PRJNA484225
Molecular, immune and microbial determinants of response and toxicity to combination CTLA-4 and PD-1 blockade
Treatment with combined immune checkpoint blockade (CICB) targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) is associated with clinical benefit across several tumor types but a high rate of immune related adverse events (irAE). Biomarkers of response and irAE to CICB represent an area of unmet medical need. To address this, we investigated genomic, immune and microbial determinants in a cohort of 53 metastatic melanoma (MM) patients and performed parallel studies in murine models. Results demonstrate similar biomarkers of response to checkpoint monotherapy, and also suggest that patients with a more antigen-experienced peripheral T cell repertoire (treated with prior immunotherapy) have a significantly lower rate of irAEs. Microbial determinants of response and toxicity to CICB were identified in the gut microbiota in human and murine cohorts, with commonalities, and evidence that targeting these taxa may reduce toxicity in preclinical models. Together, these findings have potentially important implications.