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

项目总结 封闭式申请提供了一种有效的树突状细胞(DC)基因抗原递送方法 触发癌症特异性免疫反应，其前提是使用“混合型”生物材料-生物递送 以聚合物涂层中的细菌核心为特征的载体。支持拟议研究的影响 包括在DC疫苗接种方面取得进展以促进持续免疫反应的最新研究 在第二阶段临床试验和目前的开放第三阶段试验中，患者存活率提高的结果(≥为10年)。 然而，广泛的疗效仍然存在挑战，因为大多数转移性患者仍然没有反应 因此，治疗提出了一个未得到满足的需要，以改进这些基于免疫的策略。使这一点复杂化 局限性是目前用于向DC运送抗原的标准方法，免疫治疗效果不佳。 假设结果是无效的抗原传递手段的结果，这些手段没有考虑到 细胞水平对DC激活和抗原运输的挑战。系统地处理DC的方方面面 我们认为，相互作用和抗原传递将对癌症领域产生变革性的影响 免疫疗法。对此，我们提出了一种生物-生物材料杂化载体的具体应用 专为DC界面识别和抗原传递而设计。在这样做的过程中，我们提出了这样的假设 技术将解决目前DC抗原递送和后续免疫治疗的局限性 有效性。研究策略提出了一个计划，通过一系列的 旨在更好地评估混合载体与DC的相互作用和激活的具体目标(目标1)；评估 杂合载体的DC细胞内转运和最终基因传递效率作为载体的函数 设计(AIM 2)；检测混合载体传递对DC介导的体内T细胞激活的影响(AIM 3)。所附项目由一支高素质和互为补充的生物工程师团队和 癌症免疫学家能够将结果定位为翻译影响。

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.