SCIDOT-23. LOW INTENSITY PULSED ULTRASOUND ENHANCES BLOOD-BRAIN BARRIER OPENING AND IMPROVES RESPONSE TO IMMUNOTHERAPY FOR GLIOBLASTOMA

Abstract

Abstract The blood-brain barrier (BBB) is a significant obstruction to the delivery of treatments for glioblastoma. Previous studies have demonstrated the use of Low Intensity Pulsed Ultrasound (LIPU) in combination with microbubbles as a safe and therapeutic method for temporary BBB disruption to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma. Glioblastoma has minimal T cell infiltration. In this work, we investigated if LIPU sonications (1 MHz, 0.3 MPa, 120 s duration) could enhance T cell delivery to the tumor microenvironment and enhance immunotherapy. NSG mice with established EGFRvIII+U87 tumors were treated intravenously with bioluminescent labeled epidermal growth factor receptor variant III (EGFRvIII) expressing chimeric antigen receptor (CAR) T cells with and without ultrasound BBB disruption. Combining systemic CAR T cell administration with ultrasound BBB disruption, resulted in a significant increase in CAR T cell delivery to the mouse CNS after 12 (p<0.005) and 24 hours (p<0.001) associated with enhanced median survival. In a second murine model of C57BL/6 mice bearing intracerebrally implanted GL261 gliomas, mice treated with anti-PD-1 and ultrasound BBB disruption survived 58 days relative to 39 days of mice treated with only anti-PD-1. Long-term survivors in the anti-PD-1 and anti-PD-1+ ultrasound treatment groups all remained alive after contralateral hemisphere rechallenge with GL261 glioma cells. LIPU-induced BBB disruption increases the delivery of immune therapeutics to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies to the clinic.