Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models.

Purpose: The blood brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary blood-brain barrier disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma. Experimental Design: We investigated if LIPU could enhance therapeutic efficacy of anti-PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically-engineered antigen-presenting cell (APC)-based therapy producing the T cell attracting chemokine CXCL10 in the GL261-bearing mice. Results: Mice treated with anti-PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti-PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T cell administration with LIPU-induced BBBD resulted in significant increases in CAR T cell delivery to the CNS after 24 (p