Ddel-13. Ultrasound-enhanced Delivery of Liposomal Doxorubicin Across the Blood Brain Barrier Induces an Ifn-gphenotype in Microglia, Macrophages, and T Cells and Improves Response to Pd-1 Blockade in Gliomas
Year: 2022
Type: conference-abstract
Abstract: INTRODUCTION Given the limited drug penetration across the blood-brain barrier (BBB), the therapeutic potential of new and existing therapies has not been fully exploited for the benefit of glioblastoma (GBM) patients. METHODS Here we employed a novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) that temporarily opens the BBB to deliver liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in mouse glioma models and 3 recurrent GBM patients. Immunological variables were evaluated in tumor and immune cells as well as efficacy in glioma-bearing mice treated with DOX delivered by LIPU. These included measurement of HLA ABC and HLA DR protein expression by tumor cells, microglia, and macrophages and IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors. We also assessed efficacy of LIPU/MB enhanced combination therapy in glioma-bearing mice. RESULTS Upregulation of HLA ABC and HLA DR was observed in GBM cell lines at low concentrations of DOX. Tumor cells from GBM patients treated with DOX, aPD-1 and LIPU/MB showed increased expression of HLA ABC and HLA DR compared to paired pretreatment samples. In both mice and humans, LIPU/MB liposomal DOX increased absolute brain drug concentrations and elicited a specific IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans. Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice and in peritumoral regions of GBM patients. Combined treatment with liposomal DOX and aPD-1 delivered with LIPU/MB resulted in long-term survival of glioma-bearing mice that relied on the activity of CD8+ T cells for its efficacy. CONCLUSIONS Overall, this translational study demonstrates the utility of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.
Source: Neuro-Oncology
Authors: Victor Arrieta, Andrew Gould, Kwang Soo Kim, Crismita Dmello, Daniel Zhang, Brandyn Castro, Li Chen, Surya Pandey, Li Kai, Joseph Duffy, Matthew McCord, Rachel Ward, Miguel Muzzio, Michael Canney, Irina Balyasnikova, Bin Zhang, Craig Horbinski, Jason Miska, Roger Stupp, Catalina Lee-Chang, Adam M Sonabend
Institutions: Northwestern University, IIT Research Institute
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W4308977065