Leveraging Zika virus and the immune system to treat glioblastoma

利用寨卡病毒和免疫系统治疗胶质母细胞瘤

基本信息

批准号：
10528449
负责人：
Milan Girish Chheda
金额：
$ 45.65万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528449
关键词：
3&apos Untranslated Regions Address Adult Antibodies Antigens Antitumor Response Biological Assay Biology Brain Brain Neoplasms CD8-Positive T-Lymphocytes CTLA4 gene Cells Cerebral hemisphere Cessation of life Clinical Clinical Skills Clinical Trials Combined Modality Therapy Deterioration Disease Epidemic Failure Flow Cytometry Genetic Glioblastoma Glioma Goals Granzyme Human Immune Immune response Immune system Immunity Immunologic Sensitization Immunologics Immunology Immunotherapy Infrastructure Innate Immune Response Interferons Intracranial Neoplasms Kinetics Knowledge Long-Term Survivors Lytic Maps Mediating Modeling Mus Neoplasm Metastasis Neurologic Neuronal Differentiation Oncolytic Operative Surgical Procedures Outcome Patients Peripheral Positioning Attribute Primary Neoplasm Property Public Health Publishing Radiation Recombinants Research Resistance Safety System T cell response T-Lymphocyte TNFSF10 gene Testing Therapeutic Tumor Antigens Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Promotion Tumor Stem Cells Tumor-Infiltrating Lymphocytes Virus Work ZIKV infection Zika Virus aggressive therapy anti-tumor immune response brain cell chemoradiation chemotherapy clinical translation cytotoxicity effector T cell epidemic virus experimental study fetal improved outcome in vivo neoplastic cell nerve stem cell novel strategies oncolytic virotherapy perforin prevent programmed cell death protein 1 recruit single-cell RNA sequencing standard of care stem cells temozolomide tumor tumor immunology virology

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is a brain tumor that causes neurological deterioration and death in most patients within 2 years. Despite aggressive therapy, most GBMs reappear within 6 months. A major reason for this outcome is because GBM stem cells (GSCs) are resistant to existing therapies. Currently, no treatment consistently kills these highly resistant cells. However, the Zika virus epidemic has provided us with a new approach to eradicate GSCs. ZIKV targets normal stem cells in the developing fetal brain, yet has minimal effects on differentiated neurons or the adult brain. Since GSCs share properties with neural stem cells, we investigated whether the natural honing and lytic activity of ZIKV could be harnessed to target and kill GSCs. We published the first use of ZIKV to kill GSCs. We showed that ZIKV kills GSCs in tumors removed from patients, with minimal impact on non-GSC tumor cells, called differentiated GBM cells. Importantly, normal human brain cells were not affected by ZIKV. After intracranial treatment with ZIKV, mice harboring gliomas survived more than twice as long as untreated mice and, in some cases, treated mice were long-term survivors. In addition to the resistance of GBM stem cell to chemoradiation, GBM is the hallmark example of an immunotherapy-resistant tumor. Importantly, we found that in vivo, ZIKV treatment reduces tumor size and extends survival beyond that expected for only anti-GSC effects. This suggested that ZIKV killing of GSCs may trigger an immune response against the remainder of the tumor. In more recent studies, we have found that CD8+ T cells are required for the efficacy of ZIKV as an oncolytic therapy in vivo. Our central hypothesis is that ZIKV elicits an anti-tumor immune response that could be made even more effective by combining it with existing immunotherapies. Aim 1 will determine how CD8+ T cells promote tumor clearance after ZIKV and Aim 2 will determine whether ZIKV can be combined with immunotherapy or standard-of-care for GBM to improve outcomes. Our long-term goal is to develop a new treatment for GBM by leveraging the immune system response to ZIKV.

项目概要胶质母细胞瘤 (GBM) 是一种脑肿瘤，可导致大多数患者神经功能恶化并在 2 年内死亡年。尽管积极治疗，大多数 GBM 仍会在 6 个月内复发。造成这个结果的一个主要原因是因为 GBM 干细胞 (GSC) 对现有疗法具有抵抗力。目前，尚无治疗方法能够持续杀死患者这些高度抵抗的细胞。然而，寨卡病毒的流行为我们提供了根除该病毒的新方法。 GSC。 ZIKV 针对发育中胎儿大脑中的正常干细胞，但对分化的影响微乎其微。神经元或成人大脑。由于 GSC 与神经干细胞具有相同的特性，我们研究了是否可以利用 ZIKV 的自然珩磨和裂解活性来瞄准和杀死 GSC。我们发布了第一个用途 ZIKV 杀死 GSC。我们发现，ZIKV 可以杀死从患者身上摘除的肿瘤中的 GSC，对患者的影响微乎其微。非 GSC 肿瘤细胞，称为分化的 GBM 细胞。重要的是，正常的人类脑细胞没有受到影响通过 ZIKV。经过 ZIKV 颅内治疗后，携带神经胶质瘤的小鼠的存活时间是普通小鼠的两倍多未经治疗的小鼠，以及在某些情况下接受治疗的小鼠都是长期幸存者。除了GBM的抵抗力从干细胞到放化疗，GBM 是免疫治疗耐药性肿瘤的标志性例子。重要的是，我们发现，在体内，ZIKV 治疗可缩小肿瘤大小并延长生存期，超出预期抗 GSC 作用。这表明 ZIKV 杀死 GSC 可能会引发针对 GSC 的免疫反应。肿瘤的剩余部分。在最近的研究中，我们发现 CD8+ T 细胞是发挥功效所必需的 ZIKV 作为一种体内溶瘤疗法。我们的中心假设是 ZIKV 引发抗肿瘤免疫反应通过将其与现有的免疫疗法相结合，可以使其更加有效。目标 1 将决定如何 CD8+ T细胞在ZIKV后促进肿瘤清除，Aim 2将决定ZIKV是否可以联合 GBM 的免疫疗法或标准护理可改善预后。我们的长期目标是开发新的利用免疫系统对 ZIKV 的反应来治疗 GBM。