Anti-CD19 CAR T cells engineered to constitutively express CD40L delayed tumor onset and increased survival in immunocompetent mice with leukemia or lymphoma compared with second-generation CAR T cells. CD40L+ CAR T cells recruited and licensed CD40+ APCs in spleens and lymph nodes, leading to increased tumor infiltration and activation of endogenous CD4+ and CD8+ T cells, increased cytokine production, and a sustained immune response that conferred long-term protection against CD19- tumor challenge. CD40L+ CAR T cells did not require preconditioning and no increase in toxicity was observed.
Chimeric antigen receptor (CAR) T cells provide great efficacy in B cell malignancies. However, improved CAR T cell therapies are still needed. Here, we engineered tumor-targeted CAR T cells to constitutively express the immune-stimulatory molecule CD40 ligand (CD40L) and explored efficacy in different mouse leukemia/lymphoma models. We observed that CD40L(+) CAR T cells circumvent tumor immune escape via antigen loss through CD40/CD40L-mediated cytotoxicity and induction of a sustained, endogenous immune response. After adoptive cell transfer, the CD40L(+) CAR T cells displayed superior antitumor efficacy, licensed antigen-presenting cells, enhanced recruitment of immune effectors, and mobilized endogenous tumor-recognizing T cells. These effects were absent in Cd40(-/-) mice and provide a rationale for the use of CD40L(+) CAR T cells in cancer treatment.
Author Info: (1) Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering
Author Info: (1) Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: brentjer@mskcc.org.
