Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy

Several studies have shown the influence of commensal mi-crobes on T cell function, specifically in the setting of check-point immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using mul-tiple preclinical models as well as clinical correlates. In two mu -rine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combi-nation with CD19-directed CAR T cell (CART-19) therapy dis-played increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leu-kemia patients treated with CART-19 and exposed to oral van-comycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types.