CAR T for R/R FL: Treatment Considerations

Ian Flinn, MD, PhD: Andy, I think we’d probably all agree that this is an exciting and evolving field, but who should be evaluated for CAR [chimeric antigen receptor] T-cell therapy? Also, equally important, who should not?

Andrew M. Evens, DO, MSc, FACP: I was not an author of that study, but I can say I was as impressed as Caron was. They were fantastic data, and she gave a great presentation at ASH [the American Society of Hematology annual meeting]. I think it will immediately move ahead of any transplant, maybe for a young patient like we talked about with terrible disease.

To me, assuming we have bispecific antibodies in the near future, that’s going to impact a lot of the decision-making—CAR T, bispecifics. I’m not sure it would be ahead of R2 [rituximab/lenalidomide], but listen, I think this is where decision-making with the patient will factor in—shared decision-making. It at least looks as good as bispecifics, and looks at least as good, if not better, than R2 [rituximab/lenalidomide].

Also, this is a one-time treatment. Yes, it’s more aggressive. Yes, there’s more acute toxicity, and I don’t mean to minimize that at all. But you would talk to a patient and say, “Listen, you could be vein to vein in 3 weeks and be recovered 3 weeks after that.” Many of the other therapies we talked about are not just a year, sometimes they require indefinite treatment. So I think there will be different patients for different situations, but it will be another kind of treatment for use in our armamentarium to discuss with patients along the way.

Ian Flinn, MD, PhD: I’m really glad you brought that issue up, about the CAR T cells. It’s good to have the problem of trying to figure out which is the best therapy here, based on having so many choices hopefully in the near future.

We spoke a bit about some of the obstacles of administering bispecifics in the community office. Although that certainly seems to be getting better with each year. Each publication, each update on the Mosun [mosunetuzumab] data looks better than the last about giving it in a safer manner. There are also real access problems in this country in terms of getting CAR T-cell therapy, whether it’s a financial barrier or a logistical barrier in getting patients to come to these larger centers. So it certainly would be a major step forward if we had bispecific antibodies that could be administered in the community that seemed to be approaching the efficacy that we’re seeing with CAR T-cell therapies.

With that said, Loretta, who are candidates and who are not for CAR T-cell therapies? It’s not the same as when you think of giving high-dose chemotherapy. It’s different. If you’re going to give a message to referring doctors, what do you tell them about when to send the patient, and what does that patient look like?

Loretta J. Nastoupil, MD: I think what’s different with follicular lymphoma as opposed to large B-cell lymphoma is we generally do have more time. And so, I don’t believe that argument that these patients are crashing before they can get to the referral center and get financial approval is as strong of an argument in follicular lymphoma. And in my opinion, any patient who’s beyond third-line therapy, because those outcomes are so poor even with some of our modern therapy, even the Mosun [mosunetuzumab] PFS [progression-free survival] wasn’t phenomenal. We’re still looking at about 11- to 12-month PFS. And so, I do think there is an argument to be made for CAR T-cell therapy, particularly in the fourth-line setting, for just about any patient.

Now, there are barriers. Sometimes there is a requirement for patients to relocate to another city. They have to have a caregiver. They have to be away from work and employment for a minimum of 4 weeks. Even in my practice, I recognize that there are patients for whom it’s just not feasible. I’m going to exhaust other therapies that don’t require as big of an impact on their day-to-day life.

But as Andy mentioned, it is a one-time therapy. So if you have folks who are willing to commit to it, I do think it probably gives us the best PFS we have available in that fourth-line or later space.

The other intriguing thought is, we could potentially even lead up to this with our PI3 kinase inhibitors and see if we could further impact that T-cell fitness. I’m a little bit more optimistic about that in follicular lymphoma, which might be contrary to others.

Ian Flinn, MD, PhD: Yes, that’s an interesting thought. Caron, could you comment on T-cell fitness? Does it matter what line of therapy someone gets CAR T? I worry about treating with bendamustine and all of these other therapies that are tremendous T-cell depleters, much less the fitness of the therapy. Is there an art to the timing of giving CAR T-cell therapy in patients with follicular lymphoma, as well as making decisions based on prior therapy?

Caron A. Jacobson, MD, MMSc: I wish I had data from ZUMA-5 to think about time from bendamustine, because I think that’s a really important point. In large B-cell lymphoma, we believe that collecting after earlier lines of therapy is a good thing. There are data that show those T cells do have a more attractive phenotype and have a better doubling time. That may mean they’re fitter and better cancer-fighting cells. In follicular lymphoma, most of our subsequent lines of therapy are not cytotoxic chemotherapy. Many of them are immunomodulatory in a favorable way.

I agree with Loretta, that even in follicular lymphoma you may find that the later you do it, the better it is. You’ll have more time from traditional bendamustine-containing chemotherapy. And actually, some of the agents that you may cycle through in between can actually improve outcomes. So stay tuned. We don’t have a lot of correlative science from these early phase 2 studies yet, but I think we’ll learn more in the coming years.

Ian Flinn, MD, PhD: Yes, there are studies in other disease states looking at co-culturing the CAR T cells with PI3 kinase inhibitors to try to improve efficacy there.

Krish, I realize there are no head-to-head data, but do you think there’s a reason to use a 4-1BB construct versus a CD28 construct in follicular lymphoma? Is there any theoretical reason why one might be better than the other in that setting? Honestly, it’s ultimately the clinical data that are going to play out here.

Krish Patel, MD: Yes. I think your point is an important one, Ian, which is that the data will tell us. But I think if we kind of borrow the concepts that are applied in large B-cell lymphoma, we know that CD28 CAR T cells typically expand faster. There’s perhaps some increased cell kill, if you will, earlier on. The 4-1BB CAR T cells have more persistence. I think in a disease that we don’t cure, an indolent disease where, for example, not all of the clones that are present are perhaps present in the same immune microenvironment or are proliferating in the same way, this concept of persistence might have some differences. I think that’s speculative, but perhaps there is a reason to believe that CAR T cells that persist for a longer period in an indolent disease might be different than those that don’t. We’ll have to see.

Transcript Edited for Clarity