Identification of novel cancer-specific antigens and application for cellular imunotherapy of hematological malignancies

新型癌症特异性抗原的鉴定及其在血液恶性肿瘤细胞免疫治疗中的应用

• 批准号: 13470206
• 负责人: YASUKAWA Masaki
• 金额: $ 8.83万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470206/
• 关键词: Cancer antigens; Immunotherapy; Leukemia; Cytotoxic T lymphocytes; HLA; WT1; Telomerase; HLA-A24; 肺がん; 自殺遺伝子

To identify the novel cancer-associated antigens and to develop the novel immunotherapy for hematological malignancies, this study was performed. The data obtained from the series of experiments are as follows.1) A WT1-specific, HLA-A24-restricted CTL clone (designated TAK-1) exhibited cytotoxicity against lung cancer cell lines bearing HLA-A24 but did not lyse cells lacking this HLA. Adoptive transfer of TAK-1 into nude mice that had been engrafted with an HLA-A24-positive lung cancer cell line resulted in inhibition of the cancer cell growth and prolonged survival. These findings strongly suggest that WT1 is a universal tumor-associated antigen and that WT1 -targeting immunotherapy offers a potentially effective treatment option for lung cancer as well as leukemia.2) A novel WT1-derived peptide-specific CD8^+ CTL line, designated NIM-1 was established. NIM-1 lysed HLA-A24-positive leukaemia cells, but not HLA-A24 negative leukaemia cells or normal cells.3) Immature dendritic cells (D … More Cs) were loaded with leukemia cells with t(6 ; 9) or t(9 ; 22) and then cocultured with the dek-can fusion peptide-specific or the bcr-abl fusion peptide-specific CD4^+ T-lymphocyte clone. The dek-can peptide-specific and bcr-abl peptide-specific CD4^+ T-lymphocyte clones produced interferon-γ(IFN-γ) when they were cocultured with HLA-DR-matched but not with mismatched DCs which had been loaded with apoptotic as well as necrotic leukemia cells with t(6 ; 9) and t(9 ; 22), respectively. These data indicate that the acute myelogenous leukemia-associated fusion protein, dek-can, and chronic myelogenous leukemia-associated fusion protein, bcr-abl, are both processed and presented by DCs to the fusion peptide-specific CD4^+ T lymphocytes.4) In order to clarify the roles of perforin in antigen-specific cytotoxicity mediated by human CD4^+ CTLs, antigen-specific human CD4^+ T-lymphocyte clones were established from a patient with hereditary perforin deficiency and their cytotoxic activities were investigated. The data demonstrated that perforin-negative CD4^+ CTLs can exert cytotoxicity against Fas-sensitive target cells ; however, perforin plays essential roles in antigen-specific cytotoxicity mediated by human CD4^+ as well as CD8^+ CTLs. Less

为了确定新颖的小说疾病，从一系列经验中获得了本研究。缺乏HLA。肽特异性CD8^+ CTL系，指定为NIM-1裂解的HLA-A24阳性白血病细胞tive白血病细胞或正常细胞。3）未成熟的树突状细胞（d ...更多的白血病细胞用T（6; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9; 9 ）或t（9; 22）和DEK-CAN融合肽特异性或BCR-ABL融合E特异性CD4^+ T- lymphocyte克隆。 DR匹配但与不匹配的DC相匹配，DC已装有凋亡的DC以及与T（6; 9）和T（9; 9; 22）SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS融合蛋白，DEK-CAN和慢性骨髓性白血病相关蛋白，与之相关的蛋白质，DEK-CAN和t（9; 22）的细胞。 BCR-ABL均由DC呈现给fuside特异性的CD4^+ Tigen特异性细胞毒性，由人CD4^+ CTL介导，抗原特异性的人CD4^+淋巴细胞克隆被预先证明了Perforin和Tototoxiciciciciticitiitigigitigitigitigitigitigitigitigitigitigitigitigitigipitigitigitigitigitigitiged。 - 阴性CD4^+ CTL可以针对对FAS敏感的靶细胞发挥作用；

项目成果

Arai, J., et al.: "Identification of human telomerase reverse transcriptase-derived peptides which induce HLA-A24-restiricted antileukemia CTLs"Blood. 97. 2903-2907 (2001)

Arai, J. 等人：“诱导 HLA-A24 限制性抗白血病 CTL 的人端粒酶逆转录酶衍生肽的鉴定”血液。

Azuma, T., et al.: "Identification of a novel WT1-derived peptide which induces HLA-A24-restricted anti-leukaemia cytotoxic T lymphocytes"British Journal of Haematology. 116. 601-603 (2002)

Azuma，T.，等人：“诱导 HLA-A24 限制性抗白血病细胞毒性 T 淋巴细胞的新型 WT1 衍生肽的鉴定”英国血液学杂志。

Makita, M., Yasukawa, M.et al.: "Antilung cancer effect of WT1-specific cytotoxic T lymphocytes"Clinical Cancer Research. 8. 2626-2613 (2002)

Makita, M., Yasukawa, M.等人：“WT1特异性细胞毒性T淋巴细胞的抗肺癌作用”临床癌症研究。

Hasegawa, A., et al.: "Transcriptional down-regulation of CXCR4 induced by impaired association of YY1 with c-Myc in HHV-6-infected cells"Journal of Immunology. 166. 1125-1131 (2001)

Hasekawa, A. 等人：“HHV-6 感染细胞中 YY1 与 c-Myc 的关联受损导致 CXCR4 转录下调”《免疫学杂志》。

Kakimoto, M., Hasegawa, A., Fujita, S. and Yasukawa, M.: "Phenotypic and functional alterations of dendritic cells induced by human herpesvirus 6 infection"J.Virol.. 76. 10338-10345 (2002)

Kakimoto, M.、Hasekawa, A.、Fujita, S. 和 Yasukawa, M.：“人疱疹病毒 6 感染诱导的树突状细胞的表型和功能改变”J.Virol.. 76. 10338-10345 (2002)