Development of novel immunogene therapy for hamatopietic malignancies

造血系统恶性肿瘤新型免疫基因疗法的开发

• 批准号: 17390278
• 负责人: YASUKAWA Masaki
• 金额: $ 9.34万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390278/
• 关键词: hematopoietic malignancies; cancer immunity; cytotoxic T lymphocyte; cancer peptide vaccine; gene therapy; 白血病; 免疫療法

We performed the series of experiments and obtained the following data. 1) Myeloma cells and lymphoma cells were both weakly positive for WT1 expression. However, only myeloma cells appeared to be sensitive to perforin-dependent cytotoxicity mediated by WT1-specific cytotoxic T lymphocytes (CTLs). These data suggest that susceptibility of membranes to perforin is an important factor determining the sensitivity of target cells to CTL-mediated cytotoxicity and that WT1 is an ideal target antigen for cellular immunotherapy of multiple myeloma..2) T-cell receptor (TCR) genes derived from HLA-A24-restricted WT1-specific CTL clone were transduced into CD4+ and CD8+ peripheral blood T lymphocytes. Consequently, TCR gene-transduced T lymphocytes could exert HLA-A24-restricted and WT1 specific reactivity. Thus, TCR gene-modified HLA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer. 3) Human hematopietic cells were transferred into new born NOD/SCID/IL2rgamma(null) mice. Human immune system was reconstituted in these mice. Thus, the NOD/SCID/IL2R gamma(null) newborn system might be an important experimental model to study the human hemato-lymphoid system. 4) We identified WT1-derived helper epitope which is recognized by HLA class II-restricted CD4+ CTLs. WT1-specific CD4+ T lymphocytes could directly recognized leukemia cells in an HLA class II-restricted manner. 5) We established CML66-specific and Aurora-A-specific CTL lines. Since these CTLs lysed leukemia cells in HLA-restricted manner, CML66 and Aurora-A appeared to be novel leukemia-associated antigens which are recognized by human CTLs. 6) Cancer peptide vaccination using WT1 peptide and hTERT peptide has been performed. No adverse event was detected, and apparent anti-cancer effect was observed in some patients.

我们进行了一系列实验，并获得了以下数据。1)骨髓瘤细胞和淋巴瘤细胞WT 1表达均呈弱阳性。然而，只有骨髓瘤细胞似乎是敏感的WT 1特异性细胞毒性T淋巴细胞（CTL）介导的穿孔素依赖性细胞毒性。这些数据表明膜对穿孔素的敏感性是决定靶细胞对CTL介导的细胞毒性的敏感性的重要因素，并且WT 1是多发性骨髓瘤细胞免疫治疗的理想靶抗原。2)将来自HLA-A24限制性WT 1特异性CTL克隆的T细胞受体（TCR）基因转导入外周血CD 4+和CD 8 + T淋巴细胞。因此，TCR基因转导的T淋巴细胞可以发挥HLA-A24限制性和WT 1特异性反应。因此，TCR基因修饰的HLA I类限制性Th 1和Tc 1细胞是应用于人类癌症过继免疫治疗的有力策略。3)将人造血细胞转移到新生N 0 D/SCID/IL 2 r γ（null）小鼠中。在这些小鼠中重建人免疫系统。因此，NOD/SCID/IL 2 R γ（null）新生儿系统可能是研究人类血液淋巴系统的重要实验模型。4)我们鉴定了WT 1衍生的辅助表位，其被HLA II类限制性CD 4 + CTL识别。WT 1特异性CD 4 + T淋巴细胞可直接识别白血病细胞，但HLA Ⅱ类分子限制性识别。5)我们建立了CML 66特异性和Aurora-A特异性CTL细胞系。由于这些CTL以HLA限制性方式裂解白血病细胞，因此CML 66和Aurora-A似乎是由人CTL识别的新的白血病相关抗原。6)已经进行了使用WT 1肽和hTERT肽的癌肽疫苗接种。未发现不良反应，部分患者有明显的抗癌作用。

项目成果

Antagosist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice.

干扰素诱导蛋白 10/CXCL10 的拮抗剂可改善 MRL/lpr 小鼠自身免疫性唾液腺炎的进展。

• 发表时间: 2006
• 期刊: Arthritis Rheum. 54
• 作者: Hasegawa H;Yasukawa M;et al.
• 通讯作者: et al.

Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions

• DOI: 10.1182/blood-2004-08-3296
• 发表时间: 2005-05-01
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Ishii, E;Ueda, I;Yasukawa, M
• 通讯作者: Yasukawa, M

Expression of SOCS3 in bone marrow cells from chronic myelogenous leukemia patients is associated with the cytogenetic response to interferon-alpha.

慢性粒细胞白血病患者骨髓细胞中 SOCS3 的表达与干扰素-α 的细胞遗传学反应相关。

• 发表时间: 2005
• 期刊: Leuk. Res. 29
• 作者: Takeuchi K;Yasukawa M;et al.
• 通讯作者: et al.

Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people

• DOI: 10.1007/s10038-005-0293-1
• 发表时间: 2005-11-01
• 期刊: JOURNAL OF HUMAN GENETICS
• 影响因子: 3.5
• 作者: Yamamoto, K;Ishii, E;Yasukawa, M
• 通讯作者: Yasukawa, M

Identification and characterization of a WT1 (Wilms tumor gene) protein-derived HLA-DRB1*0405-restricted 16-mer helper peptide that promotes the induction and activation of WT1-specific cytotoxic T lymphocytes

• DOI: 10.1097/01.cji.0000211337.91513.94
• 发表时间: 2007-04-01
• 期刊: JOURNAL OF IMMUNOTHERAPY
• 影响因子: 3.9
• 作者: Fujiki, Fumihiro;Oka, Yoshihiro;Sugiyama, Haruo
• 通讯作者: Sugiyama, Haruo