The Potential of CAR T-Cell Therapy for Chronic Lymphocytic Leukemia (CLL)

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and 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, Director of International Programs for the Cancer Institute, and Co-Director of the Sarcoma Program here at Cleveland Clinic. Today I'm happy to be joined again by Dr. Jos Melenhorst, Vice Chair of the Center for Immunotherapy & Precision Immuno-Oncology, and Director of the Cell Therapy and Immune Engineering Program here at Cleveland Clinic.

He was previously a guest on this podcast to discuss the future of CAR T-cell therapy, and that episode is still available for you to listen to. He's here today to talk about the potential of CAR T-cell therapy for patients with chronic lymphocytic leukemia, so welcome back.

Joseph Melenhorst, PhD: Thank you very much, Dr. Shepard. I always enjoy listening to your podcast on Thursday to learn more about exciting clinical and translational research happening here at the clinic. As you may recall, I was recruited in March of 2022 to develop and direct a cell therapy and immune engineering program, like you said, and to build a translation immunology program focusing on creating safer and more effective immunotherapies for cancer. My work primarily targets cancers like lymphoma and leukemias, but we're also developing cellular therapy for solid tumors like melanoma and glioblastoma. We are currently designing and building also a Cleveland Clinic GMP facility, the first at Cleveland Clinic, but I'll save that topic for another conversation, if you like.

Dale Shepard, MD, PhD: Well, of course, we'll have you back for that.

Joseph Melenhorst, PhD: Thank you.

Dale Shepard, MD, PhD: Today we're going to talk about CLL, and sort of use of CAR T therapy. Briefly give us a little bit of an idea about CLL, how it's sort of more traditionally been managed, and then why we're thinking about CAR T therapies.

Joseph Melenhorst, PhD: Thank you. In CAR T therapy, patients' immune cells are genetically modified in the lab to express a novel protein known as a chimeric antitumor receptor or CAR. This receptor enables the T cells to recognize and bind the tumor cells, and subsequently they become activated and kill these tumor cells. What makes CAR T therapy different from standard of care therapy such as small molecules is that these cells that are engineered with a CAR will stably express the protein and also persist after tumor is cleared. In essence, it's a self-replicating drug that continuously suppresses tumor recurrence. Since the first two patients were infused with CAR T cells in the summer of 2010, we have observed that these patients with CLL who achieved remissions tend to sustain remission, and we claim that to be a cure. Findings of these two patients were published in Nature of 2022.

Dale Shepard, MD, PhD: When we think about our other traditional agents we use for CLL, we really don't use that word, cure.

Joseph Melenhorst, PhD: Right, because the patients over time develop a resistance, requiring additional novel therapies, novel iterations of these, like Bruton's tyrosine kinase inhibitors or other apoptosis inhibitors that are currently use in trials.

Dale Shepard, MD, PhD: CAR T therapies have been certainly approved in other things, B-cell malignancies and things. Is there something specific about CLL that's unique or made it more of a challenge to use CAR T therapies, or are we sort of just at a point where we're getting to looking at CLL?

Joseph Melenhorst, PhD: I think that's a great question. I think CLL is among the most, as you know, most prevalent blood cancer in the western world, and was the first leukemia actually to be treated with CAR T cells at the University of Pennsylvania, which was my previous institution before joining the clinic. Though with CAR T cells, the first two patients responded incredibly well and the third patient achieved a partial remission, the overall response rates in CLL were much lower than we have seen in acute lymphoblastic leukemias or even B-cell lymphomas, and even in myeloma. My team, while still at Penn, demonstrated the main reason for CAR T cell failure in CLL was due to T cell exhaustion. Before you collect T cells, they are already exhausted and are unable to control the tumors. Others have since confirmed also in CLL that the response rates are very low. Even in the most recently published trial in CLL by Bristol Myers Squibb, they achieved an 18% complete response rate, and that actually led to the FDA approval of their drug. The challenge in CLL, in a nutshell, is a profoundly dysfunctional T cell pool. An additional challenge is the relatively paucity of these cells, these immune cells in the blood, which is a challenge I hope to tackle with one of my collaborators here at the Taussig Institute, Dr. Paul Caimi, via a leukemia/lymphoma funded project.

Dale Shepard, MD, PhD: We think about that T cell exhaustion, is that a function of the disease itself or is that from their prior therapies, that have led to the exhaustion?

Joseph Melenhorst, PhD: We don't know for sure what the reason for T cell exhaustion or dysfunction is in these patients. It looks like the number of prior therapies does not necessarily impact T cell function. I think it's more the long-term exposure of T cells to dysfunctional environments that leads to T cell exhaustion.

