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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

基本信息

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
项目类别：
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

项目摘要

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