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

通过新型混合生物-生物材料载体系统进行靶向基因递送和人类树突状细胞成熟

• 批准号: 10586414
• 负责人: Jason B Muhitch
• 金额: $ 49.94万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586414
• 关键词: Address; Adjuvant; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Antitumor Response; Autologous; Biocompatible Materials; Biological; Biological Assay; Biomedical Engineering; CD80 gene; CD86 gene; Cancer Patient; Cell Communication; Cell Maturation; Cell Separation; Consensus; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease model; Disparate; Effectiveness; Effector Cell; Engineering; Flow Cytometry; Future; Gene Delivery; Genetic; Goals; Hand; Human; Hybrids; Immune; Immune response; Immune system; Immunization; Immunologist; Immunotherapeutic agent; Immunotherapy; Individual; Interleukin-12; Intracellular Transport; Kinetics; Location; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Methods; Modeling; Monitor; Mus; Outcome; Patients; Peptides; Phase II Clinical Trials; Plasmids; Polymers; Positioning Attribute; Protocols documentation; Qualifying; Reporter; Research; Sampling; Science; Series; Signal Transduction; Site; Surface; System; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Tumor Antigens; Tumor Expansion; Vaccination; Vaccines; Variant; Visualization; antigen processing; antigen-specific T cells; cancer immunotherapy; cell preparation; cytokine; delivery vehicle; dendritic cell vaccination; design; experimental study; flexibility; glycosylation; immune checkpoint blockade; improved; in vivo; interfacial; lymph nodes; macromolecule; meter; monocyte; mouse model; novel; phase III trial; rare cancer; response; trafficking; translational impact; tumor; vaccine platform; vector

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.

项目概要 随附的申请提出了一种有效的树突状细胞 (DC) 遗传抗原递送方法 触发癌症特异性免疫反应，基于“混合”生物材料-生物递送的使用 具有聚合物涂层内细菌核心的载体支持拟议研究的影响。 包括证明 DC 疫苗接种可促进持续免疫反应的进展的新兴研究 在 II 期临床试验和当前开放的 III 期试验中，患者生存率得到改善（≥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，改善这些基于免疫的策略的需求尚未得到满足。 其局限性在于目前用于向 DC 递送抗原的标准方法，免疫治疗效果不佳 所追求的结果是无效的抗原递送方式的结果，没有考虑到 系统地处理 DC 的各个方面，从而解决 DC 激活和抗原转运的细胞水平挑战。 我们认为，相互作用和抗原递送将对癌症领域产生变革性影响 作为回应，我们特别建议应用生物-生物材料混合载体。 设计用于 DC 界面识别和抗原递送。在此过程中，我们提出了这样的假设： 技术将解决目前基于 DC 的抗原递送和后续免疫治疗的局限性 研究策略提出了一个计划，通过一系列的研究来系统地检验这一假设。 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）； 混合载体的 DC 细胞内运输和最终基因传递效率与载体的关系 设计（目标 2）；并检查混合载体递送对 DC 介导的 T 细胞体内激活的影响（目标 3). 封闭项目得到了高素质且互补的生物工程师团队的支持 癌症免疫学家能够定位结果以产生转化影响。