Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
Clin Cancer Res. 2019 Mar 1;25(5):1557-1563. doi: 10.1158/1078-0432.CCR-18-2795. Epub 2018 Nov 8.
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.
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-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.
Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (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; = 0.037] and 0.70 at EDT (95% CI, 0.55-0.85; = 0.017) using ROC analysis.
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 IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity..
PD-1 和 CTLA-4 抑制剂联合治疗显著改善了晚期黑色素瘤患者的生存率，但也与显著的免疫相关毒性相关。本研究旨在确定治疗反应和免疫相关毒性的循环细胞因子生物标志物。
对 98 例接受 PD-1 抑制剂单药或联合抗 CTLA-4 治疗的黑色素瘤患者和 49 例接受联合抗 PD-1 和抗 CTLA-4 治疗的独立验证队列患者的 65 种细胞因子的表达进行了纵向分析。细胞因子表达与 RECIST 反应和免疫相关毒性相关，定义为需要永久停止治疗和使用大剂量类固醇的毒性。
11 种细胞因子在基线（PRE）和早期治疗（EDT）时严重免疫相关毒性患者中显著上调。这 11 种细胞因子的表达被整合到一个单一的毒性评分中，即 CYTOX（细胞因子毒性）评分，该评分在发现和验证队列中得到了验证。验证队列中 PRE 时 CYTOX 评分的 AUC 为 0.68（95%置信区间，0.51-0.84； = 0.037），EDT 时为 0.70（95%置信区间，0.55-0.85； = 0.017），ROC 分析。
CYTOX 评分可预测接受抗 CTLA-4 和抗 PD-1 免疫治疗的黑色素瘤患者严重的免疫相关毒性。该评分包括白细胞介素 1a、白细胞介素 2 和干扰素-α2 等促炎细胞因子，可能有助于早期管理严重的、潜在危及生命的免疫相关毒性。
