INSP-16. Focused ultrasound-mediated blood-brain barrier disruption for the treatment of pediatric high-grade glioma

Pediatric patients with high-grade glioma (HGG), such as glioblastoma (GBM) and H3K27M-altered diffuse midline glioma (DMG) suffer from a dismal prognosis and a poor quality of life. So far, no therapeutic strategy has resulted in significant long-term survival benefit for these patients. Drug therapies have largely failed due to inadequate drug delivery to the brain as a result of the blood-brain barrier, preventing most drugs from entering the brain. Intrinsic and acquired tumor heterogeneity, with drug-resistant tumor cell subpopulations add to the therapeutic failure. Furthermore, these tumors evade the immune system by creating a highly tumor-promoting and immunosuppressive tumor immune microenvironment, which is composed of microglia and tumor-associated macrophages. Recently, microbubble-assisted, focused ultrasound-mediated blood-brain barrier disruption (FUS-BBBD) has emerged as a promising and clinically available technology to circumvent part of these problems. FUS-BBBD allows improved delivery of therapeutics (chemotherapy, small molecules, monoclonal antibodies, immunotherapies) to the brain. The technology is emerging both in preclinical and clinical pediatric neuro-oncology research, with invasive and minimally invasive clinical FUS-BBBD systems available for early phase clinical trials. How the right drugs in the optimal combination can be delivered with the best timing (pharmacokinetics) via FUS-BBBD has yet to be ascertained and is subject of in vitro and in vivo drug studies. Combining FUS-BBBD with compounds targeting microglia and tumor-associated macrophages potentially reverts the ‘immuno-cold’ tumor immune micro-environment towards an ‘immuno-hot’ state and might enhance systemic immunotherapies such as immune checkpoint inhibitor and CAR-T cell approaches. Furthermore, recent preclinical research evidenced that FUS-BBBD is able to enhance liquid biopsies by increasing the concentration of circulating biomarkers in blood. It could therefore be used for longitudinal monitoring of site-specific chemoresistance development during therapy. This presentation will provide an overview on preclinical and clinical developments in the field of FUS-BBBD-enhanced drug delivery, immune modulation and liquid biopsies. International collaboration in (pre)clinical studies with FUS-BBBD is needed to bring the field forward.