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Gut Microbiota Modulation through Akkermansia spp. Supplementation Increases CAR T-cell Potency.

Laura Marcos-Kovandzic^1,2,3, Michele Avagliano⁴, Myriam Ben Khelil^3,5

¹Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

Cancer Discovery

|June 11, 2025

Summary

Gut microbiome dysbiosis, particularly low Akkermansia, hinders anti-CD19 CAR-T cell therapy. Supplementing Akkermansia improves CAR-T cell infiltration and tumor control by modulating the aryl hydrocarbon receptor pathway.

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Area of Science:

Microbiology
Immunology
Oncology

Background:

Gut microbiome dysbiosis is linked to cancer treatment outcomes.
The role of specific gut bacteria in CAR-T cell therapy efficacy remains under investigation.

Purpose of the Study:

To investigate the clinical relevance of gut microbiome composition and function in anti-CD19 CAR-T cell therapy.
To explore the mechanistic link between Akkermansia species, host metabolism, and CAR-T cell activity.

Main Methods:

Analysis of gut microbiome taxonomic and metabolic profiles in B cell lymphoma patients undergoing CAR-T therapy.
Preclinical syngeneic tumor model studies involving Akkermansia massiliensis supplementation.
Genetic manipulation of CAR-T cells to assess the role of the aryl hydrocarbon receptor (Ahr).

Main Results:

CAR-T therapy induced intestinal dysbiosis, characterized by reduced bacterial richness and Akkermansia species, correlating with therapy resistance.
Oral Akkermansia supplementation enhanced CAR-T cell infiltration, improved CD4/CD8 ratios, promoted Tc1 polarization, and increased indole metabolite production.
The therapeutic benefits of Akkermansia were dependent on CAR-T cell expression of the aryl hydrocarbon receptor (Ahr), with indole metabolites alone being insufficient.

Conclusions:

Akkermansia species play a crucial role in the efficacy of anti-CD19 CAR-T cell therapy.
Targeting the gut microbiome, specifically Akkermansia deficiency, represents a potential strategy to enhance CAR-T cell therapy outcomes.
The Ahr pathway is a key mediator of Akkermansia-driven improvements in CAR-T cell function.