Novel nano-vaccine technology for inducing immunity against gliomas

用于诱导神经胶质瘤免疫力的新型纳米疫苗技术

• 批准号: 10443896
• 负责人: Maria G Castro
• 金额: $ 50.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443896
• 关键词: 19q; ATRX gene; Address; Adjuvant; Adult Glioma; Antigen Presentation; Antigen-Presenting Cells; Antigens; Benchmarking; Biocompatible Materials; Biology; Blood; Bone Marrow; Cancer Patient; Cells; Clinical; Engineering; Epitopes; Exhibits; Genetic; Genetic Engineering; Genomic DNA; Glioma; Goals; High Density Lipoproteins; Human; Immune; Immune response; Immunity; Immunization; Immunocompetent; Immunologic Memory; Immunologics; Immunotherapeutic agent; Immunotherapy; Implant; Intracranial Neoplasms; Isocitrate Dehydrogenase; Knowledge; Lead; Lesion; Light; Lipids; Lymphatic; Lymphoid Tissue; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Mus; Mutation; Nanotechnology; Neurosphere; Operative Surgical Procedures; Patients; Physiological; Production; Prognosis; Public Health; Radiation; Recurrence; Research; Role; Serum; Sleeping Beauty; Solid Neoplasm; Spleen; Subgroup; T cell response; T memory cell; T-Lymphocyte; TP53 gene; Technology; Testing; Transplantation; Transposase; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Vaccination; Vaccine Antigen; Vaccines; Work; alpha ketoglutarate; anti-PD-L1; anti-tumor immune response; antigen-specific T cells; base; cancer immunotherapy; cancer therapy; cytotoxic; design; draining lymph node; gain of function mutation; human disease; immune checkpoint; immune checkpoint blockade; immune function; improved; in vivo; mutant; nanodisc technology; nanodisk; nanomaterials; nanoparticle; nanovaccine; nerve stem cell; nondeletion type alpha-thalassemia/mental retardation syndrome; novel; novel strategies; novel vaccines; personalized immunotherapy; promoter; response; standard of care; success; treatment strategy; tumor; tumor-immune system interactions; uptake; vaccine delivery; vaccine platform; virtual

Abstract Despite the success of immune checkpoint blockade in cancer therapy, their use has benefited only a subset of cancer patients. The multiple mechanisms utilized by tumors to inhibit an anti-tumor immune response have impeded their widespread use as monotherapies, and this is particularly true for gliomas. Therefore, there exists a critical need for new, complementary strategies for achieving powerful and durable immune responses against gliomas. In particular, mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. We have developed a fully immune competent murine mIDH1 model by incorporating genetic lesions encountered in the human disease into the genomic DNA of neural progenitor cells using Sleeping Beauty Transposase and shown that these intracranial tumors exhibit the hallmarks of human mIDH1 glioma. Our long- term research goal is to develop novel strategies that can achieve immune stimulation with potent anti-mIDH1 glioma immunity. Our main objectives in this application are to engineer a powerful and safe platform vaccine technology for inducing robust, durable anti-tumor memory T-cell responses against mIDH1 gliomas. To this end, we have developed a new vaccine technology based on synthetic high-density lipoprotein (sHDL) nanodiscs. We have shown that sHDL nanodiscs efficiently deliver antigens and adjuvant molecules to antigen- presenting cells and achieve strong T-cell responses with robust cytotoxic potential. Here, we propose to evaluate the therapeutic efficacy of sHDL nanoparticles in genetically engineered murine glioma models and transplantable intracranial gliomas. Specifically, we propose to (1) optimize our nanotechnology for improved mIDH1 Ag delivery and elicit durable memory T-cell responses against mIDH1 glioma (Aim 1); (2) evaluate their efficacy to eradicate mIDH1 gliomas using neurospheres derived from the mIDH1 genetically engineered glioma model (GEM) implanted into immunocompetent mice (Aim 2); (3) test the hypothesis that combining nanodisc vaccination with standard of care (radiation) and anti-PD-L1 immune checkpoint blockade will elicit robust anti- mIDH1 glioma immunity with long-term immunological memory in mIDH1 GEMs. These studies will shed new light on nano-vaccine delivery platforms for precision immunotherapy. More broadly, the work proposed will address current technical limitations in vaccine technologies and potentially lead to a new treatment option for mIDH1 glioma patients.

摘要