iwCAR-T 2025 | CAR T-cells and bispecific antibodies in lymphoma: current perspectives and future considerations

Krish Patel:
Hi, I’m Krish Patel from the Sarah Cannon Research Institute. My pleasure to be joined by my colleagues

Alexey Danilov:
Alexey Danilov, City of Hope.

Tycel Phillips:
Tycel Phillips, City of Hope.

Krish Patel:
So guys, we just got out of one of the most engaging sessions at the iwCAR-T meeting, the discussion around lymphoma. And just to recap some common things that we heard, we heard a lot about challenges in terms of access to CAR T-cells, about the relative difficulty of developing in a post-CAR-T world in terms of new therapies and how to move things forward, and the challenge that poses specifically for technologies like allogeneic CAR T-cells and bispecifics.

So maybe, Dr Phillips, I’ll start with you. What were some of the take-home points in terms of access that you thought about, and what are some of the strategies that we’re using to kind of improve access to autologous CAR T-cells?

Tycel Phillips:
Yeah, I mean, I think as Dr Westin sort of elucidated, I mean, access is a multi-pronged problem. I don’t think there’s one clear solution. You know, obviously the easiest thing for us to do is continue with physician education and comfortability with the autoCAR products. I think unfortunately, you know, the reach of autoCARs will still be limited to specialized centers, but I do think we can do a better job as far as educating some of the referring centers about the potential benefits of CAR T-cell therapy. And another way, we sort of loosen some of the restrictions that are probably keeping patients from wanting to undergo auto-CAR, especially some of the strict vicinity requirements that are required within the first 30 days to try to at least allow some patients who live close enough to these centers to actually stay at home and not necessarily live at the CAR T-cell site.

Krish Patel:
Yeah, that I recall was a really common theme in every talk is that it’s a big burden for patients and their families to have to sometimes uproot and get to a CAR-T center.

Dr Danilov, you talked a lot about bispecific antibodies and kind of where we are today. How do you think bispecifics are posed to help address some of those challenges? Are they going to be the replacement for CAR-T in the community? Are they complementary? What are your thoughts?

Alexey Danilov:
Yeah, that’s an interesting question, and I think time will tell. But in principle, or at least theoretically, bispecific antibodies being off-the-shelf and associated with somewhat less toxicities and ease of administration could potentially be the community version of T-cell-engager therapy. And yet, uptake of bispecific therapies in the community has still been pretty slow, as you know. And I think we do face some of the same barriers. At this point, maybe not so much travel time and necessity to stay in the hospital for administration of CAR-T. Bispecifics, you can do them outpatient. However, there are some of the same issues, you know, how to manage CRS or physician education, availability of, say, the tocilizumab at a smaller center when you need it, and training of physicians and education will be also very important in setting up this program. So you still need the availability of pharmacy, advanced practitioner support staff. There are some of the same wheels that will have to go into motion with bispecific antibodies. But certainly the barrier is a bit lower with these antibodies being readily available through the pharmacy off-the-shelf. So we do see that some maybe of the larger community practices are using bispecifics quite frequently now.

Krish Patel:
Yeah, no, I think it’s a great point. You still have this need to recognize certain adverse events and manage those and have a management plan. So perhaps we are uncoupling a bit from infrastructure like apheresis and cell labs, but still need to educate those physicians and the patients and their caregivers around those unique toxicities. You also raised this question around alloCAR-T, there was this great discussion about allogeneic CAR T-cell therapy. We heard about the data from the ANTLER study today, which is an allogeneic CD19 CAR. Yesterday, we heard a lot about rapid manufacturer autologous CARs. Can you maybe share with the audience kind of what’s happening in that space to try to shorten the time to delivery and what problem do you think that’s solving?

Alexey Danilov:
Yeah, I think in general, the development path for alloCAR-T is going to be difficult, I would say, you know, and like we were discussing, Krish, before, I think it would be more interesting to focus the development of alloCAR-T in the future on some of the novel targets that you mentioned in your talk. Because, you know, for full approval, you would need to potentially run some randomized studies against existing CD19 CAR T-cell therapies. Will they have to be non-inferiority studies, large non-inferiority studies, which will be really difficult to enroll to? And that’s in a setting where we have multiple CD19 autologous products approved, which we don’t even know which one is better than the other. So even that is a problem. So I think it is going to be a difficult development path, but certainly not impossible. But the big advantage of allogeneic CAR-Ts is, of course, again, availability off-the-shelf. They do seem to be efficacious, as efficacious, at least with the amount of follow-up that we currently have. They do seem to be very efficacious products, so maybe not as much of a concern. There is no need for apheresis, and depending on a center, which may take from five days to a few weeks to schedule. So there are some clear benefits to these products, potentially. But as you mentioned, as the manufacturing time for autologous products is getting shorter, some of these benefits also might be going away. So we’ll see. I don’t really have a great answer for that, what the development path is going to look like.

Krish Patel:
Yeah, I think you raised a lot of important points which highlight that we have to move beyond just a single antigen target or whether it’s with alloCARs or autoCARs or bispecifics, we still have patients who relapse. Dr Phillips, can you kind of summarize for us some of the things that you think are going to be complementary to all of those modalities that move forward? Is it going to be different antigen targets? Is it going to be combinations? Is it going to be immunomodulatory drugs? We heard a little bit about that in these sessions as well.

Tycel Phillips:
Yeah, I mean, I think you bring up good points. I think with the bispecifics, I mean, we are seeing a lot more antigen loss than what we saw with CAR T-cell therapy and definitely than what we saw with monoclonal antibodies, so I do think novel targets will be beneficial. But also to that point, there are other drugs that we can combine with bispecifics because combinability is easy with these drugs, easier than what we can do with CAR-T cell therapy. So obviously the immunomodulatory drugs like golcadomide which is a new CELMoD, but more importantly, the ADCs seem to potentiate quite a bit, the bispecific antibody therapy. A lot of these ADCs target a different antigen receptor. So it does give some dual targeting, which obviously may prevent some of the resistance mechanisms from being driven by specifically going after one target. We’ve seen a lot, at least with polatuzumab, with the Genentech products, but I mean, there are other ADCs like loncastuximab, which is with Lotus 7, seems to have very impressive data with the bispecific antibodies. So potentially anything that has sort of that antibody-drug conjugate, sort of a targeted sort of precision missile, potentially can augment some of the antigen sort of benefit from these bispecific antibodies. With cell lysis, you may get more antigen exposure, more T-cell activity, more synergy in that situation, and also less resistance.

Krish Patel:
Yeah. So lots more to come, lots of different targets, lots of different products that are in trial. So again, a really exciting session in lymphoma at the iwCAR-T meeting.

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