The DAV132 colon-targeted adsorbent does not interfere with plasma concentrations of antibiotics but prevents antibiotic-related dysbiosis: a randomized phase I trial in healthy volunteers.

Date publication

septembre 2024

Journal

Nature communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain , Pr GHIRINGHELLI François , Mme TRUNTZER Caroline

Tous les auteurs :
Messaoudene M, Ferreira S, Saint-Lu N, Ponce M, Truntzer C, Boidot R, Le Bescop C, Loppinet T, Corbel T, Féger C, Bertrand K, Elkrief A, Isaksen M, Vitry F, Sablier-Gallis F, Andremont A, Bod L, Ghiringhelli F, de Gunzburg J, Routy B

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39278946

Résumé

The deleterious impact of antibiotics (ATB) on the microbiome negatively influences immune checkpoint inhibitors (ICI) response in patients with cancer. We conducted a randomized phase I study (EudraCT:2019-A00240-57) with 148 healthy volunteers (HV) to test two doses of DAV132, a colon-targeted adsorbent, alongside intravenous ceftazidime-avibactam (CZA), piperacillin-tazobactam (PTZ) or ceftriaxone (CRO) and a group without ATB. The primary objective of the study was to assess the effect of DAV132 on ATB plasma concentrations and both doses of DAV132 did not alter ATB levels. Secondary objectives included safety, darkening of the feces, and fecal ATB concentrations. DAV132 was well tolerated, with no severe toxicity and similar darkening at both DAV132 doses. DAV132 led to significant decrease in CZA or PTZ feces concentration. When co-administered with CZA or PTZ, DAV132 preserved microbiome diversity, accelerated recovery to baseline composition and protected key commensals. Fecal microbiota transplantation (FMT) in preclinical cancer models in female mice from HV treated with CZA or PTZ alone inhibited anti-PD-1 response, while transplanted samples from HV treated with ATB + DAV132 circumvented resistance to anti-PD-1. This effect was linked to activated CD8 T cell populations in the tumor microenvironment. DAV132 represents a promising strategy for overcoming ATB-related dysbiosis and further studies are warranted to evaluate its efficacy in cancer patients.

Mots clés

Humans, Anti-Bacterial Agents, pharmacology, Healthy Volunteers, Animals, Dysbiosis, microbiology, Female, Mice, Adult, Male, Gastrointestinal Microbiome, drug effects, Colon, microbiology, Feces, microbiology, Middle Aged, Fecal Microbiota Transplantation, Young Adult, Immune Checkpoint Inhibitors

Référence

Nat Commun. 2024 09 15;15(1):8083