IL-15 overexpression promotes memory program and anti-tumor activity of CD64 CAR T cells in a preclinical AML model

The prognosis of relapsed or refractory acute myeloid leukemia (r/r AML) patients remains poor due to lack of novel therapies. We previous demonstrated that chimeric antigen receptor (CAR) T cells targeting CD64 have the potential to treat AML with minimal toxicity to hematopoietic stem/progenitor cells. However, the efficacy was limited in AML mouse models. Interleukin-15 (IL-15), a cytokine that promotes T cell survival and proliferation, has been shown to enhance CAR T cell activity. Here, we engineer CD64 CAR T cells with overexpression of IL-15 and evaluate the function. IL-15-armed CAR T cells exhibit enhanced cytolytic activity against AML cells, improve expansion and persistence in vitro, and favor a memory phenotype while reducing exhaustion and apoptosis. In mouse model, IL-15-armed CAR T cells show robust expansion, prolong mouse survival, and no obvious toxicity. These findings suggest that IL-15-armed CD64 CAR T cells may be a promising strategy for r/r AML. IL-15-armed CD64 CAR T cells exhibit enhanced expansion, persistence, and anti-leukemia efficacy. This strategy prolongs survival in mouse models without obvious toxicity, presenting a promising therapeutic approach for acute myeloid leukemia.