CAR-T Cell Therapy Use in B-Cell Malignancies - Episode 17
Krishna V. Komanduri, MD: In some sense, we’re here talking about, again, aggressive lymphomas and ALL, but in some ways, our experience at University of Pennsylvania—which really resulted in those early just absolutely spectacular advances that were reported in New England Journal of Medicine and other places—started with low-grade lymphoma and CLL. Can you kind of circle back to that now?
Stephen J. Schuster, MD: Yes. Well, the very first experiences were ALL, but CLL was the next group of patients who were treated and it was just a small study. And, again, efficacy was shown. And the way I see it, if I’m looking at all the lymphoid malignancies, the best results we get are in ALL, 75% to 80% remission. And when I say remissions, I mean of some duration, not just a blip. Second would be low-grade follicular lymphoma, specifically. I can’t generalize the low-grade, haven’t done enough other ones. There, it’s 70%. Large-cell lymphoma, it’s between 40% and 50%, and then CLL is about one-third successful.
So, why is that? Are the T cells, that we generate the products from, different in those patients? What is the mechanism by which deferent lymphoid malignancies that are CD19-expressing have different susceptibilities or success rates with this form of therapy? So, one of the things we observed, both in the lab and then moved to the clinic at Penn, is that the BTK inhibitor, ibrutinib, has off-target effects on T cells. It shifts their cytokine profile in such a way that they’re more polarized towards TH1. So, we actually are conducting a trial in CLL patients who are being treated with ibrutinib that have less than a partial response after 6 months. They’re eligible for the study, or if they have very adverse cytogenetics and adverse history, they are eligible for that study. And the early results look great. So, we may be able to go much beyond 33% by using a combination strategy with ibrutinib. In the first 11 patients, I think 9 of them were MRD-negative.
Krishna V. Komanduri, MD: I think the other thing is that when we think about the patients’ T cells, especially because we’re transducing patient T cells to make CAR T cells, we know from multiple groups that cells can be what we call “exhausted” or be in various stages. And we know that in the setting of solid tumors that the checkpoint inhibitors can overcome this exhaustion. So, one of the possibilities is to combine CAR T-cell therapy with checkpoint inhibition. You want to talk about that?
Stephen J. Schuster, MD: Yes. Call your attention to an abstract. It’s a preliminary that’s going to be presented at this meeting by one of our Fellows. And we’ve used the strategy of rescuing patients who are having progressive disease during the early phases of CAR T-cell therapy while there’s actually expansion of T cells in the blood. Interestingly, what we’ve seen is expansion in patients who respond and expansion in patients who fail. In the stuff that we’re publishing now, we’ve not been able to distinguish by looking at the rate of proliferation, somebody who is going to respond and somebody who’s not. And this may be different than others experience, but our data will speak for themselves.
Anyway, those patients we began to employ checkpoint inhibitors, and initially off trial and after, some very interesting results. One anecdote, which was published last December in Blood, we saw that in a patient who during the early phases of CAR T-cell therapy was having expansion of CAR cells that were taking on a progressively exhausted phenotype. That patient was treated during progression with pembrolizumab, and what we were able to see is basically a reversal of phenotype and logarithmic expansion of the CAR cells. So, it’s possible that in some patients who are failing because of T-cell exhaustion, you can reverse the process with a checkpoint inhibitor. In the cases where patients are treated early with a checkpoint inhibitor, you actually have enough CAR cells in the blood that you can do very expansive phenotyping because there’s a lot of cells.
We’ve treated patients a month later, 2 months later, where there’s less cells present, and there, you can see changes in the populations using quantitative PCR but you can’t get the expanded phenotyping. So, we’re working on some technical approaches in those patients with lesser numbers of circulating cells to be able to characterize the phenotype. If it doesn’t work in 100% of patients, what we’re showing now is the most preliminary stuff, but I hope soon to have a lot more information.
Krishna V. Komanduri, MD: There are going to be results reported at this meeting with the combination of axi-cel and atezolizumab, and I can tell you in a completely different context, we have a study in our institution where axitinib, an antiangiogenic drug, is being combined with pembrolizumab. And in that setting and other settings, surrogates like PD-L1 expression in the tumor microenvironment and PD-1 expression and markers of exhaustion in the T cells can predict outcomes. I think we’re going to see more of those correlates between pathological outcomes, T-cell phenotypes, and then these more rationale…
David Maloney, MD, PhD: I think it highlights the issue that not all T cells are the same, No. 1. No. 2, the interaction of a T cell with the microenvironment, we don’t understand, and there are many ways to potentially manipulate that.
Transcript Edited for Clarity