Development of novel immunogene therapy for hematological malignancies

血液系统恶性肿瘤新型免疫基因疗法的开发

• 批准号: 12557081
• 负责人: YASUKAWA Masaki
• 金额: $ 7.68万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557081/
• 关键词: Leukemia; Malignant lymphoma; Immunotherapy; Gene therapy; Cytotoxic T lymphocytes; 造血器腫瘍; 細胞免疫療法; WT1; テロメラーゼ; 細胞障害性T細胞; 自殺遺伝子; 不死化細胞; HLA; hTERT

This study was performed to develop the novel immunotherapy for hematological malignancies. The data obtained from the series of experiments are as follows.1) 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.2) 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.3) Immature dendritic cells (DCs) were loaded with leukemia cells with t(6 ; 9) or t … More (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 perform 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

该研究是为了开发新型WT1衍生的肽特异性CD8^+ CTL系的血肿恶性肿瘤。 -A24阴性白血病细胞或正常细胞。2）WT1特异性的HLA-A24限制克隆（指定的TAK-1）表现出对带有HLA-A24的肺癌细胞系的细胞毒性，但没有缺乏此HLA被HLA-A24阳性癌细胞系植入的裸体导致癌细胞生长的抑制和延长的生存率。肺癌和白血病的Potentilly Enterm Ent选项。3）未成熟的树突状细胞（DC），用t（6; 9）或T…更多（9; 22）和DEK-CAN融合肽特异性的白血病细胞加载。或BCR ABL融合肽特异性CD4^+ T淋巴细胞。 with ApoptottiC as WeLL AS NECROTIC Leukemia Cells with T (6 9) And T (9; 22), These Data Indicate The Acute Myelogenous Leukemia-Associated Fusion Protein, Dek-Can and CHROGENIC US Leukemia-Associated Fusion Protein, BCR-ABL, ARE Both Processed and Presented by DCS to THE FUSION PEPTIDE-SPECIFIC CD4^+ Tlymphocytes.4) In Order to Clarify The Roles of Perform in Atigen-Specific CytotoxIted by Humd4 ^+ CTLS, Antigen-Specific Human CD4^+ T-Lymphocyte Clones是从遗传性穿孔蛋白的患者中建立的，其细胞毒性激活了

项目成果

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., Hiraki, A., Azuma, T., Tsuboi, A., Oka, Y., Sugiyama, H., Fujita, S., Tanimoto, M., Harada, M. and Yasukawa, M.: "Antilung cancer effect of WT1-specific cytotoxic T lymphocytes"Clin.Cancer Res.. 8. 2626-2631 (2002)

牧田 M.、平木 A.、东 T.、坪井 A.、冈 Y.、杉山 H.、藤田 S.、谷本 M.、原田 M. 和安川 M.：

Azuma, T., Makita, M., Nimomiya, K., Fujita, S., Harada, M., and Yasukawa, M.: "Identification of a novel WT1-derived peptide which induces human leucocyte antigen-A24-restricted anti-leukaemia cytotoxic T lymphocytes"Br.J.Haematol.. 116. 601-603 (2002)

Azuma, T.、Makita, M.、Nimomiya, K.、Fujita, S.、Harada, M. 和 Yasukawa, M.：“鉴定一种新型 WT1 衍生肽，可诱导人白细胞抗原 A24 限制性抗

Arai J.,Yasukawa M., et al.: "Identification of human telomerase reverse transcriptase-derived peptides which induce HLA-A24-restricted anti-leukemia cytotoxic T lymphocytes"Blood. (in press). (2001)

Arai J.、Yasukawa M.等人：“诱导 HLA-A24 限制性抗白血病细胞毒性 T 淋巴细胞的人端粒酶逆转录酶衍生肽的鉴定”血液。

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》。