MDB-108. MRI-GUIDED FOCUSED ULTRASOUND BLOOD BRAIN/TUMOR BARRIER DISRUPTION FOR AUGMENTATION OF ANTIBODY DELIVERY TO HIGH-RISK MEDULLOBLASTOMAS

Abstract

Abstract BACKGROUND Medulloblastoma is the most common pediatric brain cancer, and among its four molecular subgroups, group 3 (G3MB) harbors the worst prognosis (5-year survival rate <50%). Effective treatment of G3MB remains difficult due to disease complexity, its challenging niche within the immunologically- and pharmacologically-privileged central nervous system, and significant risk of long-term developmental deficits due to treatment toxicities. MRI-guided focused ultrasound (MRgFUS) holds the potential to revolutionize care as a non-invasive, non-ionizing approach for spatially precise intervention in G3MBs. Given that the utility of FUS in MBs remains unknown, we implemented FUS-mediated blood brain/tumor barrier disruption (BBB/BTB-D) in a high-fidelity model of G3MB and evaluated its impact on localized antibody delivery – with an eye toward future applications in immuno-oncology. METHODS An orthotopic syngeneic model was established via stereotactic implantation of G3MB cells (Gfi1/c-MYC driven) into the cerebellum. G3MB growth kinetics were validated via serial MRI. Multiple protocols for naive cerebellum or G3MB BBB/BTB-D were established with a 1.15 MHz FUS system under 9.4T MRI guidance. Across both settings, mice were sonicated with concomitant intravenous administration of microbubbles and fluorescently-labeled IgG. Safety was confirmed by acoustic emissions monitoring, susceptibility-weighted imaging, histology, and acute activity monitoring. Antibody delivery was evaluated via ex vivo epifluorescence imaging. RESULTS Post-contrast T1w-MRI depicted clear evidence of localized BBB/BTB-D in naive and G3MB mice. No damage was noted by imaging or histopathologic analysis, and mice displayed normal cardiorespiratory and motor functions following FUS. FUS conferred significantly increased epifluorescence signal in targeted cerebellum (1.3x) and G3MBs (1.5x) relative to controls, indicating improved antibody access. CONCLUSIONS Our findings support the safety and feasibility of FUS BBB/BTB-D in naive and G3MB-bearing cerebellum. We demonstrate that FUS markedly improves antibody penetrance within G3MBs. Ongoing studies are evaluating FUS in combination with novel immunotherapeutic antibodies for G3MB therapy.