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: 10543178
• 负责人: Abhinav Acharya
• 金额: $ 32.28万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543178
• 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; Collecting Cell; Combination immunotherapy; 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; Liver; Lysine; Macrophage; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Measures; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Mus; NF-kappa B; Organ; Oxygen Consumption; Pathway interactions; Peptides; Phagocytosis; Poly I-C; Polymers; Production; Proliferating; Public Health; Publishing; Reaction; Reactive Oxygen Species; Research; Research Project Grants; Respiration; Role; Safety; Sorting; 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; cancer cell; cancer type; cytotoxic; draining lymph node; ethylene glycol; exhaust; experimental study; extracellular; in vivo; inhibitor; inorganic phosphate; long term memory; lymph nodes; melanoma; metabolic fitness; mitochondrial fitness; mouse model; mutant; nanoparticle; neoplasm immunotherapy; novel; particle; prevent; programmed cell death protein 1; programs; 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.

摘要 该提案的主要目标是开发基于生物材料的技术， 在存在全身递送的代谢抑制剂的情况下引流淋巴结中的DC和T细胞。的 该建议的假设是，由中心碳产生的基于聚合物生物材料的颗粒 代谢物（通过吞噬作用靶向DC）可以在存在下重新启动DC中的糖酵解/TCA循环。 代谢抑制剂，并且还将在免疫活性小鼠中诱导稳健的疫苗应答。值得注意的是， 已经从糖酵解和TCA循环中产生了中心碳代谢物的聚合物，这些聚合物能够 即使在代谢抑制剂存在下也能激活DC。此外，这些粒子能够拯救 代谢抑制，如通过上调细胞外酸化率（ECAR）和氧 消耗率（OCR）。递送TRP-2的体内PEGS颗粒制剂 肽（没有任何佐剂）能够防止皮下B16 F10肿瘤在小鼠中的生长。 CB-839是一种转氨酶抑制剂。类似地，递送TRP 2肽的F16 BP疫苗颗粒 抗原沿着以poly（I：C）作为佐剂和PFK 15（一种糖酵解抑制剂）能够逆转 皮下YUMM1.1肿瘤。本提案的假设将使用以下具体指标进行检验 目的：目的1：评价F16 BP颗粒是否在小鼠中诱导抗原特异性长期记忆T细胞应答。 在糖酵解抑制剂PFK 15的存在下，对免疫活性小鼠进行了细胞培养。目的2：确定PEGS颗粒是否可以 在存在转氨酶的情况下在免疫活性小鼠中诱导抗原特异性长期T细胞应答 抑制剂CB-839。目的3：确定疫苗的毒性特征和最大耐受剂量。结果 从这些实验中获得的结果将揭示代谢重编程对药物疗效的影响。 疫苗疗法