TY  - JOUR
AU  - Scheck, Jonas
AU  - Boztepe, Berin
AU  - Kernbach, Julius M
AU  - Karimian-Jazi, Kianush
AU  - Heinz, Lennart
AU  - Schregel, Katharina
AU  - Sturm, Volker
AU  - Schell, Marianne
AU  - Bojcevski, Jovana
AU  - Fischer, Manuel
AU  - Eurich, Rosa
AU  - Poschke, Isabel
AU  - Schwarz, Julius
AU  - Agardy, Dennis A
AU  - Jünger, Simone
AU  - Schulz, Christian
AU  - Althammer, Ferdinand
AU  - Osidach, Alexander R
AU  - Abdollahi, Amir
AU  - Bunse, Lukas
AU  - Venkataramani, Varun
AU  - Pfister, Stefan M
AU  - Winkler, Frank
AU  - Kessler, Tobias
AU  - Wick, Wolfgang
AU  - Heiland, Sabine
AU  - Platten, Michael
AU  - Rodell, Christopher
AU  - Bendszus, Martin
AU  - Weidenfeld, Ina
AU  - Breckwoldt, Michael
TI  - Multimodality mapping of immunotherapy distribution as a predictive marker in glioma.
JO  - Neuro-Oncology
VL  - nn
SN  - 1522-8517
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2026-00015
SP  - nn
PY  - 2025
N1  - #EA:E210#LA:E210#LA:D170# / epub
AB  - 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.
KW  - blood-brain barrier disruption (Other)
KW  - drug distribution (Other)
KW  - glioma (Other)
KW  - immunotherapy (Other)
KW  - tumor microenvironment (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41476211
DO  - DOI:10.1093/neuonc/noaf295
UR  - https://inrepo02.dkfz.de/record/307510
ER  -