Association of intestinal exfoliome and Prevotellaceae with toxicity and clinical outcome during immune-checkpoint blockade.

2664 Background: Immune-related adverse events (irAEs) are autoimmune side effects related to ICI, varying in severity, onset and organ involvement that may be hard to differentiate from non-irAEs. Some reports have demonstrated that gut microbiota (GM) plays a role in modulating the risk of AEs. In this study, we combine gut mamalian and microbial metagenomics sequencing (MGS) to explore the influence of GM on treatment response and risk of AEs. Methods: NCT04567446 allowed fecal MGS at baseline and longitudinally in patients (pts) with advanced non-small cell lung cancer (), renal cell carcinoma and bladder cancer treated with ICI alone (ICI cohort, n = 542pts) or in combination with chemotherapy (CT+ICI cohort, n = 122 pts) in France and Canada. Pts who experienced severe (≥ grade 3) irAEs after ICI+/-CT were compared to those who did not, using microbial MGS parameters (Shannon diversity, TOPOSCORE, PCoA and LEfSe). Multivariate Cox regression models to analyze factors influencing overall survival (OS) included microbiota composition and the host exfoliome (i.e., mammalian eukaryotic DNA read counts within stools). Results: Pts with severe irAEs (10%) presented a less diverse microbiome, a lower TOPOSCORE and a distinct microbial community compared to those without severe irAEs, showing an overabundance of several members of the Prevotellaceae family. Interestingly, CT+ICI pts who experienced severe irAEs had the most dysbiotic microbiome, characterized by a lower alpha-diversity and TOPOSCORE, dominated by oral taxa ( Ligilactobacillus salivarius) and tolerogenic Hungatella spp. and Enterocloster spp. Among pts screened for exfoliation, 44% presented hstool mammalian DNA than healthy subjects, showed a GM enriched with pathobionts, including the Enterocloster genus, and exhibited worse OS (HR 1.212, p = 0.0135) in univariate and multivariate analyses (HR 1.18, p = 0.049). Although there was no significant correlation between toxicity and exfoliation, either in CT+ICI or ICI alone, pts enriched with Prevotellaceae family appeared to exhibit the highest levels of exfoliation. Conclusions: Host-microbial interactions influence immunity and therefore ICI prognosis and toxicity. We found Prevotellaceae members as potential biomarkers for ICI-related toxicity. The host exfoliome is an interesting parameter that may reflect gut fitness, requiring further investigation. Clinical trial information: NCT04567446 .