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 BBB 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 Ill (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 G1,261-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-I, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR 1-cell administration with LIPU-induced BBBD resulted in significant increases in CAR T-cell delivery to the CNS after 24 (P < 0.005) and 72 (P < 0.001) hours and increased median survival by greater than 129%, in comparison with CART cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with L1PU enhanced 1-cell glioma infiltration during the therapeutic window (P 0.004) and markedly enhanced survival (P < 0.05). Conclusions: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain.