Role of Bispecifics and Future Promising Treatments in DLBCL

Grzegorz S. Nowakowski, MD: Fred, what’s big? What’s exciting in the future?

Frederick Locke, MD: For me, on the horizon are certainly all the bispecifics and how they’re going to be utilized in our armamentarium. How are we going to sequence those? There are outstanding questions. But I focus on cell therapy, so 1 question is: can we do off-the-shelf allogeneic CAR [chimeric antigen receptor] T-cell therapy? There’s certainly promise. There are a number of companies developing these technologies where there’s gene editing, removal of the T-cell receptor or β2 microglobulin. But it’s clear that those cells can probably be rejected, so strategies are evolving to increase the lymphodepletion.

For large B-cell lymphoma, these remissions can happen very quickly. There’s hope that these allogeneic products can get on the market and maybe not compete directly or take over for autologous CARs but fill a niche and be another therapy we can offer. I also think NK [natural killer] CARs and gamma-delta CARs are exciting and on the horizon. I’d add that it’s very difficult to develop new cell therapies in the current landscape because you have these big phase 3 randomized trials showing that 2 of these work well and should be used. How do you put someone on a trial who hasn’t seen either of those 2 things with something that we still aren’t sure works or is safe? The opportunities are after CAR relapse or to be creative. These are very exciting times, and they’re clearly making a difference for our patients.

Grzegorz S. Nowakowski, MD: Do you think some of these off-the-shelf products will face a bit of a higher bar because, as Matt alluded to, this brain-to-vein time keeps coming back? Some patients are very high risk, rapidly progressive, and never necessarily made it to CAR T-cell trials, and now those patients will be treated with off-the-shelf products.

Frederick Locke, MD: Yes. When you have a trial patient, you have to check their eligibility and enroll them. Certainly, we hope we can get somebody an allogeneic CAR quicker, but at least for these trials, that clock starts at the time of enrollment, consent signing, and things like that. Keep in mind that it’s an intent to treat vs a modified intent to treat. You have to keep in mind for the allogeneic CARs that more patients are getting it. The bar in some ways should be a little lower because we aren’t looking at those who got the therapy. Or they all got the therapy vs autologous CAR, where at least in the initial pivotal trials we were focused on those who got CAR T-cell therapy. You have to keep all that in mind. But the real problem is: where are the patients? Which population are you going to go after? How is that going to work out in a trial?

Grzegorz S. Nowakowski, MD: Caron, what’s the next big thing, in your view?

Caron Jacobson, MD: When we’re talking about noncellular therapies, CD20 bispecifics are the most exciting thing we’ve seen. I’m particularly fascinated by the frontline studies, the mosunetuzumab study combined with CHP [cyclophosphamide, hydroxydaunorubicin hydrochloride, prednisone] or polatuzumab–CHP [cyclophosphamide, hydroxydaunorubicin hydrochloride, prednisone]. I was worried, just as I was worried about immune checkpoint inhibitors for Hodgkin lymphoma in combination with chemotherapy, that you’d lead to lack of activation of the cognate T cell. We aren’t seeing that, so that’s interesting and exciting.

In the cell therapy space, there are companies that are starting to think about viral vectors or in vivo transfection. That gets the brain-to-vein time down and gets rid of the immune response against the cellular immunotherapy. It seemed like science fiction to me 3 years ago, and all of a sudden clinical trials are being written. It’s going so fast.

One other thing that’s an untapped area is something that Fred has contributed a lot to: the tumor microenvironment, the myeloid cells within the tumor microenvironment, and peripherally how they impact CAR T-cell expansion and activity. There’s room here to think about how to condition the patient either before you collect their CAR T cells or with lymphodepletion to see if you can shift that myeloid component to a less oppressive phenotype. That might be the thing that helps these current CD19 CARs move the needle.

Leo Gordon, MD: There’s 1 thing I’d add about the bispecifics combined with chemotherapy. I still have a concern about that. If you look back at R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], it originally wasn’t given on the same day for follicular lymphoma. That’s the first study that was done by [Andreas] Mayer and [L. Stirling] Churchman. It was given at least a few days later. We have data on brentuximab in older people with Hodgkin lymphoma, where we gave it up front and then gave AVD [hydroxydaunorubicin hydrochloride, vinblastine, dacarbazine]. Pamela Allen and Jane Winter have studies in Hodgkin lymphoma looking at pembrolizumab first, and the current KEYNOTE study is doing the same thing. I still have concerns about defeating ourselves by giving chemotherapy on the same day that we’re giving an immune-based therapy. We do it for convenience, but is that the right way to do it? I don’t know. I’m just raising a question.

Caron Jacobson, MD: With mosunetuzumab, you’re replacing Rituxan [rituximab], which is the only thing that has improved survival in large cell lymphoma in the past 20 years or more. If you’re potentially replacing it with something less effective because you’re combining it with chemotherapy, that’s very worrisome to me.

Grzegorz S. Nowakowski, MD: I share some of those concerns as well, although people probably had the same concerns 25 years ago designing R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] trials. In the end, it was a success.

Leo Gordon, MD: But could it have been better? That’s the question.

Grzegorz S. Nowakowski, MD: That’s absolutely right. For me, what’s exciting is the development of the therapies in the relapsed/refractory space, which will be moving to frontline therapy. As Matt said, POLARIX created a crack in the wall of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], which we’ve been struggling with for a long time. It proves that we can probably improve our therapy. There was some nihilism developing there after many failed trials, but we can improve it.

Transcript edited for clarity.