Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia

作者：Catherine Pham‐Danis, Amanda J Novak, Etienne P. Danis, Samantha M. McClellan, Lillie Leach, Michael C. Yarnell, Christopher C. Ebmeier, Sarah Kathleen Tasian, Mark Eric Kohler · 发表于：Cancer Cell · 年份：2025 · DOI：10.1016/j.ccell.2025.02.008 · 被引用次数：20 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、Immunotherapy and Immune Responses

Chimeric antigen receptor (CAR) T cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by relapse. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T cells and underlies most relapses following CD22BBz CAR T cell therapy. Here, we interrogate CD22BBz CAR signaling in response to low antigen and find inefficient phosphorylation of the linker for activation of T cells (LAT) limiting downstream signaling. To overcome this, we designed the adjunctive LAT-activating CAR T cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrate reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling, and AP-1 activity. ALA-CART cells show improved cytotoxicity, proliferation, persistence, and efficacy against antigen-low leukemias that were refractory to clinically active CD22BBz CAR T cells. Restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T cell failure.