Resistance with CAR-T Therapy

Transcript:Ian W. Flinn, MD: What causes resistance after CAR-T cells? If they’re persisting, and sometimes they’re not, what’s the mechanism of escape? Do we know anything about that?

Krishna V. Komanduri, MD: Well, one of the things that can happen is that the cancer cells can actually change their expression of CD19, which is a target. I, in some ways, conceptually think of cancer cells as like bacteria. So, if you give an antibiotic, you’ll often see antibiotic resistance. There’s remarkable plasticity and the ability for these cells to evolve and basically genetically mutate, such that they don’t look like the cells that were susceptible. That’s true for chemotherapy and that’s also true for immune therapy.

Frederick L. Locke, MD: Yes. We know for ALL that resistance can develop through loss of the CD19 epitope that’s recognized by the CAR-T cells, and the mechanisms for that are starting to be understood. In fact, there can be alternative splicing of exon 2 of CD19, and that leads to an altered CD19. It loses its normal signaling properties, but it no longer becomes visible to the CAR-T cell. And yet, that same altered epitope also confers survival advantages to those ALL cells. Then, recently, Cameron Turtle reported on a second mechanism of resistance in ALL. In patients who have an MLL fusion of their ALL, a known resistance mechanism to chemotherapy was also found in CAR-T cell-treated patients where they switched lineage. They went from an ALL lineage to an AML lineage. So, they no longer expressed CD19. Those are two mechanisms of relapse in ALL. In diffuse large B-cell lymphoma, we have to do the experiments to figure out why patients aren’t responding or why they’re relapsing.

Ian W. Flinn, MD: So, if one mechanism of resistance is modulation of CD19, are we going to see combination cocktails of CAR-T cells targeting other B-cell antigens, such as CD20 and CD23? You started off by talking about why everyone settled on CD19 as the antigen of choice.

Frederick L. Locke, MD: Yes. I think that people are already looking at alternative targets. CD19 is tough because of rituximab and the heavily pretreatment that the patients will have received, but there’s alternate antigens that are on B cells. You might conceivably get a cocktail of CAR-T cells or in sequence against different targets. We mentioned briefly multiple myeloma. There are, in development, CAR-T cells against BCMA, B-cell maturation antigen, which is expressed on multiple myeloma cells. So, this is coming along. The other way to think about the next step here is to combine it with some of those checkpoint blockade antibodies that we talked about earlier. Combining CAR-T cells with anti-PD-1 or anti-PD ligand 1 is likely to be another strategy.

Krishna V. Komanduri, MD: One thing I have to add about that is we talked about this issue of one costimulatory domain versus the other and the benefit of persistence versus the downside of, maybe, overexpansion that then leads to toxicity. In all of these studies, it’s true that there is a subset of patients that may benefit from disinhibition of their T-cell response because maybe those T cells can get exhausted, as well. On the other hand, will that lead to more toxicity? I think this is a really critical question.

Frederick L. Locke, MD: Absolutely. Again, it’s in the early days. We need to do these studies and figure out the safest way to administer them, figure out what responses we can expect.

Transcript Edited for Clarity