<i>Alistipes</i> and <i>Eggerthella</i> shape the response to oncolytic adenovirus therapy in mice and humans through short-chain fatty acid metabolism

Abstract

<p>Accumulating evidence implicates the microbiome as an important determinant of clinical outcomes in cancer therapies; however, the role of the microbiome in oncolytic virus therapy remains largely unexplored. We investigated the gut microbiome of cancer patients following treatment with the oncolytic adenovirus igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123). Baseline fecal samples from phase I clinical trials (NCT04695327 and NCT05271318) were analyzed using shotgun metagenomic sequencing and compared to treatment outcomes. A higher relative abundance of <em>Alistipes</em> was observed in patients with treatment benefit, while elevated <em>Eggerthella</em> was observed with reduced benefit. These associations were validated in a preclinical mouse model where administration of <em>Alistipes shahii</em> improved the efficacy of adenovirus therapy. In addition, enrichment analysis in patient samples showed a positive correlation between higher relative abundance of <em>Alistipes</em> and elevated short-chain fatty acids in both feces and serum, which in turn revealed higher circulating neutrophil counts. Finally, in a case study, we observed that adenovirus treatment resulted in increased <em>Alistipes</em> relative abundance and reduced <em>Eggerthella</em> relative abundance, indicating that adenovirus therapy may beneficially modulate the microbiome. Overall, our findings reveal a novel association between <em>Alistipes</em>, <em>Eggerthella</em>, and the therapeutic response to oncolytic adenovirus therapy, highlighting their potential as biomarkers or targets for microbiome-based interventions such as pre-, pro-, or postbiotics.<br></p>