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ASH 2025 | CAR T-cell durability in LBCL: antigen presentation, immune engagement, and HLA loss
Frederick Locke, MD, Moffitt Cancer Center, Tampa, FL, discusses how CAR T-cell durability in large B-cell lymphoma (LBCL) depends on effective antigen presentation and endogenous immune engagement, while genomic instability and HLA loss limit long-term responses. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
We did a super cool analysis, really a team science effort. We collaborated with Francesco Mora, who’s now at Memorial Sloan Kettering, a bioinformatician, John Schatz, who’s at the University of Miami, who is an animal modeler and a lymphoma expert, as well as Sandy Anderson, who’s an integrated mathematical oncologist who works at Moffitt Cancer Center. And all of these investigators and myself and our lab evaluated patients undergoing CAR T cell therapy as a treatment for diffuse large B cell lymphoma...
We did a super cool analysis, really a team science effort. We collaborated with Francesco Mora, who’s now at Memorial Sloan Kettering, a bioinformatician, John Schatz, who’s at the University of Miami, who is an animal modeler and a lymphoma expert, as well as Sandy Anderson, who’s an integrated mathematical oncologist who works at Moffitt Cancer Center. And all of these investigators and myself and our lab evaluated patients undergoing CAR T cell therapy as a treatment for diffuse large B cell lymphoma. We asked a simple question, are there targets on those lymphoma cells that could increase the durability of remission. And so we looked for neoepitopes or mutated antigens. And we found, actually, that more antigens, more mutated neoantigens, was associated with worse response. And those were associated with genomic complexity, really bad tumors where the chromosomes are all messed up. And so those patients had high mutational burden, but they also had loss of the antigen presentation machinery, HLA, and other antigen presentation machinery necessary to present antigen and lead to durable remissions. And so then we modeled that out both mathematically and in animal models to show that it is absolutely the case that you need epitope spreading, you need the endogenous immune response to contribute to durable ongoing remissions in large B cell lymphoma after CAR T cell therapy. It’s a really cool team science project and we’re happy to have presented it here at ASH.
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