Enhancement of Gene Transfer & Prostate Cancer Immunity

描述(申请人提供)：正在研究开发激素非依赖性前列腺癌新疗法的许多策略，包括基因疗法和免疫疗法。虽然通过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开发一直存在问题。免疫治疗反应弱的原因有很多，其中包括低效的基因转移。在初步研究中，我们使用明胶海绵作为一种可生物降解的胶原输送系统(CODES)，观察到它可以增强实体瘤和良性狗前列腺中的基因转移。此外，密码子介导的基因转移增强了T细胞免疫，显著增强了对前列腺癌的抗肿瘤活性。本申请中概述的研究将评估密码子在动物模型中发挥作用的机制，还将测试密码子增强前列腺癌患者基因转移和增强免疫力的能力。初步研究表明，通过血小板诱导免疫调节因子的表达和释放的密码子，调节免疫和基因表达，提示密码子、血小板衍生的天然免疫介质和适应性T细胞免疫之间存在联系。如果得到证实，这项观察将首次将血小板激活与适应性免疫的激活联系起来。此外，它可能为开发新的方法来增强基因转移和增强肿瘤免疫提供基础，并增加对能够调节对外来抗原的免疫反应的因子的现有知识。将动物模型中的观察结果转化为临床试验的研究将检验这样一种假设，即使用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，密码可以增强人类前列腺组织中的基因传递。第二项临床研究验证了前列腺癌患者编码增强免疫力的假设，将使用携带前列腺特异性抗原基因的腺病毒进行研究。

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.