Targeted Gene Delivery and Human Dendritic Cell Maturation Through a Novel Hybrid Biological-Biomaterial Vector System

项目摘要 所附申请提出了一种用于有效的树突细胞（DC）遗传抗原递送至 触发癌症特异性免疫反应，基于使用“混合”生物材料-生物递送 载体具有聚合物涂层内的细菌核心。支持拟议研究的影响 包括新兴的研究，证明DC疫苗接种的进展，以促进持续的免疫反应 II期临床试验和当前开放III期试验中患者生存期改善的结局（≥10年）。 然而，对于广泛的疗效仍然存在挑战，因为大多数转移性患者仍然不响应于化疗。 因此，治疗提出了改进这些基于免疫的策略的未满足的需求。加上这个 局限性是目前用于抗原递送至DC的标准方法，具有较差的免疫治疗 假设结果是无效的抗原递送手段的结果， 细胞水平对DC活化和抗原转运的挑战。系统地处理DC的各个方面 在我们看来，相互作用和抗原递送将对癌症领域产生变革性的影响。 免疫疗法作为回应，我们提出了生物-生物材料混合载体的具体应用 设计用于DC界面识别和抗原递送。在这样做的时候，我们提出了一个假设， 该技术将解决目前基于DC的抗原递送和随后的免疫治疗的局限性 有效性研究战略提出了一个计划，通过一系列的系统测试这一假设， 旨在更好地评估混合载体与DC的相互作用和DC的激活的特定目标（目标1）; 混合载体的DC细胞内运输和作为载体的函数的最终基因递送有效性 设计（目的2）;并检查杂交载体递送对DC介导的体内T细胞活化的影响（目的 3）。所附项目得到了一个合格和互补的生物工程师团队的支持， 癌症免疫学家能够定位翻译影响的结果。

PROJECT SUMMARY The enclosed application presents an approach for effective dendritic cell (DC) genetic antigen delivery to trigger cancer-specific immune reactivity, predicated upon the use of a “hybrid” biomaterial-biological delivery vector featuring a bacterial core within a polymeric coating. Support for the impact of the proposed study includes emerging research demonstrating advances in DC vaccination to prompt sustained immune response outcomes (≥10 years) with improved patient survival in Phase II clinical trials and current open Phase III trials. However, there remain challenges to broad efficacy in that most metastatic patients still do not respond to treatment, thus, presenting an unmet need to improve these immune-based strategies. Compounding this limitation are the standard methods currently utilized for antigen delivery to DCs, with poor immunotherapy outcomes hypothesized to be the result of ineffectual means of antigen delivery that do not consider the cellular-level challenges to DC activation and antigen transport. Systematically dealing with every aspect of DC interaction and antigen delivery, in our view, will have transformative impact on the field of cancer immunotherapy. In response, we propose the application of a biological-biomaterial hybrid vector specifically designed for DC interfacial recognition and antigen delivery. In so doing, we put forth the hypothesis that this technology will address current limitations with DC-based antigen delivery and subsequent immunotherapy effectiveness. The research strategy presents a plan to systematically test this hypothesis through a series of specific aims designed to better assess hybrid vector interaction with and activation of DC (Aim 1); evaluate DC intracellular trafficking of the hybrid vector and final gene delivery effectiveness as a function of vector design (Aim 2); and examine the impact of hybrid vector delivery on DC-mediated T cell activation in vivo (Aim 3). The enclosed project is supported by a well-qualified and complementary team of biological engineers and cancer immunologists capable of positioning the results for translational impact.