Uribe-Herranz, Beghi, and Ruella et al. showed that manipulation of the gut microbiome by oral treatment with vancomycin synergized with CD19-CAR T cell therapy in murine CD19+ A20 lymphoma and CD19+ B16 melanoma models due to increased TAA expression, enhanced TAA cross-presentation by DCs, and increased CD8+ T cell responses to endogenous antigens. These results were recapitulated in mice that had received fecal microbiota transplant from healthy human donors. In a retrospective analysis, adults with B-ALL who had been exposed to vancomycin shortly after treatment with CART-19 showed higher peak expansion of CAR T cells.
Contributed by Lauren Hitchings
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 CAR T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, the hematopoietic CD19(+)-A20 lymphoma and the 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 to CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in nave gut microbiota mice. Lastly, B-cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared to 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.
Author Info: (1) Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Immunology
Author Info: (1) Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Immunology Department, Hospital Clnic of Barcelona, Barcelona, 08036, Spain. (2) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA. (3) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (4) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, 19104, USA. (5) Unit of Biostatistics, Epidemiology and Public Health, University of Padova, Padova, Italy. (6) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA. (7) Bioinformatics Core, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (8) Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA; The Ovarian Cancer Research Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (9) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA. (10) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (12) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (13) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (14) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (15) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, 19104, USA. (16) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, 19104, USA. (17) Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02142, USA. (18) Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA. (19) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, 19104, USA. (20) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA. (21) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA. (22) Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania; Philadelphia, Pennsylvania 19104, USA. (23) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA. (24) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (25) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA. (26) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, 19104, USA. (28) Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine; Philadelphia, PA, 19104, USA; Division of Radiation Oncology, Hospital of the University of Pennsylvania; Philadelphia, PA, 19104, USA; The Ovarian Cancer Research Center, University of Pennsylvania; Philadelphia, PA, 19104, USA. Electronic address: Andrea.Facciabene@pennmedicine.upenn.edu.
