iwCAR-T 2025 | T-cell engagers and CAR T-cells in R/R CLL: clinical data and future directions

David Maloney

Hi, I’m Dr David Maloney from the Fred Hutchison Cancer Center in Seattle. 

Mazyar Shadman

I’m Dr Mazyar Shatman. I’m also from Fred Hutch Cancer Center in Seattle. 

Alexey Danilov

And I’m Alexey Denilov from City of Hope in Los Angeles. 

David Maloney

All right, we’re here on our first day at the iwCAR-T meeting. We had a session on chronic lymphocytic leukemia and heard two very great talks, one on bispecific antibodies by Dr Danilov and one on CAR T-cells by Dr Shadman. Can you each just summarize quickly the high points of your talks? 

Mazyar Shadman

Sure. We had a great session today. I talked about data on lisocabtagene maraleucel or liso-cel, which is currently approved by the FDA for treatment of relapsed/refractory CLL or SLL in patients who have been treated with BTK inhibitors and venetoclax. So we covered some of the long-term follow-up data from Fred Hutch. We have 80 months of follow-up now and showing that in 20% of patients, actually, we’re seeing long remissions, and these are patients who are enjoying their long remissions without having to take any medications. We also reviewed the TRANSCEND data from the study that led to the approval of liso-cel, both the monotherapy cohort and the recently presented ibrutinib cohort, basically showing that depending on which cohort you look at, there’s between 20 to 40% of patients who achieve a complete remission, and these patients happen to have long remissions. Now, there is some signal of maybe safety profile is also improved by adding ibrutinib. And this is in fact consistent with the data that was generated at different academic places like Fred Hutch, University of Pennsylvania and others. So we discussed continuing BTK inhibitors. These days, we use non-covalent BTK inhibitor pirtobrutinib before referral is made for CAR T-cell therapy. And in many cases, we continue that drug, sometimes even after administrating the cells. One of the discussions that led to some great panel question and answers was what to do to make CAR T’s more effective in CLL. We talked about the treatment landscape. And for example, I mentioned an investigator-initiated study at Fred Hutch that we are adding nemtabrutinib, a non-covalent BTK inhibitor to CLL. So highlighting the importance of early referral for CAR T-cell therapy in patients who are having a controlled disease, responsive to their prior treatment, not to wait until disease takes an kind of explosive course, and really making sure that patients get to CAR T-cell therapy with less bulky disease and before their, kind of coming with too many comorbidity factors. And still room for improvement, either in adding things to liso-cel or even using novel cellular therapeutic agents, either autologous or allogeneic. 

David Maloney

Dr Danilov, you showed us really exciting data with epcoritamab in CLL. Can you walk us through that data? 

Alexey Danilov

Yeah, absolutely. So in CLL, CAR T-cells actually seem to have to have somewhat lower efficacy than in other B-cell non-Hodgkin lymphomas. And that may have to do with the fact that the tumor microenvironment is highly dysfunctional in CLL. Dysfunctional macrophages, mesenchymal stem cells, mesenchymal stromal cells, T-cells, neutrophils, you name it. And therefore, there need to be strategies to improve on CAR T-cell efficacy in CLL, some of which Dr Shadman has begun to outline. But also there may be other approaches such as bispecific antibodies. And as those are also T-cell engaging therapies, it is possible that bispecific antibodies could have higher efficacy if we had optimized T-cell function in CLL. But nevertheless, even early single agent data looks really good. So epcoritamab is a CD3, CD20 bispecific antibody, which has been studied in a Phase I study in patients with CLL who had received a median of four prior therapies. Patients were heavily pretreated. Most of them were double refractory to both BTK inhibitor, BCL2 inhibitor. They all received prior chemoimmunotherapy. The majority had P53 aberrations as well. So difficult to treat patient population. In this patient population, the response rate was 67% with about 40% of patients achieving complete remission. And responses are durable. Some patients actually continue in response after discontinuing epcoritamab early. And it’s a very convenient off-the-shelf subcutaneous therapy, which is administered initially weekly with a ramp up of the dose because of risks of tumor lysis syndrome and cytokine release syndrome, similar with CAR T-cell therapy. But the risks of both can be mitigated by extending the ramp-up by adding additional three milligram epcoritamab dose into the ramp-up. This was done as part of the optimization cohort in the study where most of CRS cases were grade one. There was no ICANS and no clinical TLS. So this is a very well tolerated treatment, which is also highly efficacious in patients with CLL, which progressed on multiple regimens. And just like with CAR-T, I do think the future of biospecifics may be in combination with both BTK inhibitors and BCL2 inhibitor, and those studies are being developed as well. 

David Maloney

Yeah, it seemed like there was a general consensus as well that taking patients without explosive disease and rapidly proliferating kinetics, getting them at lower disease burden would likely help in both cases by minimizing cytokine release syndrome and other toxicity. I was struck, though, by there seemed to be more CRS with epco in the CLL setting than there was in the large cell setting. Is that your take, too? 

