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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的尽管免疫检查点阻断在癌症治疗中取得了成功，但它们的使用仅使一小部分人受益癌症患者。肿瘤利用多种机制抑制抗肿瘤免疫反应阻碍了它们作为单一疗法的广泛使用，对于神经胶质瘤尤其如此。因此，存在迫切需要新的补充策略来实现强大而持久的免疫反应神经胶质瘤。特别是，突变异柠檬酸脱氢酶-1（IDH1-R132H；mIDH1）是成人神经胶质瘤的标志。我们通过整合遗传损伤开发了完全免疫能力的小鼠 mIDH1 模型使用《睡美人》将人类疾病中遇到的问题转化为神经祖细胞的基因组 DNA 转座酶并显示这些颅内肿瘤表现出人类 mIDH1 神经胶质瘤的特征。我们的长期本学期的研究目标是开发新的策略，通过有效的抗 mIDH1 来实现免疫刺激胶质瘤免疫。我们在此应用中的主要目标是设计一种强大且安全的平台疫苗用于诱导针对 mIDH1 神经胶质瘤的强大、持久的抗肿瘤记忆 T 细胞反应的技术。对此最后，我们开发了一种基于合成高密度脂蛋白（sHDL）的新疫苗技术纳米圆盘。我们已经证明 sHDL 纳米圆盘可以有效地将抗原和佐剂分子递送至抗原- 呈递细胞并实现具有强大细胞毒性潜力的强烈 T 细胞反应。在此，我们建议评估 sHDL 纳米颗粒在基因工程鼠神经胶质瘤模型中的治疗效果可移植颅内神经胶质瘤。具体来说，我们建议（1）优化我们的纳米技术以改进 mIDH1 Ag 递送并引发针对 mIDH1 神经胶质瘤的持久记忆 T 细胞反应（目标 1）； (2)评价他们的使用源自 mIDH1 基因工程神经胶质瘤的神经球根除 mIDH1 神经胶质瘤的功效模型（GEM）植入免疫活性小鼠（目标 2）； (3) 检验结合纳米盘的假设采用标准护理（放射）和抗 PD-L1 免疫检查点封锁的疫苗接种将引发强大的抗- mIDH1 GEM 中具有长期免疫记忆的 mIDH1 神经胶质瘤免疫。这些研究将揭示新的用于精准免疫治疗的纳米疫苗输送平台。更广泛地说，拟议的工作将解决疫苗技术当前的技术限制，并可能为以下疾病带来新的治疗选择 mIDH1 神经胶质瘤患者。