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ASH 2025 | CAR T-cell–driven induction of iNOS in TAMs promotes CAR T-cell resistance in B-cell lymphoma
Marco Davila, MD, PhD, Roswell Park Comprehensive Cancer Center, Buffalo, NY, discusses research identifying tumor-associated macrophages (TAMs) as a key driver of resistance to CD19 CAR T-cell therapy in lymphoma. Preclinical models demonstrated TAMs can impair or kill CAR T-cells through metabolic and proteomic mechanisms, highlighting inducible nitric oxide synthase (iNOS) as a potential therapeutic target to improve durable responses. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
CD19 CAR T-cells have been approved for patients with lymphoma for about eight years now. Phenomenal success with it, but patients still do have toxicities, and about half of the patients don’t respond long-term, meaning they don’t have durable remission. So it still becomes a major problem in terms of how can we help those patients, you know, convert them to a long-term remission. So in a collaboration with clinicians from the Moffitt Cancer Center, we looked at lymphoma samples from patients with lymphoma treated with CAR T-cells and determined that patients that had the worst responses long-term, meaning that they didn’t get an initial remission or that it lasted a short period of time, had an infiltration of macrophages within their lymphoma...
CD19 CAR T-cells have been approved for patients with lymphoma for about eight years now. Phenomenal success with it, but patients still do have toxicities, and about half of the patients don’t respond long-term, meaning they don’t have durable remission. So it still becomes a major problem in terms of how can we help those patients, you know, convert them to a long-term remission. So in a collaboration with clinicians from the Moffitt Cancer Center, we looked at lymphoma samples from patients with lymphoma treated with CAR T-cells and determined that patients that had the worst responses long-term, meaning that they didn’t get an initial remission or that it lasted a short period of time, had an infiltration of macrophages within their lymphoma. So that was kind of a novel insight. So the next thing we did was took that information in the laboratory, developed preclinical models to go, how might macrophages be kind of regulating CAR T cell function? Turns out that macrophages can kill CAR T cells. They can metabolically and proteomically render them dysfunctional as well. So we think that’s likely the mechanism. iNOS is a critical kind of feature of that process. Potentially, it can be a target for preventing that type of treatment resistance.
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