Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy

Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity. Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 melanoma patients treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high dose steroids. Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline and early during treatment. The expression of these eleven cytokines was integrated into a single toxicity score, the CYTOX score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The area under the curve for the CYTOX score in the validation cohort was 0.68 at PRE (95% CI, 0.51-0.84, p=0.037) and 0.70 at EDT (95% CI, 0.55-0.85, p=0.017) using receiver operating characteristic (ROC) analysis. Conclusions:The CYTOX score is predictive of severe immune-related toxicity in melanoma patients treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes pro-inflammatory cytokines such as IL-1a, IL-2 and IFNa2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

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