2. Academic Validation
  3. Gut microbiota modulation through Akkermansia spp. supplementation increases CAR-T cell potency

Gut microbiota modulation through Akkermansia spp. supplementation increases CAR-T cell potency

  • Cancer Discov. 2025 Jun 11. doi: 10.1158/2159-8290.CD-24-1230.
Laura Marcos-Kovandzic 1,  Michele Avagliano 2,  Myriam Ben Khelil 3,  Janesa Srikanthan 1,  Rim Abdallah 4,  Valentina Petrocelli 5,  Jessica Rengassamy 1,  Alexia Alfaro 3,  Mathilde Bied 6,  Marine Fidelle 3,  Gladys Ferrere 6,  Romain Daillere 3,  Ahmadreza Arbab 3,  Roula Amine-Hneineh 1,  Arnaud Pages 3,  Peggy Dartigues 3,  Pierre Ly 7,  Sylvain Simon 8,  Sylvere Durand 9,  Adrian Gottschlich 10,  Florent Ginhoux 11,  Camille Bleriot 3,  Peng Liu 3,  Liwei Zhao 6,  Laura Creusot 12,  Nathalie Rolhion 12,  Lisa Derosa 7,  Guido Kroemer 13,  Laurie Menger 14,  Sebastian Kobold 10,  Cristina Castilla-Llorente 15,  Harry Sokol 16,  Stefano Casola 17,  Edoardo Pasolli 2,  Laurence Zitvogel 3,  Camille Bigenwald 3
Affiliations

Affiliations

  • 1 Institut Gustave Roussy, Villejuif, île-de-france, France.
  • 2 University of Naples Federico II, Italy.
  • 3 Institut Gustave Roussy, Villejuif, France.
  • 4 Inserm, Paris, France.
  • 5 FIRC Institute of Molecular Oncology, Milan, Italy.
  • 6 Institut Gustave Roussy, France.
  • 7 Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
  • 8 fred hutchinson cancer center, France.
  • 9 INSERM U1138, Villejuif, France.
  • 10 LMU Klinikum, Munich, Germany.
  • 11 Singapore Immunology Network Agency for Science, Technology, and Research, Singapore, Singapore.
  • 12 Centre de Recherche Saint-Antoine, France.
  • 13 Gustave Roussy Cancer Campus, Paris, France.
  • 14 Institute Curie, Paris, France.
  • 15 Institut Gustave Roussy, French Guiana.
  • 16 Hôpital Saint-Antoine, Paris, France.
  • 17 IFOM ETS-The AIRC Institute of Molecular Oncology, Milano, Italy, Milano, Italy.
PMID: 40498998 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 CAR-T cell therapy, both in patients and in a preclinical syngeneic tumor model. B cell lymphoma patients treated with CD19-CAR-T cells exhibited profound intestinal dysbiosis, exacerbated after CAR-T infusion. This dysbiosis was characterized by low Bacterial richness, low sMAdCAM-1 and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR-T cell infiltration into bone marrow, inverted the CD4/CD8 CAR-T ratio, favored Tc1 CD8+ T cell polarization and promoted 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 for the indole receptor, Aryl Hydrocarbon Receptor (Ahr). Ahr-agonistic indoles alone failed to replicate the bacterium's Anticancer effects. These findings suggest Akkermansia supplementation could improve CAR-T cell potency in patients with intestinal Akkermansia deficiency.

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