Fundamental study for improvement of cancer immunotherapy based on gene analysis

基于基因分析改进癌症免疫治疗的基础研究

• 批准号: 14370396
• 负责人: YAMANA Hideaki
• 金额: $ 8.83万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370396/
• 关键词: advanced cancers; Phase I; II trial; activated T lymphocytes; cancer peptide vaccine; gene expression; regulatory T cell; CD4;; CD25+ T cell; proteasome inhibitor; CD4+CD25+T cell; Chemothrapy; 第II相試験; IL-2 receptor; 抗IL-2 receptor抗体; TRAIL

We are performing adoptive immunotherapy using autologous cancer specific cytotoxic T lymphocytes (CTLs). In this clinical trial, peripheral blood mononuclear cells (PBMC) obtained from advanced cancer patient were cultured for about 14 days under the addition of IL-2 (100U/ml) and patient's irradiated tumor cells. Following the cultivation, predominant CTLs including NK cells and LAK cells were recognized in most PBMC. Further more, we are performing phase I/II trial for advanced or recurrent cancer patients using CTL precursor-oriented cancer vaccine. For cancer samples obtained from these patients, gene analysis using DNA tip was planned to define effective cases of immunotherapy prior to treatment. In this study, II cancer samples were stocked, 6 were effective case samples and 5 were non effective case samples. However we have failed to stock cancer samples in many cases due to no tumor lesion or rejection of gene analysis.In the fundamental studies on regulatory T cell analysis, CD4+/CD25+ T-cells were dominant in cultured lymphocytes more than 14 days. These regulatory T-cells were reduced by in vitro treatment of anti-IL-2 receptor α antibody. By this treatment, production of TGF-β was also reduced. We performed further fundamental study on proteasome inhibitor (PI) to improve the effect of cancer immunotherapy. By the PI treatment of cancer cells with weak expression of TRAIL receptor, TRAIL receptor was markedly expressed and TRAIL activity was significantly improved.From these results, we have to control regulatory T-cell and TRAIL activity to improve the clinical effect of cancer immunotherapy. Further we will continue the storage of cancer samples to investigate gene analysis by DNA tip.

我们正在使用自体癌症特异性细胞毒性T淋巴细胞（CTL）进行过继免疫治疗。在该临床试验中，从晚期癌症患者获得的外周血单个核细胞（PBMC）在添加IL-2（100 U/ml）和患者的放射性肿瘤细胞的情况下培养约14天。培养后，在大多数PBMC中识别出主要的CTL，包括NK细胞和LAK细胞。此外，我们正在使用CTL靶向癌症疫苗对晚期或复发性癌症患者进行I/II期试验。对于从这些患者中获得的癌症样本，计划使用DNA尖端进行基因分析，以在治疗前确定免疫治疗的有效病例。本研究共储存了12例癌症样本，其中6例为有效病例样本，5例为无效病例样本。在调节性T细胞分析的基础研究中，培养14天以上的淋巴细胞中，CD 4 +/CD 25 + T细胞占优势。这些调节性T细胞通过抗IL-2受体α抗体的体外处理而减少。通过这种治疗，TGF-β的产生也减少。我们对蛋白酶体抑制剂（PI）进行了进一步的基础研究，以提高癌症免疫治疗的效果。PI处理TRAIL受体弱表达的癌细胞后，TRAIL受体表达明显增强，TRAIL活性明显提高，提示我们有必要控制调节性T细胞和TRAIL活性，以提高肿瘤免疫治疗的临床效果。此外，我们将继续储存癌症样本，以研究DNA尖端的基因分析。

项目成果

Ando N: "Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus"J Clin Oncol. 21・24. 4592-4596 (2003)

Ando N：“胸段食管局部鳞状细胞癌的手术加化疗与单独手术的比较”J Clin Oncol 21・24 (2003)。

Toh U: "Locoregional adoptive immunotherapy resulted in regression in distant metastases of a recurrent esophageal cancer"Int J Clin Oncol.. 7(6). 372-375 (2002)

Toh U：“局部过继免疫疗法导致复发性食管癌远处转移的消退”Int J Clin Oncol.. 7(6)。

Expression of tumor rejection antigens in colorectal carcinomas

• DOI: 10.1002/cncr.10421
• 发表时间: 2002-03-15
• 期刊: CANCER
• 影响因子: 6.2
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• 通讯作者: Shirouzu, K

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• 发表时间: 2004
• 作者: 松木 充;奥田準二;谷川允彦;谷川充彦;奥田準二;N.Tanigawa;K.Takaori;谷川允彦;奥田準二;高折恭一;奥田準二;谷川允彦;谷川允彦
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• DOI: 10.1158/1535-7163.1485.3.11
• 发表时间: 2004-11
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: M. Kuwano;Y. Oda;H. Izumi;Song‐Ju Yang;T. Uchiumi;Y. Iwamoto;M. Toi;T. Fujii;H. Yamana;H. Kinoshita;T. Kamura;M. Tsuneyoshi;K. Yasumoto;K. Kohno