(SST) Ronald L. Bittner Award on Brain Tumor Research (2023 Award Winner): Enhanced Delivery of Liposomal Doxorubicin to the Brain by Ultrasound Induces an Ifn-g Phenotype of Microglia, Macrophages, and T Cells That Improves Response to PD-1 Blockade in Glioblastoma
Postdoctoral Fellow Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine Chicago, Illinois, United States
Disclosure(s):
Victor A. Arrieta González, MD/PhD: No financial relationships to disclose
Introduction: The limited drug penetration across the blood-brain barrier (BBB) represents a challenge for the treatment of glioblastoma (GBM) patients. A novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) overcomes this challenge by opening the BBB. In this translational study, we hypothesize that LIPU/MB enhances the therapeutic effect of both liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in gliomas by eliciting local immune responses.
Methods: We employed LIPU/MB to deliver DOX and aPD-1 in mouse glioma models and 4 recurrent GBM patients. By multiplex immunofluorescence and flow cytometry, we evaluated HLA ABC and HLA DR expression on tumor cells, microglia, and macrophages as well as IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors treated with DOX and aPD-1 delivered by LIPU/MB. Furthermore, we assessed the efficacy of LIPU/MB-enhanced combination therapy in glioma-bearing mice.
Results: LIPU/MB induced a 2-fold increase in DOX concentrations in sonicated peritumoral brain samples compared to those not sonicated (P=0.012). DOX elicited an IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans (P < 0.0001). Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice (6.3-fold increase, P< 0.01) and GBM patients (2-fold increase, P=0.049). Tumor cells from GBM patients treated with DOX, aPD-1, and LIPU/MB showed increased expression of HLA ABC (P=0.055) and HLA DR (P=0.022). Treatment with liposomal DOX and aPD-1 delivered with LIPU/MB increased the percentage of IFN-g+ CD8+ and CD4+ T cells in the tumors of GBM patients (P < 0.05). In glioma-bearing mice, this combined treatment resulted in long-term survival that relied on the activity of CD8+ T cells for its efficacy (P < 0.0001).
Conclusion : This translational study demonstrates the power and potential of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.
