156P - Microbiota-related multiomics to assess the clinical relevance of antibiotics (ATB) in immunotherapy (ICI)

Background

Early data revealed that ATB-induced gut dysbiosis negatively influences response to ICI, especially when ATB are taken close to ICI initiation. Little is known about surrogate markers of ATB-related immunosuppression.

Methods

NCT04567446 prospectively enrolled lung (NSCLC), kidney (RCC) and bladder (UC) cancer pts undergoing ICI at Gustave Roussy. Pts who never received ATB (noATB) were compared with those receiving ATB within the window of 60 days before to 42 days after ICI start (ATBin) and pts with ATB intake outside the window (ATBout). We performed stool metagenomics (MGS) and culturomics, ELISA/VIDAS assays for microbiota-specific memory T cells, IgG/IgA detection by flow cytometry and mass spectrometric-based metabolomics on blood. Objective Response Rate (ORR) and Overall Survival (OS) were assessed.

Results

From Jan. ‘21 to Apr. ‘24, 161 pts were included, of which 342 stool and 315 blood samples were collected longitudinally. Median fup was 14.5 months, 65% had NSCLC, 23% RCC and 12% UC. Most pts were treated in 1L (78%) and with ICI-based combinations (72%). Of 90 pts who received ATB at least once, 47% pts were ATBin and 53% ATBout. ATBin resulted in lower ORR (41%) compared to ATBout (70%) and noATB (44%) (p=0.011). Based on MGS, ATBin compared to noATB +/- ATBout displayed a tolerogenic microbiota dominated by oral taxa and Enterocloster spp. at the relative expense of A. muciniphila (Akk) and F. prausnitzii. Of ATBin, 7% had a negative fungal culture (vs 26% in all other pts, p<0.05) with distinct species such as C. albicans and/or G. candidum affecting OS in ATB pts. ATBin had a lower peripheral immune tonus (T_H1 response) against Akk compared to ATBout+noATB pts (p=0.012). In the NSCLC subset, high levels of IgG anti-Akk correlated with worse OS, with even poorer survival for ATBin pts (p<0.001). ATBin decreased distinct short chain fatty acids, metabolites significantly related to better ORR, while increasing shuttle and long chain carnitines associated with worse ORR.

Conclusions

Microbiota-related multiomics analysis assessing the immunosuppressive effect of ATB helps unveiling several molecular and cellular mechanisms that could be targeted with tailored microbiota-centered interventions to improve response to ICI.

Clinical trial identification

NCT04567446.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

RHU5 “ANR-21-RHUS-0017” IMMUNOLIFE” RHU LUMIERE: ANR-16-RHUS-0008 SIGN'IT ARC foundation 2020 and 2023.

Disclosure

L. Zitvogel: Financial Interests, Institutional, Project Lead: Everimmune, Everimmune SAB. All other authors have declared no conflicts of interest.