Genetic immunotherapy for malignancy: murine modeling

恶性肿瘤的基因免疫疗法：小鼠模型

• 批准号: 6772248
• 负责人: DENNIS Patrick Meehan HUGHES
• 金额: $ 5.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6772248
• 关键词: Retroviridae; T cell receptor; T lymphocyte; biotechnology; cell line; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene therapy; genetically modified animals; immunogenetics; interleukin 2; laboratory mouse; lymphoma; mouse leukemia; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; ovalbumin; postdoctoral investigator; transfection; transfection /expression vector

DESCRIPTION (provided by applicant): Adoptive immunotherapy has great promise as a fourth treatment modality for malignancy, but significant obstacles remain, including tumor specificity, maintenance of effector T cell function and optimal activation strategy. We have developed a system of primary T cell activation with anti-CD3 and anti-CD28 followed by retroviral transduction to generate T cells expressing genetically engineered, tumor-specific receptors. While preliminary experiments show therapeutic promise, the kinetics, function and IL-2 dependence of such cells in vivo has not been rigorously studied. The efficacy of gene-therapy modified primary T cells expressing a new, tumor-specific alpha/beta T cell receptor (TCR) in vivo remains to be demonstrated. Ovalbumin has been used as a surrogate tumor antigen in many systems. We propose to create a bicistronic retroviral expression vector encoding the ovalbumin-specific T cell receptor alpha and beta genes from the OT-1 T cell receptor transgenic mouse (OT-1 Tg). We will use Ly 5.1 congenic donors to compare gene-therapy modified T cells to OT-1 Tg T cells for kinetics, IL-2 dependence and antigen response after adoptive transfer. Using the murine lymphoma model cell line EL-4 and the murine leukemia model cell line C 1498, each transduced to express ovalbumin, we will test the therapeutic efficacy of gene-therapy modified T cells. These studies will provide data important for modeling future clinical trials of adoptive immunotherapy with genetically modified T cells to treat lymphoma and leukemia.

描述（由申请人提供）：过继免疫治疗作为恶性肿瘤的第四种治疗方式有很大的希望，但仍然存在重大障碍，包括肿瘤特异性，维持效应T细胞功能和最佳激活策略。我们已经开发了一种原代T细胞活化系统，通过抗cd3和抗cd28，然后通过逆转录病毒转导产生表达基因工程的肿瘤特异性受体的T细胞。虽然初步实验显示出治疗前景，但这些细胞在体内的动力学、功能和IL-2依赖性尚未得到严格研究。基因疗法修饰原代T细胞在体内表达一种新的肿瘤特异性α / β T细胞受体（TCR）的有效性仍有待证实。卵清蛋白在许多系统中被用作替代肿瘤抗原。我们建议从OT-1 T细胞受体转基因小鼠（OT-1 Tg）中创建一个双链逆转录病毒表达载体，编码卵清蛋白特异性T细胞受体α和β基因。我们将使用Ly 5.1同源供体来比较基因治疗修饰的T细胞与OT-1 Tg T细胞在过继转移后的动力学、IL-2依赖性和抗原反应。使用小鼠淋巴瘤模型细胞系EL-4和小鼠白血病模型细胞系C 1498，分别转导表达卵清蛋白，我们将测试基因治疗修饰T细胞的治疗效果。这些研究将提供重要的数据，以模拟未来的临床试验，过继免疫疗法与基因修饰的T细胞治疗淋巴瘤和白血病。