Abstract 346P
Background
Retrospective and prospective studies have demonstrated that ABX blunt the efficacy of immunotherapy regimens such as immune checkpoint inhibitors (ICI). To date, we lack studies assessing biological mechanisms underlying ABX-mediated immunosuppression.
Methods
The prospective Immunolife1 (IML1) study aim to evaluate effects of ABX on the host’s gut microbiota (GM), metabolism and immunity based on a multi-omics approach across a retrospective cohort of 481 pts with non-small cell lung cancer (NSCLC) and the IML1 cohort of 145 pts with NSCLC, bladder, and kidney cancers eligible to ICI (NCT04567446). Multi-omics approach included fecal shotgun metagenomics sequencing and fungal culturomics, and blood metabolomics, spectral flow cytometry and in vitro DC/T cell assay.
Results
Broad-spectrum ABX (but not narrow) in the −60 to +42 days window of ICI start impact clinical benefit. ABX use leads to reduced microbial (both fungal and bacterial) diversity and a GM compositional shift: “blooming” of tolerogenic microbes (mostly Enterocloster spp.) and loss of Methanomethylophilaceae archaea. Moreover, fungal stool culturomics were more likely to be positive and dominated by ethanolproducing (Candida spp. and Cladosporium cladosporioides). Pts were not defective in fungal-specific recall responses (90% versus 60% of heamth individuals), mostly Th1 and/or Th17. ABX impact bile acid metabolism (loss of glyco-and tauro-conjugated primary and secondary bile acids) and disrupt the intestinal regulation of lymphocyte migration through the gut immune checkpoint MAdCAM-1. ABX intake was associated with CD8+ T cell exhaustion. Importantly, GM composition and MAdCAM-1 levels did not recover until 90 days after ABX stop. We identified biomarkers of favorable prognosis despite ABX use (Methanomethylophilaceae archaea, Geotrichum candidum, and taurocholic acid).
Conclusions
Our study emphasize the need for microbiota-centered interventions to accelerate recovery of gut fitness to promote optimal clinical benefit. These findings reveal new hallmarks of ATB-associated dysbiosis that merit further investigation.
Clinical trial identification
NCT04567446.
Legal entity responsible for the study
Gustave Roussy.
Funding
RHU Lumière, ARC SIGN’IT, Seerave.
Disclosure
B. Besse: Financial Interests, Institutional, Invited Speaker: AbbVie AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Hedera Dx, Janssen, MSD, Roche, Sanofi Aventis Springer Healthcare Ltd; Financial Interests, Institutional, Advisory Role: AstraZeneca, BeiGene, GENMAB A/S, GSK, Janssen, MSD, Ose Immunotherapeutics, PharmaMar, Roche-Genentech, Sanofi, Takeda, AbbVie, Eli Lilly, Ellipses pharma Ltd, F.Hoffmann-La Roche Ltd, Genmab, Immunocore, Janssen, MSD, Ose Immunotherapeutics, Owkin, Taiho oncology; Financial Interests, Institutional, Advisory Board: AbbVie, Biontech SE, Bristol Myer Squibb, Chugai pharmaceutical, CureVac AG, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, PharmaMar, Regeneron, Sanofi aventis, Turning Point Therapeutics. L. Zitvogel: Financial Interests, Institutional, Advisory Board: L.Zi. founded EverImmune and is the SAB president of everImmune.; Financial Interests, Institutional, Research Grant: L.Zi. had grant support from Daiichi Sankyo, Kaleido, 9 meters and Pileje. L. Derosa: Non-Financial Interests, Institutional, Other, SAB member: EverImmune. All other authors have declared no conflicts of interest.