DDDR-38. Leveraging the immunomodulatory effects of dordaviprone (ONC201) to induce long-term survival response in diffuse midline glioma patients and models

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.

Authors

Institutions

Publication Details

Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.0675
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

DDDR-38. Leveraging the immunomodulatory effects of dordaviprone (ONC201) to induce long-term survival response in diffuse midline glioma patients and models

Evangeline R. Jackson, Carl Koschmann, Izac J. Findlay, Mika L. Persson et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

DDDR-38. Leveraging the immunomodulatory effects of dordaviprone (ONC201) to induce long-term survival response in diffuse midline glioma patients and models

Evangeline R. Jackson, Carl Koschmann, Izac J. Findlay, Mika L. Persson, Tuan Vo, Marta M. Alonso, Jemma Mayall, Javad Nazarian, Rodrigo T. Cartaxo, Liesl Bramberger, Jay C. Horvat, Matthew D. Dun, Martin R. Larsen, Yolanda Colino‐Sanguino, Ryan J. Duchatel, Nicholas A. Vitanza, Fátima Valdés‐Mora, Hubert Hondermarck, Jeff Holst, Alicia M. Douglas, Holly P. McEwen, Andrea Franson, Tyrone S. Beitaki, Cassie Kline, Brett Nixon, Daniel de la Nava, Esther Hulleman, Pouya Faridi, Jasper van der Lugt, Tiago Carvalheiro, Laura Rodríguez de la Fuente, Bryce Thomas, Sabine Mueller, Clara Savary, Sriram Venneti
article en

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.

Neuro-OncologyVol. 27(Supplement_5)
University of New Caledonia (NC), Center for Infectious Disease Research (US), Seattle Children's Hospital (US), Children's Hospital of Philadelphia (US), University of Southern Denmark (DK), University of California, San Francisco (US), University of Washington (US), University of Michigan (US), UNSW Sydney (AU), Hunter Medical Research Institute (AU), Seattle Children's Hospital (US), Children's Cancer Institute Australia (AU), Michigan Medicine (US), Sydney Children's Hospital (AU), Princess Máxima Center (NL), University Children's Hospital Zurich (CH), Clinica Universidad de Navarra (ES), Monash University (AU), Seattle University (US), University of Newcastle Australia (AU), University of Pennsylvania (US), Neuroscience Research Australia (AU)
Openalex Percentile: Top 51%
Glioma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.