期刊
CLINICAL CANCER RESEARCH
卷 25, 期 5, 页码 1557-1563出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-2795
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资金
- NHMRC [1130423, 1093017]
- Cancer Institute NSW Sydney Vital Translational Cancer Research Centre
- Priority-driven Collaborative Cancer Research Scheme [1123911]
- Cancer Australia
- Cure Cancer Australia Foundation
- Cancer Institute NSW Fellowship
- NHMRC Practitioner Fellowships
- NHMRC Research Fellowship
- National Health and Medical Research Council of Australia [1130423, 1093017] Funding Source: NHMRC
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 patients with melanoma 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-CTLA4. 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 base-line (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51-0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55-0.85; P = 0.017) using ROC analysis. Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1 alpha, IL2, and IFN alpha 2, may help in the early management of severe, potentially lifethreatening immune-related toxicity.
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