Activation of the Immune System by TNFerade

TNFerade 激活免疫系统

• 批准号: 6738332
• 负责人: C. RICHTER KING
• 金额: $ 9.95万
• 依托单位: GENVEC, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738332
• 关键词: Adenoviridae; SCID mouse; biological signal transduction; biotechnology; cytokine receptors; cytolysis; enzyme linked immunosorbent assay; gene delivery system; gene therapy; immune response; immunoregulation; neoplasm /cancer radiation therapy; radiation therapy dosage; sarcoma; technology /technique development; transfection /expression vector; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): This proposal will investigate the mechanism of action of TNFerade, a promising cancer treatment now in clinical testing. In TNFerade, the TNF coding sequence is controlled by a radiation responsive promoter, egr-1, is contained within an adenovirus vector. Direct injection of TNFerade into a tumor restricts the expression of TNFerade to the region of radiation therapy. Early but encouraging data suggests that TNFerade causes complete tumor responses in multiple tumor types and in very large lesions. These results indicate that TNFerade acts by mechanisms in addition to the direct TNF induced cytolysis of cancer cells. In the phase I portion of the SBIR grant, the hypothesis that the host immune system contributes to the anti-tumor activity of TNFerade will be tested in animal models. To date, all published reports of TNFerade in animal models involve compromised immune systems and limited TNF signal transduction. In the first specific aim, a vector will be constructed that is equivalent to TNFerade but containing a murine TNF coding sequence to allow for the full induction of host TNF receptors. The anti-tumor activity of this vector in immuno-competent (syngeneic) animals will be compared with immuno-compromised animals. In a second specific aim, induced immune responses will be measured at distant, noninjected, tumors. This feasibility study will allow more detailed analysis of the TNFerade mechanism in the phase II portion of the grant leading to improvements in the clinical testing of TNFerade and the design of follow up products with improved efficacy for treatment of cancers.

描述（由申请人提供）：该提案将研究 TNFerade 的作用机制，TNFerade 是一种有前途的癌症治疗方法，目前正在进行临床测试。在 TNFerade 中，TNF 编码序列受辐射响应启动子 egr-1 控制，包含在腺病毒载体内。将 TNFerade 直接注射到肿瘤中可将 TNFerade 的表达限制在放射治疗区域。早期但令人鼓舞的数据表明，TNFerade 在多种肿瘤类型和非常大的病变中引起完全肿瘤反应。这些结果表明，除了直接 TNF 诱导的癌细胞细胞溶解之外，TNFerade 还通过其他机制发挥作用。在 SBIR 资助的第一阶段部分，宿主免疫系统有助于 TNFerade 抗肿瘤活性的假设将在动物模型中进行测试。迄今为止，所有已发表的 TNFerade 在动物模型中的报告均涉及免疫系统受损和 TNF 信号转导有限。在第一个具体目标中，将构建与 TNFerade 等效但包含鼠 TNF 编码序列的载体，以允许宿主 TNF 受体的完全诱导。该载体在免疫活性（同基因）动物中的抗肿瘤活性将与免疫受损的动物进行比较。在第二个具体目标中，将在远处、未注射的肿瘤处测量诱导的免疫反应。这项可行性研究将允许在资助的第二阶段部分对 TNFerade 机制进行更详细的分析，从而改进 TNFerade 的临床测试，并设计出具有更高癌症治疗功效的后续产品。