Alexey Danilov

Well, you know, it’s difficult to make cross-trial comparisons, of course. Again, you’re right. In the original expansion cohort, there was quite a bit of CRS with the rapid ramp-up of epcoritamab. But in the optimization cohort with the three-step ramp-up, this was actually very well controlled with only maybe about 10% of patients having grade 2 CRS, majority having grade 1 CRS. One feature in CLL that I have observed in my experience is that although CRS often happens with first full dose of epcoritamab, 48 milligram, I have seen that sometimes it does linger and happens again with subsequent dose administrations. And in that sense, yes, CLL seems to be somewhat different, and that may have to do with bone marrow infiltration by CLL cells, with circulating CLL cells, which may not be immediately cleared with lower doses of epcoritamab. 

David Maloney

So how do we choose patients for each of these therapies, and what are your thoughts? It’s not going to be frontline therapy, obviously, at this point. We do have liso-cel approved, I think, for the double refractory population or double exposed. Epco, not yet, but where do you see this coming down the pike eventually? 

Mazyar Shadman

Great question. I mean, the way I look at the treatment options for patients with CLL diagnosis, so as soon as I have a patient for whom the covalent BTK inhibitors and the BCL2 inhibitor as the two main classes for CLL, as soon as I don’t have those two as an option, either because of disease progression or patients who don’t tolerate even our second generation BTKis, I immediately start those patients. And of course, we are discussing off clinical trial kind of practice in here. So start with pirtobrutinib to have the disease control. But in my opinion, that’s the time to start talking about next step and considering CAR-T therapy as a consolidative approach. Because we know from the BRUIN study and from the BRUIN-321 study that the medium progression free survival for these patients after failure of those two classes is between 15 to 19 months. So it’s not that pirtobrutinib will work forever. And the option would be waiting until pirtobrutinib stops working, which will be a difficult clinical scenario for us to kind of handle and for patients to tolerate. Starting pirotbrutinib, get that initial control and use that opportunity to provide CAR-T therapy when patients have controlled disease, when they have less bulky disease, and also most importantly, when they still have pirtobrutinib as an option post-SCAR if they need a treatment. So that’s where we start talking about CAR-T. It’s not an immediate decision most of the time. Patients need to think about it and plan for CAR-T therapy. But the best time to do it is when pirto has established its efficacy and patients are in a good shape. 

David Maloney

I mean, we both are in a situation where CAR T-cells are complicated. You have to apheres a patient. It’s complicated to make the CAR T-cells. Epco is on the shelf, basically. Take it off the shelf and treat. Do you see, how would you position, if it was available, which it’s not yet, but where do you think we’re going to be using it? 

Mazyar Shadman

Yeah, that’s a very good point. I do think that the initial use might be in patients at least exposed to BTK inhibitors because BTK inhibitors is by far the easiest, although I’m sure future trials will demonstrate what the place of epcoritamab is. But it is certainly a big advantage. And I will say that we all know that uptake of bispecific antibody therapy in the community is a bit slow, or so it seems. But as the community gets comfortable with treating non-Hodgkin Lymphoma with bispecifics, I don’t see why epcoritamab couldn’t be added to armamentarium of CLL therapy in the community as well. So I think that alone might sort of nudge it a bit forward ahead of CAR-T, because as you said, CAR-T is quite a lot of song and dance around it, so quite a lot of work and many steps and has to be done at the tertiary care center. And patient can’t always travel. They don’t have the means or a center maybe too far. So multiple issues there. So I think the ease and availability of bispecific antibodies will be one of the strongest assets. 

David Maloney

And I think the other thing that came out in the discussion was the patients treated on these clinical trials are not necessarily the same patients that we’re gonna see in the next 10 years going forward. As we discussed, many of our patients originally had failed FCR chemotherapy, which is not even used at all, and it was the absolute gold standard. In fact, it was a requirement to be on some of our earlier trials that you had to have failed that. So I think we’ll see a different population, less genetic instability, and maybe even increasing results. There was a lot of interest in trying to say, well, could one of these agents or both of these agents be used to consolidate a remission, to eliminate MRD? And I think all those kinds of trials are looking forward. Any other last thoughts? 

Alexey Danilov

Well, I think we are actually lucky to have all this exciting new therapies in CLL. So liso-cel bispecific antibodies, both epcoritamab and mosunetuzumab are in clinical trials. Now we also have BTK degraders, a whole new class of drugs, which also is being studied in double refractory CLL now, and that’s a pill form. So I think this is exciting time to be in CLL clinical research and therapy. 

David Maloney

Well, thanks for joining us. 

Mazyar Shadman

Thank you. 

Alexey Danilov

Thank you.

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