DDEL-29. Convection-enhanced delivery of dexamethasone potently suppresses glioma-associated inflammation in a mechanistically distinct way from systemic drug delivery

Abstract Dexamethasone is widely used to manage inflammation and cerebral edema in glioblastoma patients, but its utility is limited by significant systemic toxicities and unfavorable prognostic outcomes. To address these issues, we evaluated convection-enhanced delivery (CED) of dexamethasone in our murine glioma model as a strategy to administer dexamethasone directly to the tumor microenvironment. CED of dexamethasone completely avoids side effects seen with systemic delivery of the drug and has a modest but significant prolongation of survival. Immunohistochemical analyses suggest local delivery of dexamethasone inhibits direct microglial activation and reduces the number of tumoral MSR1+ macrophages to a greater extent than systemic drug delivery. Analysis of single-nucleus RNA sequencing revealed that systemic dexamethasone increased the expression of an immunosuppressive gene program, which was previously reported to be induced by systemic dexamethasone exposure in human glioblastoma patients. Local delivery of dexamethasone, in contrast, led to a negative enrichment in this immunosuppressive program, suggesting a potential mechanism for the survival and histological differences seen between local and systemic drug delivery. Pharmacokinetic studies demonstrate that CED led to higher peritumoral dexamethasone concentrations than systemic delivery, with improved partitioning between the murine brain and peripheral organs. Also, CED of dexamethasone led to a ten-fold increase in AUC compared to systemic delivery, with no measured physiological side effects. Analysis of MRI-localized biopsies showed that the brain penetrance of dexamethasone is limited in human glioblastoma patients. We observed that contrast-enhancing tumor samples had a dexamethasone concentration of 73±25% of corresponding plasma samples, while non-enhancing samples had a dexamethasone concentration of 20±10%. CED of dexamethasone achieves therapeutically effective intratumoral drug concentrations without systemic side effects and may offer mechanistic advantages over systemic drug delivery. Given this, CED of dexamethasone represents a promising approach to improve the management of glioma-associated inflammation.