ACTIVE SPECIFIC IMMUNE-INDUCTION BY TUMOR-ANTIGEN DERIVED-PEPTIDE RECOGNIZED BY T CELLS

T 细胞识别的肿瘤抗原衍生肽的主动特异性免疫诱导

• 批准号: 07807110
• 负责人: OKINO Takashi
• 金额: $ 1.28万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07807110/
• 关键词: tumor antigen; MAGE gene; peptide; specific immunotherapy; dendritic cells; HLA-A2; digestive tract cancer; GM-CSF; 樹状細胞

We have investigated the expression of genes of MAGE-1, MAGE-3 and HLA-A1 for 10 breast cancer, 31 esophgeal cancer and 4 pancreatic cancer patients. There was no patint who had HLA-A1. The expression of MAGE-1 and MAGE-3 was one out of ten (10%) and 3 (30%), in breast cancer patients, respectively. In esophageal cancer patients, 7 out of 31 (23%) expressed MAGE-1 and 14 (47%) did MAGE-3, while 3 (10%) had both MAGE-1 and MAGE-3. In pancreatic cancer, 1 out of 4 (25%) expressed MAGE-1 and 2 (50%) showed MAGE-3, one (25%) had both MAGE-1 and MAGE-3. These gene expression was confirmed to be translated into the corresponding protein by Western blot analysis except for one breast cancer. Survival of those esophageal cancer patients whose tumor expressed both MAGE-1 and MAGE-3 were significantly better than that of other patients. In preparation for clinical application of active specific immunotherapy, we made experiments using materials from a esophageal cancer patient who is HLA-A2 positive and whose tumor expressed MAGE-3. The patint's peripheral blood lymphocytes proliferated significantly when they were stimulated with HLA-A2 restriced MAGE-3-derived-pepitde-pulsed cultured dendritic cells while they did not proliferate in the presence of HLA-A1 restriced peptide-pulsed dentritic cells. The appropriately stimulated lymphocytes produced tumor necrotizing factor. Finally, those lymphocytes showed significant cytotoxicity against HLA-A2&MAGE-3 positive autologous cancer cell line and had less cytotoxicity against HLA-A24/MAGE-3 positive allogeneic cell line. These results clearly show the potentiality of clinical application of peptide based tumor immunotherapy using professional antigen presenting cells. To identify the repertoire of T cell receptor in this system in under progress by lymphocyte cloning.

我们检测了10例乳腺癌、31例乳腺癌和4例胰腺癌患者的法师-1、法师-3和HLA-A1基因的表达。无HLA-A1阳性者。法师-1和法师-3在乳腺癌患者中的表达分别为十分之一（10%）和三分之一（30%）。在食管癌患者中，31例中有7例（23%）表达法师-1，14例（47%）表达法师-3，而3例（10%）同时表达法师-1和法师-3。在胰腺癌中，1/4例（25%）表达法师-1，2例（50%）显示法师-3，1例（25%）同时表达法师-1和法师-3。Western blot分析证实，除1例乳腺癌外，这些基因表达均被翻译成相应的蛋白。同时表达法师-1和法师-3的食管癌患者的生存率明显高于其他患者。为准备主动特异性免疫治疗的临床应用，我们使用来自HLA-A2阳性且肿瘤表达法师-3的食管癌患者的材料进行实验。用HLA-A2限制性法师-3肽致敏的树突状细胞刺激患者外周血淋巴细胞，可使淋巴细胞显著增殖，而用HLA-A1限制性肽致敏的树突状细胞刺激患者外周血淋巴细胞，则淋巴细胞不增殖。适当刺激淋巴细胞产生肿瘤坏死因子。最后，这些淋巴细胞对HLA-A2和法师-3阳性的自体癌细胞系显示出显著的细胞毒性，而对HLA-A24/法师-3阳性的同种异体细胞系的细胞毒性较小。这些结果清楚地显示了使用专业抗原呈递细胞的基于肽的肿瘤免疫治疗的临床应用的潜力。通过淋巴细胞克隆的方法鉴定该系统中的T细胞受体库。

项目成果

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Seiji Yamasaki：“使用 HLA-A2 患者的肽脉冲培养树突状细胞诱导肽特异性淋巴细胞