Abstract
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
Highlights
Treatment with combined immune checkpoint blockade (CICB) is associated with high rates of objective responses[1], a substantial proportion of patients experience immune-related adverse events[2,3]
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and progressive disease (PD)-1 is associated with clinical bene t across tumor types, but a high rate of immune-related adverse events
We pro led the blood, tumor and gut microbiome of 77 advanced melanoma patients treated with CICB, with a high rate of any ≥Grade 3 immune-related adverse events (irAE) (49%) with parallel studies in pre-clinical models
Summary
Treatment with CICB is associated with high rates of objective responses[1], a substantial proportion of patients experience immune-related adverse events (irAE)[2,3]. The relative abundance of P. distasonis was signi cantly higher in mice that became eventually tumor-free post-CICB (Fig. 2f) and was negatively correlated with tumor size (Extended Data Fig. 4b) Together, these data identify associations between distinct commensal species such as P. distasonis and bene cial tumor responses to CICB, with some overlap noted between taxa identi ed in murine tumor models and in our patient cohort. Polyclonal expansion of T cell clones from baseline to on-treatment was observed, with patients experiencing grade ≥3 toxicity on CICB having expansion of ≥55 circulating CD8+ T cell clones compared to those with grade
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