TMIC-66. Multimodality mapping of immunotherapy distribution as a prognostic marker in glioma

Abstract Glioblastoma (GBM) is notoriously resistant to treatment. Scarce T cell infiltration, immunosuppressive tumor-associated macrophages (TAMs) and ineffective drug delivery drive tumor progression. To overcome resistance, suitable imaging biomarkers that guide therapy development are essential to ultimately improve outcomes. We find that in contrast to the susceptible Gl261 glioma model, SB28 gliomas are characterized by poor immunogenicity due to low MHC expression and resistance to Toll-like receptor (TLR) 7 targeted therapy by CDNP-R848 nanoparticles. SB28 resistance is driven by strong microvascular pathology, vasogenic edema and drug off-targeting to tumor adjacent white matter tracts. To tackle therapeutic resistance and map drug delivery to the TME, we developed a 3D MRI-lightsheet microscopy platform (MR-LSM) to monitor immunotherapy distribution at the cellular level. Using this platform we find that 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 off-targeting of immunotherapies. Mechanistically, tumor control is orchestrated by vascular normalization, enhanced cytotoxic CD8+ T cell influx and a proinflammatory shift of myeloid cells along with strong IL-12 /IL-13 upregulation and normalization of drug delivery. In a translational analysis of the multicenter N2M2/NOA20 trial we validate that edema and microvascular pathology are also associated with poor prognosis in glioblastoma patients treated with anti-PD-L1 immunotherapy and that patients without edema have increased progression free survival (PFS). In summary, we develop a customizable imaging platform (3D-MR-LSM) to three-dimensionally map drug delivery to the central nervous system (CNS) with broad applicability in neuroscience and oncology.