Oka Yoshihiro, Tsuboi Akihiro, Fujiki Fumihiro, Shirakata Toshiaki, Nishida Sumiyuki, Hosen Naoki, Nakajima Hiroko, Li Zheyu, Kawase Ichiro, Oji Yusuke, Sugiyama Haruo
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2, Yamada-Oka, Suita City, Osaka 565-0871, Japan.
Curr Med Chem. 2008;15(29):3052-61. doi: 10.2174/092986708786848631.
Cancer immunotherapy targeting tumor-associated antigens is now being developed. Wilms' tumor gene WT1-encoding protein is one of the promising target antigens for cancer immunotherapy, because the gene has an oncogenic function and is expressed in many kinds of malignancies. Furthermore, a series of investigations indicated that WT1 protein was highly immunogenic in cancer patients. Based on the analysis of anchor residues that were important for the interaction between peptides and HLA class I molecules, WT1 cytotoxic T lymphocyte (CTL) epitopes with the restriction of HLA-A 0201 and HLA-A 2402 were identified, and clinical trials of WT1 peptide vaccination for cancer patients with these HLA class I types were started. The vaccination-driven immunological and/or clinical responses were reported in patients with myeloid malignancies, multiple myeloma, and several solid cancers. Pediatric malignancies also may be target diseases for WT1 peptide vaccination in the future. Addition of HLA class II-restricted WT1 helper epitope peptide, chemotherapy, or molecular-target-based drug to WT1 CTL epitope peptide-based vaccination may enhance the power and usefulness of WT1 peptide vaccine. Other modalities, including gene therapy using genes encoding WT1-specific T cell receptor or DNA vaccination, are also expected to be developed.
目前正在开发针对肿瘤相关抗原的癌症免疫疗法。威尔姆斯瘤基因WT1编码的蛋白质是癌症免疫疗法中颇具前景的靶抗原之一，因为该基因具有致癌功能且在多种恶性肿瘤中表达。此外，一系列研究表明WT1蛋白在癌症患者中具有高度免疫原性。基于对肽与HLA-I类分子相互作用至关重要的锚定残基的分析，鉴定出了受HLA-A 0201和HLA-A 2402限制的WT1细胞毒性T淋巴细胞（CTL）表位，并针对具有这些HLA-I类类型的癌症患者开展了WT1肽疫苗接种的临床试验。在髓系恶性肿瘤、多发性骨髓瘤和几种实体癌患者中报告了疫苗接种驱动的免疫和/或临床反应。小儿恶性肿瘤未来也可能成为WT1肽疫苗接种的靶疾病。在基于WT1 CTL表位肽的疫苗接种中添加HLA-II类限制的WT1辅助表位肽、化疗或基于分子靶点的药物可能会增强WT1肽疫苗的效力和实用性。其他方法，包括使用编码WT1特异性T细胞受体的基因进行基因治疗或DNA疫苗接种，也有望得到开发。
