Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities
Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony J. Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter J. Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby L. Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J.A. Gill, Peter Canoll, Jeffrey N. Bruce
Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony J. Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter J. Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby L. Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J.A. Gill, Peter Canoll, Jeffrey N. Bruce
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Research Article Inflammation Oncology

Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities

Abstract

Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral antiinflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In 2 glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell–derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP-1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

Authors

Nathaniel W. Rolfe, Nicholas B. Dadario, Liang Lei, Anthony J. Tang, Misha Amini, Damian E. Teasley, Nkechime Ifediora, Peter J. Chabot, Nathan J. Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H. Stucke, Nivia M. Urena, Yanping Sun, Abby L. Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G. Argenziano, Colin P. Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A. Sims, Brian J.A. Gill, Peter Canoll, Jeffrey N. Bruce

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Figure 1

CED-dexamethasone demonstrated intracranial drug distribution without significant weight loss, and prolonged survival in mice with APCL tumors, but did not significantly improve survival in the GL261 model.

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CED-dexamethasone demonstrated intracranial drug distribution without si...
(A) Representative MRI images from mice demonstrating the volume of gadolinium distribution between control and CED-dexamethasone treatment conditions. (B) The majority of mice gained or lost a negligible amount of weight in our 3 treatment conditions. Mice receiving PBS (vehicle control) gained 0.7 ± 1.0 g (mean ± SD), mice receiving systemic dexamethasone gained 0.4 ± 0.8 g, and mice receiving CED-dexamethasone lost 0.1 ± 1.7 g. There was no significant difference in weight change between treatment groups (Kruskal-Wallis, P = 0.15). (C) Survival curves of vehicle-treated or CED-dexamethasone–treated mice with APCL tumors. Mean survival for control mice was 35 days while median survival for CED-dexamethasone–treated mice was 41 days (log-rank P = 0.03). (D) Survival curves of vehicle-, CED-dexamethasone–, and systemic dexamethasone–treated mice with GL261 tumors. Mean survival for control mice was 23 days, mean survival for systemically treated mice was 22 days, and mean survival for CED-dexamethasone–treated mice was 25 days (log-rank P = 0.39).