Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy
Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy
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DOI：
10.1158/1078-0432.ccr-18-2795
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发表时间：
2019-03-01
影响因子：
11.5
通讯作者：
Rizos, Helen
中科院分区：
文献类型：
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作者：
Lim, Su Y.;Lee, Jenny H.;Rizos, Helen
目的：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toxicity.Experimental Design的循环细胞因子生物标志物：65细胞因子的表达是纵向分布在98例黑色素瘤患者与PD-1抑制剂治疗，单独或与抗CTLA-4的组合，并在一个独立的验证队列的49例患者与抗PD-1和抗CTLA-4的组合治疗。细胞因子的表达与RECIST反应和免疫相关的毒性，定义为毒性，保证永久停止治疗和管理的高剂量steroids.Results：11细胞因子在基线（PRE）和治疗早期（EDT）严重的免疫相关毒性的患者中显着上调。将这11种细胞因子的表达整合到单个毒性评分（CYTOX（细胞因子毒性）评分）中，并在发现和验证队列中证实了该评分的预测效用。验证队列中CYTOX评分的AUC在PRE时为0.68 [95%置信区间（CI），0.51-0.84; P = 0.037]，在EDT时为0.70（95%CI，0.55-0.85; P = 0.017）。CYTOX评分可预测用抗CTLA-4和抗PD-1免疫疗法组合治疗的黑素瘤患者中的严重免疫相关毒性。该评分包括促炎细胞因子，如IL 1 α、IL 2和IFN α 2，可能有助于早期管理严重的、可能危及生命的免疫相关毒性。
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.