A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C
A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C
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DOI：
10.1016/j.jhep.2013.02.022
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发表时间：
2013-07-01
影响因子：
25.7
通讯作者：
Prieto, Jesus
中科院分区：
文献类型：
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作者：
Sangro, Bruno;Gomez-Martin, Carlos;Prieto, Jesus
背景与目的：Tremelimumab是一种单克隆抗体，可阻断细胞毒性T淋巴细胞相关抗原4 (CTLA-4)， CTLA-4是一种干扰T细胞活化和增殖的抑制性共受体。该临床试验的目的是检测tremelimumab对肝细胞癌（HCC）和慢性丙型肝炎病毒（HCV）感染患者的抗肿瘤和抗病毒作用；并研究其对肝硬化患者用药的安全性。方法：每90天给予Tremelimumab 15mg /kg IV剂量，直到肿瘤进展或严重毒性。20例可评估毒性和病毒反应，17例可评估肿瘤反应。大多数患者处于晚期，43%的患者肝功能改变（Child-Pugh B级）。结果：记录了良好的安全性，没有患者因为严重的免疫介导的不良事件而需要类固醇。一些患者在第一次给药后出现短暂的转氨酶升高，但在随后的周期中没有。部分缓解率为17.6%，疾病控制率为76.4%。进展时间为6.48个月（95% CI 3.95-9.14）。当HCV高变区1的新变体取代治疗前存在的主要变体时，观察到病毒载量显著下降，特别是在那些病毒载量下降更明显的患者中。这种抗病毒作用与增强的特异性抗hcv免疫反应有关。结论：Tremelimumab在hcv诱导的肝硬化晚期HCC患者中的安全性、抗肿瘤和抗病毒活性支持进一步的研究。(C) 2013欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients.Methods: Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B).Results: A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response.Conclusions: Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.