Heat shock protein 105 peptide vaccine could induce antitumor immune reactions in a phase I clinical trial
Heat shock protein 105 peptide vaccine could induce antitumor immune reactions in a phase I clinical trial
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DOI：
10.1111/cas.14165
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发表时间：
2019-09-19
期刊：
影响因子：
5.7
通讯作者：
Nakatsura, Tetsuya
中科院分区：
文献类型：
--
作者：
Shimizu, Yasuhiro;Yoshikawa, Toshiaki;Nakatsura, Tetsuya
热休克蛋白105（HSP 105）在许多癌症中过表达，包括结肠直肠癌（CRC）和食管癌（EC）。我们在CRC或EC患者中进行了HLA-A24和HLA-A2限制性HSP 105肽疫苗的I期临床试验。在这项试验的附加研究中，我们检查了新型疫苗的免疫功效。30例晚期CRC或EC患者接受了HSP 105肽疫苗接种。采用离体和体外γ-干扰素酶联免疫斑点试验评价免疫应答，并分析其与患者预后的相关性。HSP 105肽疫苗在30名患者中的15名中诱导肽特异性CTL。在HLA-A24患者（n = 15）中，7例显示仅离体诱导CTL，而在HLA-A2患者（n = 15）中，4例显示离体诱导，6例在体外诱导。热休克蛋白105特异性CTL诱导与癌症进展的抑制相关，并被揭示为无进展生存的潜在预测生物标志物（P = 0.008;风险比= 3.03; 95%置信区间，1.34-6.85）和总生存期（P = 0.025;风险比= 2.72; 95%置信区间，1.13-6.52）。在注射部位（皮肤）和肿瘤组织观察到HSP 105肽特异性CTL产生细胞因子，表明HSP 105特异性CTL不仅在疫苗接种部位积累，而且还浸润肿瘤。此外，我们建立了2个HSP 105肽特异性CTL克隆，它们显示出HSP 105特异性细胞因子分泌和细胞毒性。提示HSP 105肽疫苗可诱导肿瘤患者产生免疫应答，改善患者预后。
Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA-A24- and HLA-A2-restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro gamma-interferon enzyme-linked immunospot assays and their correlation with patients' prognosis was analyzed. The HSP105 peptide vaccines induced peptide-specific CTLs in 15 of 30 patients. Among HLA-A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA-A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105-specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression-free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34-6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13-6.52). Production of cytokines by HSP105 peptide-specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105-specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide-specific CTL clones, which showed HSP105-specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.