Neuro-oncology · 2026
Multimodality mapping of immunotherapy distribution as a predictive marker in glioma.
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Scheck Jonas G, Boztepe Berin, Kernbach Julius M, Karimian-Jazi Kianush, Heinz Lennart, Schregel Katharina, Sturm Volker, Schell Marianne, Bojcevski Jovana, Fischer Manuel, Eurich Rosa, Poschke Isabel, Schwarz Julius, Agardy Dennis A, Jünger Simone, Schulz Christian, Althammer Ferdinand, Osidach Alexander R, Abdollahi Amir, Bunse Lukas, Venkataramani Varun, Pfister Stefan M, Winkler Frank, Kessler Tobias, Wick Wolfgang, Heiland Sabine, Platten Michael, Rodell Christopher, Bendszus Martin, Weidenfeld Ina, Breckwoldt Michael O
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: . We develop a customizable imaging platform to map drug delivery to glioma with broad applicability in neuroscience and neuro-oncology.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: . We develop a customizable imaging platform to map drug delivery to glioma with broad applicability in neuroscience and neuro-oncology.