804MO - Gut microbiota composition is predictive of CAR-T cells response and its modulation enhances CAR-T cells activity

Background

Nowadays, anti-CD19 CAR-T cells represent the standard treatment for refractory B-cell lymphoma. However, there is still a 50% non-response rate in aggressive lymphoma cases. Some factors, such as gut microbiota composition, can influence T cell function and therapeutic response, mainly studied in the setting of immune checkpoint blockade and recently demonstrated to impact the efficacy of CAR-T cells in pre-clinical models and patients.

Methods

We prospectively and longitudinally collected fecal material from patients receiving commercial anti-CD19 CAR-T cells at different time-points (PIONEER NCT04567446). With no difference in alpha and beta diversity, the patient’s fecal samples at baseline revealed a distinct bacterial composition associated with response at 6 months, showing a higher prevalence of Akkermansia spp. amongst responders. Then, we validated the effect of this specific bacteria in treatment efficacy by using our fully immunocompetent B-cell lymphoma anti-CD19 CAR-T cell murine model.

Results

We observed a significant increase in overall survival and a higher anti-tumoral effect in the mice receiving the combination treatment of Akkermansia spp. + CAR-T. Moreover, the supplementation of Akkermansia spp. lead to a higher CAR-T infiltration in all explored organs and tumors, highlighting a significant higher early infiltration in the bone marrow, indicating the relevance of this compartment at early treatment stages. The infiltrating CAR-T cells had a higher cytotoxic phenotype (CD8+CD44hiCD62 low) and higher IFNγ production when Akkermansia spp. was added. Moreover, the increased cytotoxic T cell effector function seems to occur via the aryl-hydrocarbon receptor on T cells, as suggested by the in vivo use of AhR agonists and AhR KO CAR-T cells in our experimental settings. Finally, the activation of this receptor via the administration of Akkermansia spp., could be through certain metabolites (e.g. indoles), exclusively produced by the gut microbiota.

Conclusions

This suggests that a favorable microbiota is associated with a better response to CAR-T cell therapy in B-cell malignancies and restoring this favorable microbiota by supplementing Akkermansia spp. may improve the response to treatment.

Clinical trial identification

PIONEER NCT04567446.

Editorial acknowledgement

Legal entity responsible for the study

Institut Gustave Roussy.

Funding

European H2020 Marie Skłodowska-Curie Program.

Disclosure

All authors have declared no conflicts of interest.