Comparing Systemic, Localized, and Focused Ultrasound-Mediated Delivery of Evolocumab (α-PCSK9) in a Murine Model of Glioblastoma 2303312

Abstract

Abstract Introduction Key challenges in treating glioblastoma are the immunosuppressive tumor microenvironment and the blood-brain barrier (BBB). The PESKe clinical trial (NCT04937413) found that evolocumab (a-PCSK9) treatment increased MHC-I expression and CD8+ T cell infiltration in contrast-enhancing tumors. However, this was not observed in non-enhancing tumors with low concentrations of drug, suggesting that delivery of evolocumab is restricted by the BBB. This study aims to determine effective mechanisms to increase evolocumab delivery to brain tumors, investigating both localized intracranial delivery and targeted focused ultrasound (FUS)-mediated delivery. Methods This study used a MTS assay to optimize in vitro parameters, flow cytometry to evaluate immune effects in vitro and in vivo, and LC-MS to quantify concentrations of intratumoral evolocumab. Results In vitro, it was determined that evolocumab significantly increased MHC-I presentation in CT-2A glioma cells. In vivo, C57Bl/6 mice bearing syngeneic CT-2A tumors were treated with evolocumab either intracranially or intravenously. Flow cytometry at multiple timepoints found no significant difference in MHC-I presentation or T cell infiltration. In the same model, FUS-mediated targeted delivery of evolocumab was compared to systemic delivery, finding that FUS significantly increased both gadolinium contrast-enhancement and intratumoral evolocumab concentrations quantified by LC-MS. There was a significant correlation between contrast-enhancement and concentrations, similar to patient data in the PESKe trial. Conclusion In conclusion, intracranial delivery of evolocumab did not significantly impact immune effects, while FUS-mediated delivery of evolocumab successfully increased intratumoral concentration. Future directions include evaluating the immune effects of FUS-mediated delivery, as well as combining FUS-mediated delivery of evolocumab with anti—PD-1 therapy to improve survival outcomes. Funding Source Duke’s Preston Robert Tisch Brain Tumor Center Topic Categories Neuroimmunology (NEUR)