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.
A promising new approach to treat brain cancer is immunotherapy (such as using anti-CD47 antibodies); however, immunotherapy cannot treat successfully all brain tumors, especially aggressive ones. The goal of our project is to investigate whether magnetic resonance-guided focused ultrasound combined with microbubbles can increase local inflammation in brain tumor tissue, increase the delivery of anti-CD47 antibodies into brain tumor tissue, and safely enhance the efficacy of the treatment. The results of these studies could be applied to other anti-tumor monoclonal antibodies, immunotherapies, and standard chemotherapeutic agents for a range of brain tumors.
