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Fundamental and clinical research for esophageal cancer rejection peptide antigens as a vaccine therapy

食管癌排斥肽抗原疫苗治疗的基础和临床研究

基本信息

批准号：
12671282
负责人：
YAMANA Hideaki
金额：
$ 2.18万
依托单位：
Kurume 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-12671282/
关键词：
adbanced esophageal canser HLA class I-restriction sutologous activated lymphocytes cancer rejection antigen gene killer T cell precursor cancer peptide vaccine Phase I cinical trial Immunomonitoring 高度進行食道癌癌特異的キラーT細胞 HLA class I 拘束性

项目摘要

We investigated the existence of cancer specific cytotoxic T lymphocytes (CTLs) against cancer cells in peripheral blood. Peripheral blood mononuclear cells (PBMC) sampled from advanced cancer patients were cultured with an addition of IL-2 (100U/ml) for about 14 days. Following the cultivation, predominant CTLs including NK cells and LAK cells were recognized in PBMC collected from many patients with advanced esophageal cancer. These CTLs expressed CD4 negative and CD8 positive. Using the CTL, new cancer rejection antigen gene was examined by expression cloning method presented by Boon in 1991.We found a new cancer rejection gene of MRP3 that connected to HLA-A24 molecule. MRP is well known as a multi drug resistant protein and usually many malignant cells express this protein. Therefore MRP3 peptide seems to be useful as a cancer vaccine.We performed a new clinical phase I trial for advanced or recurrent cancer patients using CTL precursor-oriented cancer vaccine method. To define the effective peptide vaccines prior to treatment, patients PBMC was examined by a stimulation of 14-cancer vaccine in vitro. hrimimoreaction was examined in vitro by a newly created method evaluating the concentration of IFN-gamma production that needs about 2 weeks. In the Phase I trial using 14 cancer vaccines, CTL precursor of many cases was increased but no clinical effect was found in patients with far advanced esophageal carcinoma due to severe progression of the cancer. This clinical result was also found in patients with advanced pancreatic cancer or gastric cancer. For the next study of cancer vaccine, we have to investigate about more effective adjuvant and/or combined therapy against esophageal carcinoma.

我们研究了外周血中是否存在针对癌细胞的癌特异性细胞毒性T淋巴细胞（CTL）。从晚期癌症患者取样的外周血单个核细胞（PBMC）在添加IL-2（100 U/ml）的情况下培养约14天。经体外培养后，从许多晚期食管癌患者的PBMC中识别出主要的CTL，包括NK细胞和LAK细胞。这些CTL表达CD 4阴性和CD 8阳性。利用CTL，采用布恩等1991年提出的表达克隆方法，对新的肿瘤排斥抗原基因进行了研究，发现了与HLA-A24分子相连的新的肿瘤排斥基因MRP 3。MRP是众所周知的多药耐药蛋白，并且通常许多恶性细胞表达该蛋白。因此，MRP 3肽似乎是有用的癌症疫苗。我们进行了一个新的临床I期试验，晚期或复发性癌症患者使用CTL靶向癌症疫苗的方法。为了在治疗前确定有效的肽疫苗，通过体外14-癌疫苗的刺激来检查患者PBMC。通过新创建的方法在体外检测拟血反应，该方法评估IFN-γ产生的浓度，需要约2周。在使用14种癌症疫苗的I期试验中，许多病例的CTL前体增加，但由于癌症严重进展，在晚期食管癌患者中没有发现临床效果。在晚期胰腺癌或胃癌患者中也发现了这种临床结果。为了进一步研究食管癌疫苗，我们必须探索更有效的食管癌辅助治疗和/或联合治疗。