Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System

摘要

Summary Chimeric antigen receptor (CAR) T?cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T?cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T?cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T?cells exhibit enhanced in?vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T?cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T?cells represent a promising strategy to enhance the clinical outcomes of adoptive T?cell therapy.