Development of cancer immunotherapy targeting WT1 which highly expresses in patients with hematopoictic maliganacies including leukemia.

开发针对 WT1 的癌症免疫疗法，WT1 在包括白血病在内的造血恶性肿瘤患者中高表达。

• 批准号: 14570976
• 负责人: OKA Yoshihiro
• 金额: $ 2.18万
• 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: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570976/
• 关键词: WT1; leukemia; cancer immunotherapy; cancer vaccine; ペプチド癌ワクチン; CTL

IgM-and IgG-type WT1 antibodies were detected in patients with heniatopoietic malignancies including MDSand leukemia, indicating that WT1 protein is highly immunogenic and not only humoral but also cellular WT1-specific immune responses which induced immunoglobulin class-switch of WT1 antibodies were spontaneously elicited in the patients. These findings provided us with a rationale for WT1 protein-directed immunotherapy for leukemia.A novel 9 mer WT1 peptide (modified WT235), in which one amino acid residue at an anchor position was replaced by another amino acid, was shown to exert very strong cytotoxicity against leukemia cells. This peptide may be very useful for cancer immunotherapy in clinical settings.In lck promotor-driven WT1-transgenic (Tg) mice, the differentiation of T-lineage cells in thymus was shown to be blocked. This result directly indicated that WT1 is involved in the differentiation of T-lineage lymphocytes. Differentiation inhibition of cells may lead to growth promotion of the cells, namely, leukemogenesis. Careful observation of the Tg-mice is ongoing.We established a mouse "therapeutic model" for WT1 peptide cancer vaccine, in which mice vaccinated with WT1 peptide in combination with BCG-CWS efficiently rejected WT1-expressing leukemia cells which had been transplanted before vaccination.We staffed Phase I clinical trial of WT1 peptide cancer vaccine for MDS or leukemia. We obtained some cases in which leukemic blast cells and/or WT1 level decreased after the vaccination, indicating that the vaccine might be useflil for the treatment of hematopoietic malignancies.

在包括 MDS 和白血病在内的造血恶性肿瘤患者中检测到了 IgM 型和 IgG 型 WT1 抗体，表明 WT1 蛋白具有高度免疫原性，患者体内不仅会自发引发体液免疫反应，还会自发引发细胞 WT1 特异性免疫反应，从而诱导 WT1 抗体的免疫球蛋白类别转换。这些发现为我们提供了WT1蛋白定向免疫治疗白血病的基本原理。一种新型9聚体WT1肽（修饰的WT235），其中锚定位置的一个氨基酸残基被另一个氨基酸取代，被证明对白血病细胞具有非常强的细胞毒性。这种肽对于临床环境中的癌症免疫治疗可能非常有用。在 lck 启动子驱动的 WT1 转基因 (Tg) 小鼠中，胸腺中 T 谱系细胞的分化被证明被阻断。这一结果直接表明WT1参与T细胞系淋巴细胞的分化。细胞分化抑制可能导致细胞生长促进，即白血病发生。对Tg小鼠的仔细观察正在进行中。我们建立了WT1肽癌症疫苗的小鼠“治疗模型”，其中联合BCG-CWS接种WT1肽的小鼠有效排斥了接种前移植的表达WT1的白血病细胞。我们为MDS或白血病开展了WT1肽癌症疫苗的I期临床试验。我们获得了一些接种疫苗后白血病母细胞和/或WT1水平下降的病例，表明该疫苗可能可用于治疗造血系统恶性肿瘤。

项目成果

Tsuboi A. et al.: "Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modifued at HLA-A^*2402-binding residues"Cancer Immunol. Immunother. 51・11-12. 614-620 (2002)

Tsuboi A. 等人：“用在 HLA-A^*2402 结合残基上修饰的 9 聚体 WT1 肽增强诱导人 WT1 特异性细胞毒性 T 淋巴细胞”癌症免疫学 51·11-12。 620（2002）

Oka Y.et al.: "Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis"Int.J.Hematol.. 78・1. 56-61 (2003)

Oka Y.等：“针对骨髓增生异常综合征（MDS）或伴有骨髓纤维化的MDS的明显白血病患者的基于Wilms肿瘤基因肽的免疫疗法”Int.J.Hematol.. 78・1（2003）。

Li H.et al.: "The lck promoter-driven expression of the Wilms' tumor gene WTl blocks intrathymic differentiation of T-lineage cells"Int. J. Hematol.. (in press).

Li H.et al.：“Wilms 肿瘤基因 WT1 的 lck 启动子驱动的表达阻断了 T 谱系细胞的胸腺内分化”Int.

Elisseeva OA et al.: "Humoral immune responses against Wilms' tumor gene WT1 product in patients with hematopoictic malignancies."Blood. 99. 3272-3279 (2002)

Elisseeva OA 等人：“造血系统恶性肿瘤患者针对维尔姆斯肿瘤基因 WT1 产物的体液免疫反应。”血液。

Oji Y.et al.: "Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma"Cancer Sci.. 94・8. 712-717 (2003)

Oji Y.等：“结直肠腺癌中维尔姆斯肿瘤基因WT1的过度表达”Cancer Sci.. 94・8 (2003)。