So patient selection sounds like a really big, big deal here.

Brian Hill, MD, PhD: Yeah. I do think there will be a day when we use biomarkers. We're not quite there for prime time, but it's an exciting period of time that we may be able to use these tools to select better treatments for our patient.

Dale Shepard, MD, PhD: And I guess just to clarify from a biomarker standpoint, there are cases in the solid tumor world where checkpoint inhibitors, for instance, in some situations they just don't work and it's not worth pursuing. So with your study with the biomarkers, did you find that some patients might benefit more than others or it's just kind of a deal breaker and it's not worth doing?

Brian Hill, MD, PhD: Well, we did find some particular mutations in some genes, cyclin-dependent kinases, and other regulators that, if you had a mutation in any one of those, your outcomes were very poor with CAR T-cell therapy. What I would caution with those type of findings is that we really need to validate this before we roll it out. And so we're looking to examine these markers in larger number of cases and get this published in the upcoming year.

Dale Shepard, MD, PhD: So this focused on diffuse large B-cell lymphoma. Is there similar work being done in other types of lymphomas?

Brian Hill, MD, PhD: Yeah, most likely there will be. The second disease that was approved was mantle cell lymphoma, which is in some ways a more difficult disease to manage over the long haul because it typically has a relentless pattern of relapse. It's also much less common as opposed to being 30%, it's only about 8% of non-Hodgkin lymphomas so there's far fewer patients with this and far fewer getting CAR T-cell. So it may be more difficult to do biomarker or molecular studies of those biopsies, but with time I suspect we or other group will explore that in detail.

Dale Shepard, MD, PhD: So while we have the opportunity to get some insight, what are the things on the horizon you're most excited about? And what do you think are the biggest gaps still in treating this disease?

Brian Hill, MD, PhD: Yeah. So for diffuse large B-cell lymphoma, we do have a recent phase three trial also presented at the ASH meeting that finally may be moving the needle a little bit improving upon R-CHOP, which includes an antibody drug conjugate, polatuzumab vedotin, which targets cd79b. It's a B-cell receptor component.

That randomized phase three trial was positive. There was about a 6% improvement in progression-free survival at two years by substitution of vincristine in the R-CHOP backbone with Polatuzumab. And so this is not an approved regimen yet. I suspect we'll be hearing from regulatory bodies in the upcoming year so we finally might be moving the needle a little bit on treatment, which can reduce the number of patients who need subsequent therapies and relapse. And then, in that setting, when we do have relapse, moving CAR T-cells earlier in blinds of therapy, I think, is going to be overall good for patient.

Dale Shepard, MD, PhD: What do you think are the biggest questions that are still unanswered?

Brian Hill, MD, PhD: Well, in the CAR T space, we still think that, in the relapse setting, autologous stem cell transplant can cure somewhere around 40 to 50% of patients who receive an auto transplant. And the way the studies were designed, we didn't quite see good outcomes with the patients who were randomized to receive standard of care because many of them were refractory to frontline therapy and didn't respond to second or salvage treatment.

So going forward, for patients who are not refractory, but have later relapses, I do think that there's still probably a role in those patients who have chemosensitive lymphoma to undergo autologous stem cell transplant and we just don't have enough good comparative data yet to compare the outcomes of CAR T-cell treatment. For instance, if you get a remission with your second line therapy, are you better off going to CAR T-cell or are you better off doing auto transplant? And I think that's right now a big unanswered question.

Dale Shepard, MD, PhD: Great insights today. Any additional thoughts?

Brian Hill, MD, PhD: No, very impressed by the level of questioning from a non-malignant hematologist, Dr Shepard. Your range of understanding of the field is very impressive.

Dale Shepard, MD, PhD: Well, you are too kind. All right. Thanks a lot for being with us today.

Brian Hill, MD, PhD: Thank you for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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