Biomaterials-based metabolic rescue of dendritic cells for vaccine design

基于生物材料的树突状细胞代谢拯救用于疫苗设计

• 批准号: 10322658
• 负责人: Abhinav Acharya
• 金额: $ 32.48万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322658
• 关键词: Adjuvant; Adoptive Transfer; Antigen-Presenting Cells; Antigens; BRAF gene; Biocompatible Materials; Biological Assay; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Carbon; Cells; Citric Acid Cycle; Complex; Contralateral; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Development; Dopachrome isomerase; Dose; Formulation; Frequencies; Fructose; Future; GATA3 gene; Generations; Genus Hippocampus; Glutaminase; Glycolysis; Glycolysis Inhibition; Glycolysis Pathway; Goals; Growth; Helper-Inducer T-Lymphocyte; Human; Immune; Immunocompetent; Immunohistochemistry; Immunotherapy; In Vitro; Intravenous; Kidney; Kinetics; Light; Liver; Lysine; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Measures; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Mus; Organ; Oxygen Consumption; Pathway interactions; Peptides; Phagocytosis; Poly I-C; Polymers; Production; Proliferating; Public Health; Publishing; Reaction; Reactive Oxygen Species; Regulatory T-Lymphocyte; Research; Research Project Grants; Respiration; Role; Safety; Sorting - Cell Movement; Stress Tests; Succinates; T cell response; T memory cell; T-Lymphocyte; Technology; Testing; Toxic effect; Treatment Protocols; Tumor Burden; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; United States National Institutes of Health; Vaccine Design; Vaccine Therapy; Vaccines; Vertebral column; Work; appropriate dose; base; cancer cell; cancer type; cytotoxic; draining lymph node; exhaust; experimental study; extracellular; in vivo; inhibitor; long term memory; lymph nodes; macrophage; melanoma; metabolic fitness; mitochondrial fitness; mouse model; mutant; nanoparticle; neoplasm immunotherapy; novel; particle; prevent; programmed cell death protein 1; response; scale up; subcutaneous; tumor; tumor growth; tumor microenvironment; vaccine efficacy; vaccine response

Abstract The main goal of this proposal is to develop biomaterial-based technologies that can modulate the functions of DCs and T-cells in the draining lymph nodes in the presence of systemically delivered metabolic inhibitors. The hypothesis of this proposal is that polymeric biomaterials-based particles generated from central-carbon metabolites (targeting DCs via phagocytosis) can restart glycolysis/TCA cycle in DCs in the presence of metabolic inhibitors and will also induce robust vaccine responses in immunocompetent mice. Notably, we have generated polymers of central-carbon metabolites from glycolysis and TCA cycle, which were able to activate DCs even in the presence of metabolic inhibitors. Moreover, these particles were able to rescue the metabolic inhibition, as observed by up-regulated extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in bone marrow derived DCs. In vivo PEGS particle formulations delivering TRP-2 peptide (without any adjuvant), were able to prevent the growth of subcutaneous B16F10 tumors in the presence of CB-839 a glutaminase inhibitor. Similarly, F16BP vaccine particles delivering TRP2 peptide antigen along with poly(I:C) as adjuvant and PFK15, a glycolytic inhibitor, were able to reverse the growth of subcutaneous YUMM1.1 tumors. The hypothesis of this proposal will be tested using the following specific aims: Aim 1: Evaluate if F16BP particles induce antigen-specific long-term memory T cell responses in immunocompetent mice in the presence of glycolytic inhibitor PFK15. Aim 2: Determine if PEGS particles can induce antigen-specific long-term T cell responses in immunocompetent mice in the presence of glutaminase inhibitor CB-839. Aim 3: Determine toxicity profile and maximum tolerable doses of vaccines. The results obtained from these experiments will shed light on the effect of metabolic reprogramming on the efficacy of vaccine therapy.

抽象的 该提案的主要目的是开发基于生物材料的技术，以调节 在系统递送的代谢抑制剂存在下排水淋巴结中的DC和T细胞。这 该提议的假设是由中央碳产生的聚合物生物材料的颗粒 在存在的情况下，代谢物（通过吞噬作用靶向DC可以在DC中重启糖酵解/TCA周期 代谢抑制剂，还将在免疫能力小鼠中诱导强大的疫苗反应。值得注意的是，我们 已经从糖酵解和TCA循环中产生了中央碳代谢产物的聚合物，这些聚合物能够 即使在存在代谢抑制剂的情况下，也会激活DC。此外，这些粒子能够拯救 代谢抑制作用，如上调的细胞外酸化速率（ECAR）和氧气所观察到的 骨髓衍生的DC中的消耗率（OCR）。体内PEGS颗粒配方提供TRP-2 肽（没有任何辅助）能够防止皮下B16F10肿瘤的生长 CB-839谷氨酰胺酶抑制剂的存在。同样，F16BP疫苗颗粒输送TRP2肽 抗原以及糖化抑制剂佐剂和PFK15的抗原，能够逆转 皮下Yumm1.1肿瘤。该提案的假设将使用以下特定 目的：目标1：评估F16bp颗粒是否诱导抗原特异性的长期记忆T细胞反应 在存在糖酵解抑制剂PFK15的情况下，免疫能力小鼠。目标2：确定钉颗粒是否可以 在存在谷氨酰胺酶的情况下，诱导免疫能力小鼠的抗原特异性长期T细胞反应 抑制剂CB-839。 AIM 3：确定毒性特征和最大耐受剂量的疫苗。结果 从这些实验获得的将阐明代谢重编程对 疫苗疗法。