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

• Published in: Molecular therapy Vol. 31; no. 3; pp. 686 - 700
• Main Authors: Uribe-Herranz, Mireia, Beghi, Silvia, Ruella, Marco, Parvathaneni, Kalpana, Salaris, Silvano, Kostopoulos, Nektarios, George, Subin S., Pierini, Stefano, Krimitza, Elisavet, Costabile, Francesca, Ghilardi, Guido, Amelsberg, Kimberly V., Lee, Yong Gu, Pajarillo, Raymone, Markmann, Caroline, McGettigan-Croce, Bevin, Agarwal, Divyansh, Frey, Noelle, Lacey, Simon F., Scholler, John, Gabunia, Khatuna, Wu, Gary, Chong, Elise, Porter, David L., June, Carl H., Schuster, Stephen J., Bhoj, Vijay, Facciabene, Andrea
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2023; American Society of Gene & Cell Therapy
• Subjects: Animals; antigen cross-presentation; Antigens, CD19; CAR T cell; Cross-Priming; Gastrointestinal Microbiome; gut microbiota; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Mice; Original; Receptors, Antigen, T-Cell - genetics; Receptors, Chimeric Antigen - genetics; T-Lymphocytes; vancomycin; Vancomycin - pharmacology; vancomycin; gut microbiota; antigen cross-presentation; CAR T cell; immunotherapy
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.01.012

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. [Display omitted] CAR T cell immunotherapy has transformed the treatment of B cell malignancies. However, a significant subset of patients fail to respond. The gut microbiome influences the response to cancer immunotherapies. We extend our mechanistic understanding, demonstrating that gut microbiome modulation enhances CAR T therapy by promoting CAR T and endogenous T cell responses.