Dale Shepard, MD, PhD: We think about, there's a low rate of response compared to some other diseases, although as a sarcoma doc, 18% is something that I might strive for. Those patients that have low response, does that tend to be durable?

Joseph Melenhorst, PhD: Yes. Yeah, those patients that do respond have durable remission. The first two patients had more than 10-year response. We have since seen other patients also maintaining their response after the CAR T therapy,

Dale Shepard, MD, PhD: Where are we in terms of improvements on our ability to use CAR T therapies?

Joseph Melenhorst, PhD: Like I said, the seventh CAR T therapy that has been approved by FDA now from Bristol Myers Squib is now available for CAR T treatments, so that I think answers your question.

Dale Shepard, MD, PhD: Are there things being done to sort of increase those response rates, make it more likely that ... Are there different targets we're looking at, different ways to try to address CLL?

Joseph Melenhorst, PhD: Some of the efforts that we undertook at Penn was to treat patients with the small molecule ibrutinib that inhibits CLL function, induces cell death, which we found, actually, and published in 2016 in Blood, not only de-bulks the tumor, if you will, but also allows restoration of T cell function over the course of six-month treatment. Based on those findings, we started the phase one trial, enrolling patients who had been on ibrutinib for six months after, which T cells were collected for manufacturing with the CD-19 targeting CAR, and then infused in these patients who were sustained on ibrutinib for at least a year.

Dale Shepard, MD, PhD: We think about, anytime we have a therapy like CAR T therapy, there are other competing ways that these patients could be treated. How's sort of that treatment landscape? How are we working in CAR T therapies compared to our historic therapies? Are people going straight to CAR T therapies? Can we predict who might be those responders? How do we make those treatment choices, and how are we incorporating now CAR T therapies into management?

Joseph Melenhorst, PhD: That's a great question for a clinician. I mean, if you look at the CAR T landscape, I think non-Hodgkin's lymphoma is more advanced in terms of implementing CAR T in therapies. They have moved it up to second line therapy. That's not where we are right now with CLL. It's still the small molecules that dominate the standard of care therapies, and the CAR Ts will come at the later time points, but I do think that it is going to be incredibly important that we do administer CAR T early on in disease.

Dale Shepard, MD, PhD: When we think about sort of looking forward and how we make further improvements, like you said, there are a number of therapies out there, and one of the focuses of your lab is how we sort of make improvements. What do you think is going to be sort of that trigger to better therapy? What do you think is going to be the next break?

Joseph Melenhorst, PhD: I think it's a combination of factors. One is what we learned from ibrutinib, that targeting the tumor before collecting T cells is really important. I've since conducted studies here at the clinic to look at other modes of therapy. The time to response with ibrutinib is roughly five months. That's a really long time for patients to actually have measurable tumor reduction. What we've seen in another small molecule study led by my post-doc, Dr. Celine Gregoire, and others, with collaborators in Europe, we've seen that venetoclax actually has a much shorter time to response, and also with obinutuzumab, which is an antibody that targets CD-20, similarly has a much shorter time to response. What we're aiming to do, so that's one, on the one end. On the other end, you asked previously, can we actually predict who's going to respond to CAR T therapy? My studies at Penn that I mentioned, we also looked at peripheral blood T cells and apheresed cells that were used for manufacturing, and see if we identified a signal that could predict response to therapy. Actually, we did find that, and actually, we showed that between 70 and 80% of CRs can be predicted based on that analysis. What we found in those analyses is that the population of T cells that sustains response, memory cells, are really important. The early memory T cell pool is relevant.

Going back to the challenge in CLL where a minority of peripheral blood cells are T cells, and a minority of that is even the early memory T cells, in non-responding subjects, even smaller, so we haven't been able to translate those findings into next generation therapies. Now, like I said, with the LLS-based trial with obinutuzumab, we see that within a matter of weeks we get a profound depletion of the CLL, recovery of T cell proportions. Numbers in T cells are always normal, if not higher, in CLL than normal, so this gives us the window of opportunity to collect the cells and then also to go after these early memory T cells. That's an innovation that I'm bringing to the clinic that's going to be part of my first phase one trial here at the clinic. Again, another topic for another conversation, I hope. When we are thinking about CLL, how can we do better? First, we need to de-bulk. Second, we need to isolate these early memory T cells, and then third, we need to engineer them with CAR T cells and infuse them back into the patient. That's sort of the trajectory, what I'm thinking about in CLL.

