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Basic studies of IL-2 gene therapy for head and neck cancer

IL-2基因治疗头颈癌的基础研究

基本信息

批准号：
10671605
负责人：
TSUKUDA Mamoru
金额：
$ 2.05万
依托单位：
Yokohama City University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671605/
关键词：
IL-2 Gene therapy Head and neck cancer Basic studies

项目摘要

Transduction of the human interleukin-2 (IL-2) gene into tumor cells was carried out in order to develop a new immunotherapy for advanced head and neck carcinomas with poor outcome. We transduced the IL-2 gene into KB cells, a head and neck squamous cell carcinoma cell line, using defective herpes simplex viral (HSV) amplicon vector as a gene transfer vehicle. A high level of IL-2 was secreted by IL-2 gene-transduced KB cells (KB/IL-2). The IL-2 producibility of irradiated KB/IL-2 cells was almost the same as that of non-irradiated cells. In the tumor establishment model in nude mice. IL-2 and interferon-γ (IFN-γ) at high concentrations were detected in the sera of mice transplanted with KB/IL-2 cells. The spleen cells of nude mice transplanted with KB/IL-2 cells exhibited high cytotoxic activity, compared to those from mice transplanted with KB cells and from untreated mice. Three of five mice transplanted with KB/IL-2 cells rejected tumors. In treatment of established tumors, therapeutic effects due to irradiated KB/IL-2 were dose-dependent. The suppressive effects on tumor growth were blocked by anti-asialo GM1, anti-human IL-2 and anti-IFN-γ antibodies. Immunohistochemical observation revealed the presence of asialo GM1ィイD1+ィエD1 cells among the KB/IL-2 cells in tumors transplanted into nude mice. Furthermore, the combination treatment of IL-2 gene therapy and exogenous murine IL-12 administration showed a synergistic anti-tumor effect. Based on these results, IL-2 gene therapy with or without IL-12 will be one of treatment strategies for advanced head and neck cancer cases with poor outcome.

将人白细胞介素-2（IL-2）基因导入肿瘤细胞，为晚期头颈部恶性肿瘤的免疫治疗提供新的思路。我们使用缺陷型单纯疱疹病毒（HSV）扩增子载体作为基因转移载体，将IL-2基因转导到头颈部鳞状细胞癌细胞系KB细胞中。IL-2基因转导的KB细胞（KB/IL-2）分泌高水平的IL-2。照射后KB/IL-2细胞产生IL-2的能力与未照射细胞基本相同。在裸鼠体内建立肿瘤模型。KB/IL-2细胞移植小鼠血清中可检测到高浓度的IL-2和IFN-γ。KB/IL-2细胞移植裸鼠脾细胞的细胞毒活性高于KB细胞移植小鼠和未移植小鼠。移植KB/IL-2细胞的5只小鼠中有3只排斥肿瘤。在已建立的肿瘤的治疗中，由于照射的KB/IL-2的治疗效果是剂量依赖性的。抗去唾液酸GM 1、抗人IL-2和抗IFN-γ抗体可阻断其对肿瘤生长的抑制作用。免疫组织化学观察显示，裸鼠移植瘤中KB/IL-2细胞中存在去唾液酸GM 1 + GM 1 + GM 1细胞。此外，IL-2基因治疗和外源性小鼠IL-12给药的组合治疗显示出协同抗肿瘤作用。基于这些结果，IL-2基因治疗联合或不联合IL-12将成为晚期头颈部恶性肿瘤预后不良的治疗策略之一。