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.

项目摘要 封闭的应用提出了一种有效树突状细胞（DC）遗传抗原递送到 触发癌症特异性免疫反应性，预测使用“混合”生物材料递送 在聚合物涂层中具有细菌芯的矢量。支持拟议研究的影响 包括新兴研究表明DC疫苗接种的进步以提示持续的免疫反应 在II期临床试验和当前开放式III期试验中，结果（≥10岁），患者生存率提高。 但是，广泛效率仍然存在挑战，因为大多数转移性患者仍然没有回应 因此，对改善这些免疫力的策略提出了未满足的需求。使这个更加复杂 限制是目前用于抗原向DC递送的标准方法，免疫疗法较差 结果认为是无效抗原递送手段的结果，这些结果不考虑 细胞水平对直流激活和抗原转运的挑战。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影响 免疫疗法。作为响应，我们提出了特定的生物生物材料杂种载体的应用 专为直流界面识别和抗原递送而设计。这样，我们提出了这样的假设 技术将通过基于直流的抗原递送和随后的免疫疗法来解决当前局限性 效力。研究策略提出了一个计划，以系统地测试该假设 旨在更好地评估与直流和激活的混合矢量相互作用的特定目标（AIM 1）；评价 DC杂种载体和最终基因递送有效性的细胞内运输作为向量的函数 设计（AIM 2）;并检查混合载体递送对体内DC介导的T细胞激活的影响（AIM 3）。封闭的项目得到了一个合格而完整的生物工程师团队的支持， 癌症免疫学家能够将结果定位为转化影响。