Journal Article

DKFZ-2025-01852

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Gut Microbiota Modulation through Akkermansia spp. Supplementation Increases CAR T-cell Potency.

Marcos-Kovandzic, L. ; Avagliano, M. ; Ben Khelil, M. ; Srikanthan, J. ; Abdallah, R. ; Petrocelli, V. ; Rengassamy, J. ; Alfaro, A. ; Bied, M. ; Fidelle, M. ; Ferrere, G. ; Daillère, R. ; Arbab, A. ; Amine-Hneineh, R. ; Pages, A. ; Dartigues, P. ; Ly, P. ; Simon, S. ; Durand, S. ; Gottschlich, A.DKFZ* ; Ginhoux, F. ; Blériot, C. ; Liu, P. ; Zhao, L. ; Creusot, L. ; Rolhion, N. ; Derosa, L. ; Kroemer, G. ; Menger, L. ; Kobold, S.DKFZ* ; Castilla-Llorente, C. ; Sokol, H. ; Casola, S. ; Pasolli, E. ; Zitvogel, L. ; Bigenwald, C.

2025
[Verlag nicht ermittelbar] Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/2159-8290.CD-24-1230

Abstract: This study investigates the clinical relevance of the gut microbiome at taxonomic and metabolic levels in anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, both in patients and in a preclinical syngeneic tumor model. Patients with B-cell lymphoma treated with CD19 CAR T cells exhibited profound intestinal dysbiosis, exacerbated after CAR T-cell infusion. This dysbiosis was characterized by low bacterial richness, low soluble MAdCAM-1, and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR T-cell infiltration into the bone marrow, inverted the CD4/CD8 CAR T-cell ratio, favored Tc1 CD8+ T-cell polarization, and promoted the release of tryptophan-derived indole metabolites, leading to better tumor control. The clinical benefit of Akkermansia spp. supplementation was abolished when CAR T cells were genetically deficient in the indole receptor, aryl hydrocarbon receptor (AhR). AhR-agonistic indoles alone failed to replicate the bacterium's anticancer effects. These findings suggest that Akkermansia supplementation could improve CAR T-cell potency in patients with intestinal Akkermansia deficiency.B-cell lymphoma patients treated with CAR T cells harbor major gut microbiota perturbations and related metabolism that restrain CAR T-cell therapy. Reprogramming the gut microbiota ecosystem by oral A. massiliensis supplementation induces CAR T-cell niching and Tc1 differentiation in the bone marrow, promoting tumor control in an AhR-dependent manner.

Keyword(s): Gastrointestinal Microbiome: immunology (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Akkermansia: immunology (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Receptors, Aryl Hydrocarbon: metabolism (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Receptors, Chimeric Antigen: metabolism (MeSH) ; Female (MeSH) ; Lymphoma, B-Cell: therapy (MeSH) ; Lymphoma, B-Cell: immunology (MeSH) ; Lymphoma, B-Cell: microbiology (MeSH) ; Dysbiosis (MeSH) ; Male (MeSH) ; Antigens, CD19: immunology (MeSH) ; Receptors, Aryl Hydrocarbon ; Receptors, Chimeric Antigen ; Antigens, CD19

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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