Phase I Trial of a Glypican-3-Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival
Phase I Trial of a Glypican-3-Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival
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DOI：
10.1158/1078-0432.ccr-11-3044
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发表时间：
2012-07-01
影响因子：
11.5
通讯作者：
Nakatsura, Tetsuya
中科院分区：
文献类型：
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作者：
Sawada, Yu;Yoshikawa, Toshiaki;Nakatsura, Tetsuya
目的：癌胚抗原磷脂酰肌醇蛋白聚糖3（GPC 3）是肝癌免疫治疗的理想靶点。在这个非随机，开放标签，I期临床试验中，我们分析了GPC 3肽疫苗接种在晚期HCC患者的安全性和有效性。实验设计：33例晚期HCC患者接受GPC 3肽疫苗接种（第1天，15日和29日与剂量递增皮内注射）。主要终点是GPC 3肽疫苗接种的安全性。次要终点是免疫应答，如通过IFN-γ ELISPOT测定所测量的，以及临床结果肿瘤应答、肿瘤进展时间和总生存期（OS）。1例患者显示部分缓解，19例患者在开始治疗后2个月显示疾病稳定。19例病情稳定的患者中有4例出现肿瘤坏死或消退，不符合部分缓解标准。9名患者的肿瘤标志物甲胎蛋白和/或脱-g-羧基凝血酶原水平暂时下降。GPC 3肽疫苗在30例患者中诱导了GPC 3特异性CTL应答。GPC 3特异性CTL频率高的患者（N = 15）的OS显著长于GPC 3特异性CTL频率低的患者（N = 18; P = 0.033）。结论：GPC 3衍生肽疫苗具有良好的耐受性，并注意到可测量的免疫应答和抗肿瘤疗效。这是第一项研究表明，肽特异性CTL频率可以是接受肽疫苗接种的HCC患者OS的预测标志物。临床癌症研究; 18（13）; 3686-96。（C）2012年AACR。
Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC.Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-gamma ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS).Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers a-fetoprotein and/or des-g-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033).Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination. Clin Cancer Res; 18(13); 3686-96. (C)2012 AACR.