Section for Cancer Immunotherapy, Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Cancer Sci. 2011 May;102(5):918-25. doi: 10.1111/j.1349-7006.2011.01896.x. Epub 2011 Mar 4.
Glypican-3 (GPC3) is an onco-fetal antigen that is overexpressed in human hepatocellular carcinoma (HCC), and is only expressed in the placenta and embryonic liver among normal tissues. Previously, we identified an HLA-A2-restricted GPC3(144-152) (FVGEFFTDV) peptide that can induce GPC3-reactive CTLs without inducing autoimmunity in HLA-A2 transgenic mice. In this study, we carried out a phase I clinical trial of HLA-A2-restricted GPC3(144-152) peptide vaccine in 14 patients with advanced HCC. Immunological responses were analyzed by ex vivo γ-interferon enzyme-linked immunospot assay. The frequency of GPC3(144-152) peptide-specific CTLs after vaccination (mean, 96; range, 5-441) was significantly larger than that before vaccination (mean, 6.5; range, 0-43) (P < 0.01). An increase in the GPC3(144-152) peptide-specific CTL frequency was observed in 12 (86%) of 14 patients after vaccination. Additionally, there was a significant correlation between the maximum value of GPC3(144-152) peptide-specific CTLs after vaccination and the dose of the peptide injected (P = 0.0166, r = 0.665). Moreover, we established several GPC3(144-152) peptide-specific CTL clones from PBMCs of patients vaccinated with GPC3(144-152) peptide by single cell sorting using Dextramer and CD107a antibody. These CTL clones had high avidity (the recognition efficiency showing 50% cytotoxicity was 10(-10) or 10(-11) M) and could recognize HCC cell lines expressing GPC3 in an HLA-class I-restricted manner. These results suggest that GPC3(144-152) peptide vaccine can induce high avidity CTLs capable of killing HCC cells expressing GPC3. This trial was registered with University Hospital Medical Information Network number 000001395.
磷脂酰聚糖 3（GPC3）是一种在人肝细胞癌（HCC）中过表达的胚胎抗原，仅在正常组织的胎盘和胚胎肝脏中表达。之前，我们鉴定了一种 HLA-A2 限制性 GPC3（144-152）（FVGEFFTDV）肽，它可以在 HLA-A2 转基因小鼠中诱导 GPC3 反应性 CTL，而不会诱导自身免疫。在这项研究中，我们在 14 名晚期 HCC 患者中进行了 HLA-A2 限制性 GPC3（144-152）肽疫苗的 I 期临床试验。通过体外 γ-干扰素酶联免疫斑点分析来分析免疫反应。接种疫苗后 GPC3（144-152）肽特异性 CTL 的频率（平均值，96；范围，5-441）明显大于接种疫苗前（平均值，6.5；范围，0-43）（P <0.01）。接种疫苗后，14 名患者中有 12 名（86%）的 GPC3（144-152）肽特异性 CTL 频率增加。此外，接种疫苗后 GPC3（144-152）肽特异性 CTL 的最大频率与注射的肽剂量之间存在显著相关性（P = 0.0166，r = 0.665）。此外，我们通过使用 Dextramer 和 CD107a 抗体通过单细胞分选从接种 GPC3（144-152）肽的患者的 PBMC 中建立了几个 GPC3（144-152）肽特异性 CTL 克隆。这些 CTL 克隆具有高亲和力（显示 50%细胞毒性的识别效率为 10（-10）或 10（-11）M），并且可以以 HLA 类 I 限制性方式识别表达 GPC3 的 HCC 细胞系。这些结果表明，GPC3（144-152）肽疫苗可以诱导能够杀伤表达 GPC3 的 HCC 细胞的高亲和力 CTL。该试验在大学医院医学信息网络注册，注册号为 000001395。
