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 microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19 ⁺ -A20 lymphoma and CD19 ⁺ -B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed 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 leukemia patients treated with CART-19 and exposed to oral vancomycin 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.
Competing Interests: Declaration of interests M.R.: BMS, BAYER, GSK, consultancy; Novartis, patents and royalties; AbClon, consultancy, research funding; Tmunity, patents and royalties; viTToria Biotherapeutics, research funding. N.F.: Sana Biotechnology, consultancy; Novartis, research funding; Kite Pharma, consultancy; Syndax Pharmaceuticals, consultancy. C.H.J.: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, and Ziopharm, current equity holder in publicly traded company; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm, consultancy; Novartis, patents and royalties. D.L.P.: American Society for Transplantation and Cellular Therapy, honoraria; ASH and DeCart, membership on the Board of Directors or advisory committee; Genentech, current employment, current equity holder in publicly traded company; Incyte and Janssen, Kite/Gilead, and National Marrow Donor Program, membership on an entity’s board of directors or advisory committee; Novartis, membership on an entity’s board of directors or advisory committee, patents and royalties, and research funding; Unity, patents and royalties; and Wiley and Sons Publishing, honoraria. S.J.S.: TG Therapeutics, research funding; Incyte, research funding; Adaptive Biotechnologies, research funding; Pharmacyclics, research funding; Merck, research funding; Genentech/Roche, consultancy, research funding; Tessa Therapeutics, consultancy; Loxo Oncology, consultancy; Juno Therapeutics, consultancy, research funding; BeiGene, consultancy; Alimera Sciences, consultancy; Acerta Pharma/AstraZeneca, consultancy; Novartis, consultancy, honoraria, patents and royalties, research funding; AbbVie, consultancy, research funding; Nordic Nanovector, consultancy; Celgene, consultancy, honoraria, research funding.
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