MR-Guided Focused Ultrasound Combined with Immunotherapy to Treat Malignant Brain Tumors

磁共振引导聚焦超声联合免疫疗法治疗恶性脑肿瘤

• 批准号: 9362814
• 负责人: Max Wintermark
• 金额: $ 65.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-12 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362814
• 关键词: 19 year old; Adolescent and Young Adult; Affect; Antibodies; Biological; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CD47 gene; Cancer Etiology; Cell Surface Proteins; Cell surface; Cessation of life; Development; Diagnosis; Eating; Excision; Focused Ultrasound; Gene Targeting; Glioblastoma; Goals; Heat shock proteins; Heat-Shock Proteins 70; Hemorrhage; Histologic; Human; Immune; Immunotherapy; Inflammation; Inflammatory; Injectable; Interferon Type II; Interleukins; Intravenous; Kinetics; Lesion; Magnetic Resonance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mechanics; Microbubbles; Molecular; Monoclonal Antibodies; Mus; PDCD1LG1 gene; Patients; Permeability; Phagocytes; Pharmaceutical Preparations; Phosphatidylserines; Primary Brain Neoplasms; Radiation; Research; Resistance; Risk; Safety; Signal Transduction; Site; Stem cells; Sterility; Survival Rate; TNF gene; Toxic effect; Treatment Efficacy; Tumor Tissue; Tumor Volume; Ultrasonic Therapy; United States; Vascular Endothelial Growth Factors; Xenograft procedure; aged; base; brain tissue; chemotherapeutic agent; chemotherapy; cranium; cytokine; experimental study; macrophage; mortality; mouse model; neoplastic cell; novel strategies; preclinical study; stem; treatment effect; tumor; tumor microenvironment

ABSTRACT In the United States, nearly 70,000 new cases of primary brain tumors are diagnosed every year. Although significant advances have been made in the diagnosis and treatment of brain cancers, the mortality rate has remained steady for more than 30 years. Patients have a five-year overall survival rate from 5% to 40% depending on the histological subtype; survival is dismal for glioblastomas (5% survival rate at five years). A promising new approach to treat brain cancer is immunotherapy. Several immune-based drugs are currently in development for brain tumors, including anti-CD47 antibodies. However, some types of brain tumors are relatively resistant to anti-CD47 antibodies, due at least in part to the difficulty in crossing the blood-brain barrier (BBB), even the abnormal BBB observed in brain tumors. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has emerged as an effective, non-invasive treatment for brain lesions through the intact skull.1 MRgFUS causes intravenously injected microbubbles to oscillate, which mechanically disrupts the BBB in a targeted, transient, and non-toxic manner, increasing its permeability to large molecules into the brain. In preclinical studies, BBB opening has been used to deliver chemotherapeutic agents, antibodies, stem cells, and targeted genes. Although studies have probed the effect of MRgFUS on normal brain tissue, including changes in BBB opening and sterile inflammation in the normal brain microenvironment, the effect of MRgFUS has not been studied in brain tumors. In this study, we will investigate the use of MRgFUS on brain tumor tissue, with the goal of enhancing the effect of immunotherapies on brain tumors. Using mice with orthotopic brain tumor grafts (mouse tumors and human glioblastomas), we will assess (1) how MRgFUS affects the microenvironment of brain tumor tissue, (2) whether MRgFUS enhances the delivery of anti-CD47 antibodies in brain tumor tissue, and (3) whether MRgFUS increases the efficacy of immunotherapy on brain tumors without increasing the risk of toxicity to the normal brain tissue. Our results could be applied to other anti-tumor monoclonal antibodies, immunotherapies, and standard chemotherapeutic agents for a range of brain tumors. By better understanding the effect of MRgFUS and MRgFUS+microbubbles on the brain tumor microenvironment, this research will open a path to safely enhancing the effect of treatments for malignant primary brain tumors.

抽象的 在美国，每年诊断出近70,000例新的原发性脑肿瘤病例。虽然很重要 在诊断和治疗脑癌方面已取得进步，死亡率保持稳定以增加 超过30年。患者的总生存率为5％至40％，具体取决于组织学亚型； 胶质母细胞瘤（五年时生存率为5％）的生存期是惨淡的。 一种有希望的治疗脑癌的新方法是免疫疗法。目前正在使用几种免疫药物 脑肿瘤的发育，包括抗CD47抗体。但是，某些类型的脑肿瘤相对 对抗CD47抗体的抗性，至少部分是由于难以越过血脑屏障（BBB）的难度 在脑肿瘤中观察到的异常BBB。 经颅磁共振引导聚焦超声（MRGFU）已成为有效的，无创的 通过完整的头骨治疗脑病变。1MRGFU会导致静脉注射的微泡振荡， 它以靶向，瞬态和无毒的方式机械破坏了BBB，增加了其对大的渗透性 分子进入大脑。在临床前研究中，BBB开放已用于提供化学治疗剂， 抗体，干细胞和靶向基因。尽管研究探讨了MRGFU对正常脑组织的影响，但 包括正常脑微环境中BBB开口和无菌炎症的变化，MRGFUS的影响 尚未在脑肿瘤中研究。 在这项研究中，我们将研究MRGFU在脑肿瘤组织上的使用，目的是增强 脑肿瘤的免疫疗法。使用与原位脑肿瘤移植物（小鼠肿瘤和人类的小鼠） 胶质母细胞瘤），我们将评估（1）MRGFU如何影响脑肿瘤组织的微环境，（2）是否是否 MRGFU增强了脑肿瘤组织中抗CD47抗体的递送，（3）MRGFU是否会增加 免疫疗法对脑肿瘤的疗效而不增加对正常脑组织毒性的风险。 我们的结果可以应用于其他抗肿瘤单克隆抗体，免疫疗法和标准化学治疗性 一系列脑肿瘤的药物。通过更好地了解MRGFU和MRGFUS+微泡对 脑肿瘤微环境，这项研究将为安全增强恶性治疗的影响开辟一条途径 原发性脑肿瘤。