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000307510 245__ $$aMultimodality mapping of immunotherapy distribution as a predictive marker in glioma.
000307510 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000307510 520__ $$aScarce T cell infiltration, immunosuppressive tumor-associated macrophages and ineffective drug delivery drive glioma progression and limit treatment efficacy. Mapping immunotherapy distribution by multimodality imaging might be a biomarker that could aid tumor monitoring and guide therapy development.To assess drug delivery, we developed a MRI-lightsheet microscopy platform (MR-LSM) to monitor immunotherapy at the cellular level in two immunocompetent glioma models (Gl261, SB28). The atezolizumab (PD-L1 inhibitor) subgroup of the multicenter N2M2/NOA20 trial in MGMT unmethylated GBM patients was assessed by CNN analysis and correlated to progression free survival.In contrast to the conventional Gl261 glioma model, SB28 gliomas are characterized by poor immunogenicity and resistance to Toll-like receptor (TLR) 7 targeted therapy delivered by CDNP-R848 nanoparticles. SB28 resistance is driven by microvascular pathology, vasogenic edema and drug off-targeting to peritumoral edema and white matter tracts. Vascular endothelial growth factor (VEGF) inhibition in conjunction with irradiation and dual immunotherapy (DIR) targeting innate (CDNP-R848) and adaptive immunity (anti-CTLA-4) breaks resistance, increases survival and reverses drug off-targeting. Mechanistically, tumor control is orchestrated by vascular normalization, enhanced CD8+ T cell influx and a proinflammatory shift of myeloid cells along with strong IL-12/IL-13 upregulation. In a translational analysis of the multicenter N2M2/NOA20 trial we validate that edema and microvascular pathology are associated with poor prognosis in glioblastoma patients treated with checkpoint immunotherapy and that patients without edema have increased PFS.We develop a customizable imaging platform to map drug delivery to glioma with broad applicability in neuroscience and neurooncology.
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000307510 650_7 $$2Other$$ablood-brain barrier disruption
000307510 650_7 $$2Other$$adrug distribution
000307510 650_7 $$2Other$$aglioma
000307510 650_7 $$2Other$$aimmunotherapy
000307510 650_7 $$2Other$$atumor microenvironment
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000307510 7001_ $$aKernbach, Julius M$$b2
000307510 7001_ $$aKarimian-Jazi, Kianush$$b3
000307510 7001_ $$aHeinz, Lennart$$b4
000307510 7001_ $$aSchregel, Katharina$$b5
000307510 7001_ $$aSturm, Volker$$b6
000307510 7001_ $$aSchell, Marianne$$b7
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000307510 7001_ $$aFischer, Manuel$$b9
000307510 7001_ $$aEurich, Rosa$$b10
000307510 7001_ $$0P:(DE-He78)e9c55f46b4b06cf835834ee7e3e00db8$$aPoschke, Isabel$$b11$$udkfz
000307510 7001_ $$aSchwarz, Julius$$b12
000307510 7001_ $$0P:(DE-He78)661f199a31f6d53b12f3c348103dc4e4$$aAgardy, Dennis A$$b13$$udkfz
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000307510 7001_ $$aSchulz, Christian$$b15
000307510 7001_ $$aAlthammer, Ferdinand$$b16
000307510 7001_ $$aOsidach, Alexander R$$b17
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000307510 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b21$$udkfz
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000307510 7001_ $$0P:(DE-He78)5c2c9cbe6ce72553684d82d94aebdadd$$aKessler, Tobias$$b23$$udkfz
000307510 7001_ $$0P:(DE-He78)92e9783ca7025f36ce14e12cd348d2ee$$aWick, Wolfgang$$b24$$udkfz
000307510 7001_ $$aHeiland, Sabine$$b25
000307510 7001_ $$0P:(DE-He78)5ef8651b0f857b9c640aa5b1498c43b5$$aPlatten, Michael$$b26$$udkfz
000307510 7001_ $$aRodell, Christopher$$b27
000307510 7001_ $$aBendszus, Martin$$b28
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