Effective induction of cytotoxic T cells recognizing an epitope peptide derived from hypoxia-inducible protein 2 (HIG2) in patients with metastatic renal cell carcinoma.
Effective induction of cytotoxic T cells recognizing an epitope peptide derived from hypoxia-inducible protein 2 (HIG2) in patients with metastatic renal cell carcinoma.
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有效诱导识别转移性肾细胞癌患者中源自缺氧诱导蛋白2（HIG2）的表位肽的细胞毒性T细胞。
DOI：
10.1007/s00262-016-1915-5
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Fujioka T
中科院分区：
文献类型：
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作者：
Obara W;Karashima T;Takeda K;Kato R;Kato Y;Kanehira M;Takata R;Inoue K;Katagiri T;Shuin T;Nakamura Y;Fujioka T
通过全基因组表达谱分析，低氧诱导蛋白2 （HIG2）已被确定为参与肾细胞癌（RCC）发生/进展的癌蛋白。随后，我们鉴定出与HIG2部分相对应的高免疫原性HLA-A*0201/0206限制性表位肽（HIG2-9-4），并将其应用于治疗性疫苗。我们进行了一项I期临床试验，使用HIG2-9-4肽治疗晚期RCC患者。9例HLA-A*0201或HLA-A*0206患者在细胞因子和/或酪氨酸激酶抑制剂治疗失败后发生转移性或不可切除的RCC。患者接受以Montanide ISA-51 VG为乳剂形式的肽以剂量递增方式皮下注射，每周一次（剂量为0.5,1.0或3.0 mg/体，每次剂量3例）。主要终点是安全性，次要终点是免疫学和临床反应。接种HIG2-9-4肽可耐受良好，无任何严重的全身不良事件。9例患者中有8例检测到肽特异性细胞毒性T淋巴细胞（CTL）反应。1.0或3.0 mg/体的剂量似乎比0.5 mg/体的剂量更能诱导CTL反应，尽管患者人数太少，无法得出确切的结论。疾病控制率（病情稳定≥4个月）为77.8%，中位无进展生存期为10.3个月。HIG2-9-4肽疫苗治疗可耐受，并可有效诱导RCC患者的肽特异性ctl。这种新的肽疫苗治疗RCC是有希望的。
Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study. The patients received subcutaneous administration of the peptide as an emulsion form with Montanide ISA-51 VG once a week in a dose-escalation manner (doses of 0.5, 1.0, or 3.0 mg/body, 3 patients for each dose). The primary endpoint was safety, and the secondary endpoints were immunological and clinical responses. Vaccinations with HIG2-9-4 peptide could be well tolerated without any serious systemic adverse events. Peptide-specific cytotoxic T lymphocyte (CTL) responses were detected in eight of the nine patients. Doses of 1.0 or 3.0 mg/body seemed to induce a CTL response better than did a dose of 0.5 mg/body, although the number of patients was too small to draw a firm conclusion. The disease control rate (stable disease for ≥4 months) was 77.8 %, and the median progression-free survival time was 10.3 months. HIG2-9-4 peptide vaccine treatment was tolerable and effectively induced peptide-specific CTLs in RCC patients. This novel peptide vaccine therapy for RCC is promising.