Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.
Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.
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DOI：
10.1016/j.jhep.2020.07.026
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发表时间：
2020-12
影响因子：
25.7
通讯作者：
El-Khoueiry A
中科院分区：
文献类型：
--
作者：
Sangro B;Melero I;Wadhawan S;Finn RS;Abou-Alfa GK;Cheng AL;Yau T;Furuse J;Park JW;Boyd Z;Tang HT;Shen Y;Tschaika M;Neely J;El-Khoueiry A
Nivolumab是一种程序性死亡（PD）-1（PD-1）抑制剂，在晚期肝细胞癌（HCC）患者中产生持久的反应，可管理的安全性和增加的生存率。在我们的回顾性分析中，我们研究了免疫生物学以及生物标志物与nivolumab在HCC中的结果之间的潜在关联。通过免疫组织化学和RNA测序分析CheckMate 040试验剂量递增和剂量扩展阶段的新鲜和存档肿瘤样本，以评估几种炎症基因表达特征，包括CD 274（PD-配体1 [PD-L1]）、CD 8A、LAG 3和STAT 1。评估生物标志物与临床结局的相关性（根据RECIST v1.1和总生存期[OS]，盲态独立中心审查的最佳总体缓解）。在接受nivolumab单药治疗的PD-L1阳性和PD-L1阴性患者中观察到完全或部分肿瘤缓解。中位OS为28.1（95% CI 18.2-n.a.）肿瘤PD-L1 ≥1%与<1%的患者分别为16.6个月（95% CI 14.2-20.2）（p = 0.03）。增加的CD 3和CD 8显示出改善OS的非显著趋势（均p = 0.08），并且巨噬细胞标志物与OS无关。肿瘤PD-1和PD-L1表达与改善OS相关（分别p = 0.05和p = 0.03）。由4个基因组成的炎症基因标签与改善的客观缓解率（p = 0.05）和OS（p = 0.01）相关。PD-1和PD-L1表达、炎症生物标志物和炎症基因特征倾向于改善生存和缓解。虽然需要在更大规模的III期试验中进一步确认，以评估这些生物标志物的预测价值，但这些探索性分析表明，抗肿瘤免疫应答可能在纳武利尤单抗治疗HCC的获益中发挥作用。某些测试可用于提供肿瘤如何逃离免疫系统的图片，使其继续生长并产生更多的肿瘤。纳武单抗等疗法旨在帮助免疫系统对抗肿瘤。这些测试可用于确定这些疗法在治疗晚期肝癌中的有效性。NCT 01658878。
Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Complete or partial tumour responses were observed in PD-L1–positive and PD-L1–negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2–n.a.) vs. 16.6 months (95% CI 14.2–20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT01658878.
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影响因子：
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