Activation of the Immune System by TNFerade

描述（由申请人提供）：本提案将研究TNFerade的作用机制，TNFerade是一种很有前途的癌症治疗药物，目前正在临床试验中。在TNFerade中，TNF编码序列由一个辐射响应启动子egr-1控制，egr-1包含在一个腺病毒载体中。在肿瘤中直接注射TNFerade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的肿瘤反应。这些结果表明，除了TNF直接诱导癌细胞溶解外，TNFerade还通过其他机制起作用。在SBIR资助的I期部分，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在动物模型中的报道都涉及免疫系统受损和TNF信号转导受限。在第一个特定目标中，将构建一个与TNFerade等效但包含小鼠TNF编码序列的载体，以允许完全诱导宿主TNF受体。将该载体在免疫正常（同基因）动物体内的抗肿瘤活性与免疫受损动物进行比较。在第二个特定目标中，诱导免疫反应将在远端非注射肿瘤中测量。这项可行性研究将允许在拨款的II期部分对TNFerade的机制进行更详细的分析，从而改进TNFerade的临床试验，并设计出治疗癌症效果更好的后续产品。

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.