Andre Goy, MD, MS: This is interesting. There are data at ASH [the American Society of Hematology annual meeting] looking at a dual costimulatory molecule, CD28 and 4-1BB, and it’s early. It’s a study from Germany and there are several trials looking at this where the CD28 typically is believed to be more for the early amplification and the 4-1BB for the persistence. They have less toxicity than expected, a small number of patients but promising data. I think understanding better how we do this construct will be critical. There’s CAR [chimeric antigen receptor] T-cell therapy combined with a cytokine and…CAR T and all that. But there’s also something that might be easier and more promising, given the complexity. The first is the off-the-shelf CAR T. Dr. Maddocks, what do you think?
Kami Maddocks, MD: I think that the ability to do that would take away some of the waiting time, and it would be helpful for them because if you can just give it to a patient once you give them another treatment, it would decrease the time to treatment, be better for not having delay, and be better for patients with aggressive disease.
Andre Goy, MD, MS: Dr Chavez, what do you think?
Julio Chavez, MD: I think allogeneic CAR Ts are another alternative to cell therapies. There are several trials looking at it, and as I mentioned, usually the turnaround is shorter. It’s available, so you can just start the patient. As an example, I had a patient post-CAR T relapse, and I was trying to enroll them on any available trial I had. I couldn’t because we couldn’t get him in. But for the allogeneic CAR T actually I was able to get him in, and he’s going to be treated next week. I think having that advantage of not waiting for 4 weeks or 3 weeks to get treated is a positive thing for allogeneic CAR T and is something that’s coming into play. The other factor is that these CAR T-cells are coming in from healthy volunteers, and they have probably the better T-cell repertoire. They’re not as exhausted. They probably can manufacture better CAR T-cells from those volunteers.
Andre Goy, MD, MS: What becomes of transplant, Nathan?
Nathan H. Fowler, MD: Especially for allogeneic transplant, I see this as really a very limited role in large cell lymphomas. Autologous transplant, we talked a little bit about ongoing trials where they are trying to randomize patients to standard transplant at relapse versus CAR T. Although that sounds like a great idea, I think we always have to remind ourselves that autologous transplant is curative in about 50% of patients. We don’t yet see that data in CAR T. The long-term cure rate with CAR T-cells is probably on the order of 30%. The hope is when we move these CAR T-cell products earlier in lines of therapy, then that’s going to be better than what we see with autologous transplant. But again, being devil’s advocate, we have not seen that chemosensitivity is really a predictor of outcome with CAR T. So, it’s a bit of a gamble whether these will replace autologous transplant. But there are ongoing randomized trials, and we should know the answer.
Andre Goy, MD, MS: Obviously CAR T is the ultimate immunotherapy for.... The first immunotherapy was allotransplant and real immunotherapy, but there are a lot of other ways to do this. Checkpoint inhibitors in lymphoma outside of Hodgkin lymphoma have not been really convincing, right? In large cell lymphoma, even in combination with IPI-NIVO [ipilimumab, nivolumab], this is not very high. There are strategies trying to build up and combine with small molecules, IMiDs [immunomodulatory imide drugs], or targeted therapy. What do you think, Grzeg? What is appealing in that setting combining with the checkpoint inhibitors?
Grzegorz S. Nowakowski, MD: I think you’re exactly right. The single-agent activity of checkpoint inhibitors is not looking as good in non-Hodgkin lymphoma—diffuse large B-cell lymphoma and follicular lymphomas—as we’ve seen in Hodgkin lymphoma. This was somewhat surprising because if you look at the microenvironment, we look at the number of cells and effector cells that appear to be there, yet it doesn’t necessarily correlate with what we see in the clinic. What other people are trying to do now is to basically alter this microenvironment and try to mobilize those immune cells to actually induce an immune response against the tumor.
HDAC [histone deacetylase] inhibitors here look quite interesting in terms of modification of PD-1 [programmed cell death protein 1], PD-L1 [programmed death-ligand 1] expression and microenvironment. Obviously, for IMiDs we have longstanding interest in this space and are also being considered. Although in the studies with myeloma, we’ve seen some toxicity, which put a temporary halt at least on some of those concepts. If you look at the preclinical studies, there are a number of small molecules that can actually modify the immune response of microenvironment, and then the logical combination for this would be to combine with PD-1 blockade.
Andre Goy, MD, MS: You guys had a study looking at acalabrutinib and PEMBRO [pembrolizumab] in large cell lymphoma and noneligible for transplant. I don’t remember all the details, but I think it was a very durable response.
Grzegorz S. Nowakowski, MD: Yes, we actually have seen quite durable responses in patients, heavily pretreated patients with diffuse large B-cell lymphoma. With the doublet, it’s sometimes difficult to differentiate the effect of BTK [Bruton tyrosine kinase] inhibition versus combination. However, typically, we do not see such responses with BTK inhibitors as well. It’s one of those very promising strategies where BTK impact on the immune compartment could actually help the PD-1 blockade to affect the tumor growth and eradication of immune therapy.
Transcript Edited for Clarity