Enhancement of Gene Transfer & Prostate Cancer Immunity

描述（由申请人提供）：目前正在研究许多开发激素依赖型前列腺癌新治疗方法的策略，包括基因治疗和免疫治疗。虽然利用基因转移技术增强了免疫激活和抗肿瘤反应，但能够消除肿瘤的免疫治疗方案的发展一直存在问题。免疫治疗反应弱的原因有很多，包括低效的基因转移。在初步研究中，我们利用明胶泡沫作为可生物降解的胶原蛋白传递系统（CODES），观察到它可以增强实体肿瘤和良性狗前列腺中的基因转移。此外，codes介导的基因转移增强了T细胞免疫，显著增强了对既定前列腺癌的抗肿瘤活性。本申请中概述的研究将评估CODES在动物模型中的作用机制，并将测试CODES在前列腺癌患者中增强基因转移和增强免疫力的能力。初步研究表明，CODES可诱导血小板表达和释放免疫调节因子，从而调节免疫和基因表达，提示CODES与血小板来源的先天免疫介质和适应性T细胞免疫之间存在联系。如果得到证实，这一观察结果将首次将血小板活化与适应性免疫的活化联系起来。此外，它可能为开发增强基因转移和增强肿瘤免疫的新方法提供基础，并增加对能够调节对外来抗原的免疫反应的因素的现有知识。将CODES在动物模型中的观察结果转化为临床试验的研究，将验证CODES通过携带人类肿瘤坏死因子相关凋亡诱导配体（Ad5-TRAIL）基因的E1A/ e1b缺失的5型腺病毒增强人类前列腺组织中基因传递的假设。第二项临床研究将使用携带前列腺特异性抗原基因的腺病毒来测试CODES增强前列腺癌患者免疫力的假设。

DESCRIPTION (provided by applicant): Many strategies to develop new treatments for hormone independent prostate cancer are being investigated, including gene therapy and immunotherapy. While immune activation and antitumor responses have been enhanced by the utilization of gene transfer techniques, the development of immunotherapy regimens capable of eliminating tumors has been problematic. Many reasons for the weak immunotherapy responses have been advocated including inefficient gene transfer. In preliminary studies, we utilized Gelfoam as a biodegradable collagen delivery system (CODES) that was observed to enhance gene transfer in solid tumors and benign dog prostate. Moreover, CODES-mediated gene transfer augmented T cell immunity, significantly enhancing antitumor activity against established prostate cancers. The studies outlined in this application will evaluate the mechanisms by which CODES functions in animal models, and also will test the ability of CODES to enhance gene transfer and augment immunity in prostate cancer patients. Preliminary studies showed CODES to induce expression and release of immunomodulatory factors by platelets, which modulated immunity and gene expression, suggesting a link between CODES, platelet-derived innate immune mediators, and adaptive T cell immunity. If validated, the observation will, for the first time, link platelet activation to the activation of adaptive immunity. Moreover, it may provide a basis for the development of novel ways to enhance gene transfer and augment tumor immunity as well as add to current knowledge of factors capable of modulating immune response to foreign antigens. Studies translating the observations with CODES in animal models into clinical trials will test the hypothesis that CODES enhances gene delivery in human prostate tissue using E1A/E1B-deleted type 5 adenovirus carrying the gene for human tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL). A second clinical study testing the hypothesis that CODES augments immunity in prostate cancer patients will be performed using adenovirus carrying the gene for prostate specific antigen.