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

Mol Ther. 2023 Mar 1;31(3):686-700. doi: 10.1016/j.ymthe.2023.01.012. Epub 2023 Jan 14.

Abstract

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.

Keywords: CAR T cell; antigen cross-presentation; gut microbiota; immunotherapy; vancomycin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD19
  • Cross-Priming
  • Gastrointestinal Microbiome*
  • Humans
  • Immunotherapy
  • Immunotherapy, Adoptive / methods
  • Mice
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Chimeric Antigen* / genetics
  • T-Lymphocytes
  • Vancomycin / pharmacology

Substances

  • Receptors, Antigen, T-Cell
  • Vancomycin
  • Receptors, Chimeric Antigen
  • Antigens, CD19