Abstract 4280: Restoration of LAT signaling via the ALA-CART platform promotes metabolic resiliency and persistence of AML CAR T cells

作者：Catherine Danis, Amanda J. Novak, Etienne Danis, Angie Vazquez, Michael Yarnell, Lillie Leach, M. Eric Kohler · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-4280 · 研究领域：CAR-T cell therapy research、Protein Degradation and Inhibitors、CRISPR and Genetic Engineering

Abstract Despite therapeutic advancements, the majority of patients with relapsed and/or refractory (r/r) acute myeloid leukemia (AML) have very poor prognoses and limited treatment options. While Chimeric Antigen Receptor (CAR) T cell therapy has transformed the treatment of r/r B-cell acute lymphoblastic leukemia (ALL), inducing remissions in up to 90% of patients, yet clinical trials of 2nd generation CAR T cells for patients with r/r AML have not replicated this success. Post-CAR T cell relapses in ALL are common and limit the long term efficacy of this therapy. Mechanisms driving ALL relapses after CAR T cells, such as short duration of activity and antigen modulated escape, have illuminated vulnerabilities of 2nd generation CAR T cells, such as exhaustion, poor persistence, and low antigen sensitivity. The mechanisms underlying AML progression after CAR T cells are not well defined, however, it is likely that similar barriers must be overcome to improve CAR T cell responses in patients with r/r AML. We recently demonstrated the Linker for Activation of T cells (LAT) is inefficiently engaged in ALL-directed CAR T cells, particularly when antigen levels are low. Through a novel Adjunctive LAT-Activating CAR T (ALA-CART) platform, LAT activity and downstream signaling were restored and ALA-CART cells demonstrated enhanced potency, expansion, and persistence. We hypothesized that CD33-directed ALA-CART cells would similarly show improved potency and persistence in pre-clini...