DDDR-38. Leveraging the immunomodulatory effects of dordaviprone (ONC201) to induce long-term survival response in diffuse midline glioma patients and models
Year: 2025
Type: conference-abstract
Abstract: Diffuse midline glioma (DMG) is a universally fatal high-grade glioma. Its immunologically cold tumor immune microenvironment (TIME) presents a major barrier to durable anti-tumor responses. Dordaviprone (ONC201) is a brain-penetrant DRD2 antagonist and ClpP agonist that disrupts mitochondrial complex II (CII) activity; currently under clinical evaluation for DMG. In melanoma, CII inhibition has been shown to enhance MHC presentation and T cell–mediated killing. Here, we investigated the immunomodulatory effects of dordaviprone in DMG mouse models, patient tumor tissues, and blood samples. Immunocompetent DMG-PPK mice (PdgfraD842V, Trp53DN, H3f3aK27M mutations) were treated with dordaviprone (125 mg/kg, twice weekly) for 1 week (acute) or 3 weeks (chronic) and compared to naïve, sham (orthotopic surgery without tumor engraftment), and vehicle-treated controls. Murine tumors were analyzed by single-cell multiome (scRNA-seq and scATAC-seq) and spatial transcriptomics. Murine blood and bone marrow (BM) and human blood samples were profiled by scRNA-seq and flow cytometry. In models, dordaviprone promoted microglial activation and macrophage infiltration within the TIME. Spatial transcriptomics identified increased expression of the MHC-I subunit B2m in tumor cells and tumor-infiltrating Cd8+ T cells following dordaviprone treatment. Flow cytometry of murine and human peripheral blood confirmed CD4+ and CD8+ lymphopenia at baseline. Dordaviprone increased circulating lymphocytes in models (log2 fold change=1.03; patient data pending), reversing DMG-induced CD3+ T cell sequestration in the BM. Immunohistochemistry confirmed elevated levels of B2M (p=0.0281) and tumor-infiltrating lymphocytes (TILs), including CD45+ (p=0.0275) and CD3+ T cells (p=0.0103) in dordaviprone-treated mice. Despite enhanced TIL recruitment, dordaviprone did not improve survival (n=10), likely due to persistent immunosuppressive myeloid activity, i.e. Havcr2 (TIM-3), Cd74, Cd274 (PD-L1). This study demonstrates that DMG tumors contribute to systemic lymphopenia, partially reversed by dordaviprone. While supporting its immunomodulatory effects, including enhanced antigen presentation and TIL recruitment, our findings highlight future combination strategies to leverage dordaviprone-induced immunoreactive TIME.
Source: Neuro-Oncology
Authors: Clara Savary, Mika L Persson, Evangeline R Jackson, Ryan J Duchatel, Tuan Vo, Izac J Findlay, Alicia M Douglas, Liesl Bramberger, Daniel de la Nava, Bryce C Thomas, Holly P McEwen, Tyrone S Beitaki, Laura Rodriguez de la Fuente, Yolanda Colino-Sanguino, Fatima Valdes Mora, Martin R Larsen, Pouya Faridi, Jeff Holst, Jemma Mayall, Cassie N Kline, Andrea T Franson, Sriram Venneti, Hubert Hondermarck, Jay Horvat, Brett Nixon, Rodrigo Cartaxo, Javad Nazarian, Esther Hulleman, Sabine Mueller, Nicholas A Vitanza, Carl Koschmann, Marta M Alonso, Tiago Ferreira Carvalheiro, Jasper van der Lugt, Matthew D Dun
Institutions: University of New Caledonia, University of Newcastle Australia, Hunter Medical Research Institute, Monash University, Michigan Medicine, UNSW Sydney, Children's Cancer Institute Australia, University of Southern Denmark, Children's Hospital of Philadelphia, University of Pennsylvania, University of Michigan, University Children's Hospital Zurich, Princess Máxima Center, University of California, San Francisco, Seattle Children's Hospital, University of Washington, Seattle Children's Research Institute, Clinica Universidad de Navarra
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416140586
Cites:
Cited by:
Related to: