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：
10655464
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/10655464
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 Classification Clinical Engineering Epitopes Exhibits Genetic Genetic Engineering Genomic DNA Glioma Goals High Density Lipoproteins Human Immune Immune response Immunity Immunocompetent Immunologic Memory Immunologic Stimulation Immunologics Immunotherapeutic agent Immunotherapy Implant Intracranial Neoplasms Isocitrate Dehydrogenase Knowledge Lesion 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 Recurrent tumor Research Role Serum Sleeping Beauty Solid Neoplasm Spleen Subgroup T cell response T memory cell T-Lymphocyte TP53 gene Technology Testing Therapeutic 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 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 nanolipoprotein particles nanomaterials nanovaccine nerve stem cell nondeletion type alpha-thalassemia/mental retardation syndrome novel novel strategies novel therapeutic intervention novel vaccines personalized immunotherapy promoter response standard of care success 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在癌症治疗中取得了成功，但它们的使用仅受益于一部分癌症患者。肿瘤用来抑制抗肿瘤免疫反应的多种机制具有阻碍了他们广泛用作单疗法的广泛使用，而对于神经胶质瘤尤其如此。因此，存在对实现强大而持久的免疫反应的新的补充策略的批判性需要神经胶质瘤。特别是，突变体异戊二酸 - 脱水酶-1（IDH1-R132H; MIDH1）是成年神经胶质瘤的标志。我们通过合并遗传病变开发了完全免疫胜任的鼠MIDH1模型在人类疾病中遇到的神经祖细胞的基因组DNA使用睡美转座酶并表明这些颅内肿瘤表现出人类MIDH1神经胶质瘤的标志。我们的长期术语研究目标是制定可以通过有效的抗中间1实现免疫刺激的新型策略神经胶质瘤免疫。我们在此应用程序中的主要目标是设计强大且安全的平台疫苗针对MIDH1胶质瘤诱导坚固，耐用的抗肿瘤记忆响应的技术。对此最后，我们开发了一种基于合成高密度脂蛋白（SHDL）的新疫苗技术纳米盘。我们已经表明，SHDL纳米散发有效地将抗原和辅助分子递送至抗原呈现细胞并具有强大的细胞毒性潜能获得强大的T细胞反应。在这里，我们建议评估SHDL纳米颗粒在基因工程的鼠神经胶质瘤模型中的治疗功效和可移植颅内神经胶质瘤。具体而言，我们建议（1）优化我们的纳米技术以改进 MIDH1 Ag的递送并引起对MIDH1神经胶质瘤的持久记忆T细胞反应（AIM 1）；（2）评估他们的使用源自MIDH1基因神经胶质瘤的神经球来根除MIDH1胶质瘤的功效植入免疫能力小鼠的模型（GEM）（AIM 2）；（3）检验结合纳米盘的假设带有护理标准（辐射）和抗PD-L1免疫检查点封锁的疫苗接种将引起强大的抗 MIDH1胶质瘤免疫，具有长期免疫记忆的MIDH1宝石。这些研究将使新纳米疫苗传递平台上的光线进行精确免疫疗法。更广泛地，提议的工作将解决疫苗技术中当前的技术限制，并有可能导致新的治疗选择 MIDH1神经胶质瘤患者。