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

in Cancer discovery by Laura Marcos-Kovandzic, Michele Avagliano, Myriam Ben Khelil, Janesa Srikanthan, Rim Abdallah, Valentina Petrocelli, Jessica Rengassamy, Alexia Alfaro, Mathilde Bied, Marine Fidelle, Gladys Ferrere, Romain Daillere, Ahmadreza Arbab, Roula Amine-Hneineh, Arnaud Pages, Peggy Dartigues, Pierre Ly, Sylvain Simon, Sylvere Durand, Adrian Gottschlich, Florent Ginhoux, Camille Bleriot, Peng Liu, Liwei Zhao, Laura Creusot, Nathalie Rolhion, Guido Kroemer, Laurie Menger, Sebastian Kobold, Cristina Castilla-Llorente, Harry Sokol, Stefano Casola, Edoardo Pasolli, Laurence Zitvogel, Camille Bigenwald

TLDR

  • The study finds that Akkermansia supplementation improves CAR-T cell therapy outcomes by increasing CAR-T cell infiltration into bone marrow and promoting anti-tumor effects.

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.

Overview

  • The study investigates the clinical relevance of the gut microbiome in anti-CD19 CAR-T cell therapy, examining taxonomic and metabolic levels in patients and a preclinical syngeneic tumor model.
  • The study reveals profound intestinal dysbiosis in B cell lymphoma patients treated with CD19-CAR-T cells, worsened after CAR-T infusion, characterized by low bacterial richness, low sMAdCAM-1, and loss of Akkermansia species.
  • The primary objective is to understand the clinical relevance of the gut microbiome in CAR-T cell therapy and identify potential therapeutic strategies to improve its efficacy.

Comparative Analysis & Findings

  • The study finds that patients with intestinal Akkermansia deficiency exhibited resistance to therapy, while those with Akkermansia supplementation showed increased CAR-T cell infiltration into bone marrow, inverted CD4/CD8 CAR-T ratio, and improved tumor control.
  • Mechanistically, Akkermansia massiliensis supplementation increased the release of tryptophan-derived indole metabolites, promoting Ahr-agonistic effects, which led 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).

Implications and Future Directions

  • The study suggests that Akkermansia supplementation could improve CAR-T cell potency in patients with intestinal Akkermansia deficiency, making it a potential therapeutic strategy for improving CAR-T cell therapy outcomes.
  • Future studies should investigate the optimal duration and dosing of Akkermansia supplementation in patients and explore the role of indole receptors in CAR-T cell therapy.
  • Further research is needed to elucidate the mechanisms by which Akkermansia spp. modulate CAR-T cell function and identify potential biomarkers for Akkermansia deficiency in patients.
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