Dale Shepard, MD, PhD: You think about CLL, I mean, historically solid tumors has been difficult to generate CAR T therapies because of heterogeneity. Do we see that same heterogeneity in CLL? Are there other markers that might be helpful as antigens, or does that end up being an issue for CLL specifically, with the lower response rates that we see compared to some other diseases?

Joseph Melenhorst, PhD: Right. No, that's an important question. If you think about CAR T developments, oftentimes people think, groups think that you need to target another antigen. That's not how it works in CLL. We know CD-19 works really well. We also know that 70 or 80% of response resistance is associated with T cell dysfunction. We also know, and it's another study that we published in 2022 as well, is that part of the resistance is actually that the CLL cells do not provide sufficient stimulation for the CAR T cells, even though the CAR has co-stimulation integrated into the receptor. We found actually that additional co-stimulatory molecules provided by CLL are important in drawing this response, so what we're thinking about is actually, so the target antigen is not as important. I think the combination therapy and prior depletion is going to be really important.

In a separate study that I've conducted with Adrian Wiesner, Dr. Adrian Wiesner at the NIH, where we examined peripheral blood and comparing that with lymph node tumor cells, which is the cradle of CLL, if you will, we actually found that peripheral blood CLL cells are refractory to even the Kymriah product, whereas the lymph node CLL cells aren't. In essence, what we're thinking is that the source of the peripheral blood pool that generates in the lymph node is depleted effectively in the lymph node, so if we can make these CAR T cells do better by all these approaches that I just mentioned, I think we have a really good chance of inducing lasting remissions without any further treatment with small molecules that are toxic both financially and clinically.

Dale Shepard, MD, PhD: What are the current barriers to people being able to use CAR T therapies for CLL?

Joseph Melenhorst, PhD: Some of the really important barriers, aside from what I just mentioned about the poor T cell quality, is access to these therapies. Typically, CAR T therapies are administered at specialized centers. They are manufactured by certain companies, like BMS, is the only one that has the FDA-approved CAR T for CLL. That's a relatively small unit that can provide these CAR T cells, so what's really important is that we fix these issues. How do we get out the valley of death, if you will, in cell therapies, as is recognized now? I think part of it is that we make better CAR T cells, which is part of my effort. Another effort is that we can actually make the CAR T cells cheaper and better, so what we have going on in the lab right now is to integrate all these findings on removing steps in the manufacturing processes that aren't necessary and actually deleterious. We know that continuous expansion of T cells in vitro is harmful to the cells. We know we can make them in less than a day. Dr. David Wald has shown it quite convincingly in non-Hodgkin's lymphoma, and we can do the same thing in other cancers, too. If we can do that, then we're one step removed from automation, then we're one step removed from actually making the whole process automated, and we can place these units in peripheral hospitals. Then patients that are at highest need, can't travel to these specialized centers, can actually receive these curative regimens.

Dale Shepard, MD, PhD: You mentioned an important point, so historically a time factor has been significant, and so it looks like that might be able to be improved as well.

Joseph Melenhorst, PhD: Yes, yes, I think so. Although, in CLL, probably a time factor is not as important, right, as an indolent disease, but certainly in acute leukemias and other aggressive malignant disease, we definitely need to fix that. Yeah.

Dale Shepard, MD, PhD: Within CLL, outside of CLL, what else do you find particularly something you're looking forward to seeing results from, next steps? What excites you in the area right now?

Joseph Melenhorst, PhD: Oh, boy. There's a lot of interesting challenges there. Yeah, good question. My phase one trial, which I find particularly exciting in non-Hodgkin's, where we'll implement this early memory T cell manufacturing, some innovations of enriching these cells, so that's a seven-day manufacturing process. The next iteration is that we do everything in half a day. That's what we're working on, hard. We are also working hard on targeting cancers that have over-expression of molecules called B7H3, and that includes acute myeloid leukemia, that includes melanoma, and also includes glioblastoma. I have a research program on these diseases, with glioblastoma collaborating with Justin Lathia at the LRI. Melanoma, I'm working with our melanoma oncologist and surgeon, in the lab. Those are areas where we can make a difference. In melanoma, I think there's also an opportunity to make anti-T cells that have a natural ability to recognize tumor cells but are rendered dysfunctional, to restore that activity. That's another area. Then, so that's our focus at this point. We're not going into sarcomas just yet, but once we have figured this out, I'm sure we'll talk again.

Dale Shepard, MD, PhD: Yeah, yeah. Fantastic. Well, certainly it's an area of active research. We've made good clinical strides, and appreciate you being here with some insights today.

Joseph Melenhorst, PhD: My pleasure. Thank you for having me.

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

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.