Immunotherapy against leukemia targeting WT1 product

针对WT1产品的白血病免疫疗法

• 批准号: 12670987
• 负责人: OKA Yoshihiro
• 金额: $ 2.11万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670987/
• 关键词: WT1; leukemia; immunotherapy; clinical trial; 免疫療法

We have identified high expression levels of the wild-type WT1 gene in leukemia cells of most of leukemia and myelodysplastic syndrome (MDS) patients. Our aim is to establish immunotherapy against malignant neoplasm including leukemia targeting WT1 product. We have already shown that WT1-specific CTLs can be generated from human PBMC, and that mice immunized with WT1 peptide can reject WT1-expressing tumor cells.During this period (2000-2001), we have further obtained the following results.1) We have established DNA vaccination system targeting WT1 product. Intramuscular injection of WT1 plasmid DNA into mice elicited CTL responses specific for WT1 protein and resulted in rejection of challenges of WT1-expressing tumor cells.2) We have identified a modified WT1 peptide with replacement of one amino-acid of anchor motif positions, which can elicit stronger CTL responses against WT1- expressing leukemia cells.3) We have identified high expression levels of WT1 gene in various kinds of solid tumors including lung cancer, and found that the solid tumors can become targets of WT1-directed immunotherapy.4) We have started phase I clinical trial of cancer immunotherapy targeting WT1 against leukemia, MDS, lung cancer, and breast cancer.

我们已经发现野生型WT 1基因在大多数白血病和骨髓增生异常综合征（MDS）患者的白血病细胞中高表达。我们的目标是建立针对WT 1产品的针对恶性肿瘤（包括白血病）的免疫疗法。本课题组在2000年至2001年的研究中，已经发现人外周血单个核细胞（PBMC）可以产生WT1特异性CTL，WT1肽段免疫小鼠可以抑制表达WT1的肿瘤细胞，并取得了以下成果：1）建立了针对WT1产物的DNA疫苗体系。将WT1质粒DNA肌肉注射到小鼠体内可引发特异性针对WT1蛋白的CTL应答，并导致对表达WT1的肿瘤细胞的攻击的排斥。2）我们已经鉴定了一种修饰的WT1肽，其具有锚基序位置的一个氨基酸的替换，其可以引发针对表达WT1的白血病细胞的更强的CTL应答。我们已经鉴定了WT1基因在包括肺癌在内的各种实体瘤中的高表达水平，并发现实体瘤可以成为WT1定向免疫治疗的靶点。4）我们已经开始针对白血病、MDS、肺癌和乳腺癌。

项目成果

岡 芳弘 他: "WT1を標的とした白血病に対する特異性免疫療法"血液フロンティア. 10(8). 47-53 (2000)

Yoshihiro Oka 等人：“针对 WT1 的白血病的特异性免疫疗法”Blood Frontier 10(8) (2000)。

Oka, Y.et al.: "WT1 as a novel target antigen for cancer immunotherapy"Current Cancer Drug Targets. (in press).

Oka, Y. 等人：“WT1 作为癌症免疫治疗的新型靶抗原”当前癌症药物靶点。

Oka Y.et al.: "Human cytotoxic T-lymphocyte responses specific for peptides of wild-type Wilms'tumor gene (WT1) product"Immunogenetics. 51. 99-107 (2000)

Oka Y.等人：“对野生型维尔姆斯肿瘤基因 (WT1) 产物的肽具有特异性的人类细胞毒性 T 淋巴细胞反应”免疫遗传学。

Kakugawa, K., et al.: "Efficient induction of peptide-specific cytotoxic T lymphocyte by LPS-activated spleen cells"Microbiol. Immunol.. 44. 123-133 (2000)

Kakukawa, K. 等人：“LPS 激活的脾细胞有效诱导肽特异性细胞毒性 T 淋巴细胞”Microbiol。

Oka, Y, et al.: "Cancer immunotherapy targeting Wilms' tumor gene WT1 product."Journal of Immunology. 164. 1873-1880 (2000)

Oka, Y 等人：“针对 Wilms 肿瘤基因 WT1 产物的癌症免疫疗法。”免疫学杂志。