Journal article
Multimodality mapping of immunotherapy distribution as a predictive marker in glioma
Neuro-oncology (Charlottesville, Va.)
31 Dec 2025
PMID: 41476211
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Scarce T cell infiltration, immunosuppressive tumor-associated macrophages and ineffective drug delivery drive glioma progression and limit treatment efficacy. Mapping immunotherapy distribution by multimodality imaging might be a biomarker that could aid tumor monitoring and guide therapy development.
To assess drug delivery, we developed a MRI-lightsheet microscopy platform (MR-LSM) to monitor immunotherapy at the cellular level in two immunocompetent glioma models (Gl261, SB28). The atezolizumab (PD-L1 inhibitor) subgroup of the multicenter N2M2/NOA20 trial in MGMT unmethylated GBM patients was assessed by CNN analysis and correlated to progression free survival.
In contrast to the conventional Gl261 glioma model, SB28 gliomas are characterized by poor immunogenicity and resistance to Toll-like receptor (TLR) 7 targeted therapy delivered by CDNP-R848 nanoparticles. SB28 resistance is driven by microvascular pathology, vasogenic edema and drug off-targeting to peritumoral edema and white matter tracts. Vascular endothelial growth factor (VEGF) inhibition in conjunction with irradiation and dual immunotherapy (DIR) targeting innate (CDNP-R848) and adaptive immunity (anti-CTLA-4) breaks resistance, increases survival and reverses drug off-targeting. Mechanistically, tumor control is orchestrated by vascular normalization, enhanced CD8+ T cell influx and a proinflammatory shift of myeloid cells along with strong IL-12/IL-13 upregulation. In a translational analysis of the multicenter N2M2/NOA20 trial we validate that edema and microvascular pathology are associated with poor prognosis in glioblastoma patients treated with checkpoint immunotherapy and that patients without edema have increased PFS.
We develop a customizable imaging platform to map drug delivery to glioma with broad applicability in neuroscience and neurooncology.
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Details
- Title
- Multimodality mapping of immunotherapy distribution as a predictive marker in glioma
- Creators
- Jonas G Scheck - German Cancer Research CenterBerin Boztepe - University Hospital HeidelbergJulius M Kernbach - University Hospital HeidelbergKianush Karimian-Jazi - University Hospital HeidelbergLennart Heinz - University Hospital HeidelbergKatharina Schregel - University Hospital HeidelbergVolker Sturm - University Hospital HeidelbergMarianne Schell - Heidelberg UniversityJovana Bojcevski - Heidelberg UniversityManuel Fischer - University Hospital HeidelbergRosa Eurich - Heidelberg UniversityIsabel Poschke - Bernstein Center for Computational Neuroscience Heidelberg-MannheimJulius Schwarz - University Hospital HeidelbergDennis A Agardy - Heidelberg UniversitySimone Jünger - Institute of Neuroimmunology of the Slovak Academy of SciencesChristian Schulz - University Medical Centre MannheimFerdinand Althammer - University Hospital HeidelbergAlexander R Osidach - Drexel UniversityAmir Abdollahi - National Center for Tumor DiseasesLukas Bunse - Bernstein Center for Computational Neuroscience Heidelberg-MannheimVarun Venkataramani - DKFZ-ZMBH AllianceStefan M Pfister - Heidelberg UniversityFrank Winkler - University Hospital HeidelbergTobias Kessler - DKTK within DKFZ, Clinical Cooperation Unit Neurooncology, Heidelberg, GermanyWolfgang Wick - DKFZ-ZMBH AllianceSabine Heiland - University Hospital HeidelbergMichael Platten - University Hospital HeidelbergChristopher Rodell - Drexel UniversityMartin Bendszus - University Hospital HeidelbergIna Weidenfeld - Heidelberg UniversityMichael O Breckwoldt - Heidelberg University
- Publication Details
- Neuro-oncology (Charlottesville, Va.)
- Publisher
- OXFORD UNIV PRESS INC; CARY
- Number of pages
- 15
- Grant note
- SFB1366-Vascular Control of Organ Function: WP C01, 259332240, RTG2099, Hallmark of Skin Cancer, P14 DFG Project: ID 394046768 Emmy Noether program of the German Research Foundation: DFG, BR 6153/1-1 Dr. Rolf M. Schwiete Foundation and the Sonderfrderlinie "Neuroinflammation" of the Ministry of Science of Baden WrttembergElse Krner-Fresenius Stiftung: 2017-A25; 2019_EKMS.23; Else Krner Clinician Scientist professorship, 2024_EKCS.06 German Cancer Aid: 70113515 German Neurology SocietyDeutsche Forschungsgemeinschaft (German Research Foundation, DFG)-Project: ID 404521405 the German Ministry of Education and Science (National Center for Tumor Diseases Heidelberg NCT 3.0 program "Precision immunotherapy of brain tumors" and the DKTK program)SFB1389-UNITE Glioblastoma: WP A01, A03, A07, B01, B03, B06N, C01, C02, C05 Emmy Noether program: AL 2466/2-1
M.O.B. was supported by the Emmy Noether program of the German Research Foundation (DFG, BR 6153/1-1) and the Else Kroner-Fresenius Stiftung (2017-A25; 2019_EKMS.23; Else Kroner Clinician Scientist professorship, 2024_EKCS.06). J.G.S. was supported by a fellowship from the German Neurology Society. W.W., M.B., L.B., V.V., M.P., F.W., S.P., T.K., A.A., and M.O.B. were supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG)-Project ID 404521405, SFB1389-UNITE Glioblastoma (WP A01, A03, A07, B01, B03, B06N, C01, C02, C05). F.A. was supported by the Emmy Noether program (AL 2466/2-1). M.P. was supported by grants from Dr. Rolf M. Schwiete Foundation and the Sonderforderlinie "Neuroinflammation" of the Ministry of Science of Baden Wurttemberg; the German Ministry of Education and Science (National Center for Tumor Diseases Heidelberg NCT 3.0 program "Precision immunotherapy of brain tumors" and the DKTK program); the DFG Project ID 394046768 (SFB1366-Vascular Control of Organ Function, WP C01), Project ID 259332240 (RTG2099, Hallmark of Skin Cancer, P14) and received project funding for "regulation of tumor immunity through the integrated stress response (ISR) in myeloid cells" by the German Cancer Aid (70113515).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001707938400001
- Scopus ID
- 2-s2.0-105037747559
- Other Identifier
- 991022148042904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology
- Oncology