MODL-19. DEVELOPMENT OF A RECURRENT GLIOBLASTOMA MURINE MODEL FOLLOWING SURGICAL RESECTION: INVESTIGATING THE TUMOR-IMMUNE MICROENVIRONMENT TO EVALUATE NOVEL PERIOPERATIVE THERAPIES

Abstract

Abstract BACKGROUND Most glioblastoma (GBM) patients experience tumor recurrence following standard-of-care treatment which includes tumor resection, radiation, and chemotherapy with concomitant and adjuvant temozolomide. Currently, no murine surgical GBM resection models to evaluate novel therapies exist and understanding of postsurgical tumor microenvironment (TME) has yet to be fully elucidated in pre-clinical GBM models. METHODS GL261 GBM cells were orthotopically implanted in C57BL/6 mice on day 1. On day 14, tumor resection was performed using the NICO Murine Neuroscience System, an automated, intraoperative, pre-clinical surgical resection system designed to minimize damage to surrounding tissue thus preventing the need for animal sacrifice. Standard T2-MRI and Terason uSmart 3200T ultrasound system were used to analyze tumor size following resection and recurrent growth. Immunological and biochemical assays were performed to explore local TME. RESULTS We observed that surgically resected GL261 GBM mice survived 55 + 8 days whereas mice with unresected GBM survived 35 + 7 days following tumor implantation. This new preclinical surgical resection recurrent immunocompetent GBM (Sur-rGBM) model was used for analyzing TME. Our results demonstrated significant changes in TME, such as an increase in astrocytic activation (GFAP+), increased microglia/macrophage (CD11b+, and IBA-1+) infiltration to surrounding tissue, increase in M2 macrophage (TGM2+ and CCL22+) and NK regulatory cells (CDC 26 +), and increased angiogenesis (VEGF) in Sur-rGBM as compared to unresected GBM. We also observed increased proliferation (Ki-67) and upregulation of stem cell markers CD133, Nestin, and Olig2 at the protein level. CONCLUSION Our data demonstrated the upregulation of tumor-promoting activation factors in Sur-rGBM as compared to unresected GBM. Currently, the Sur-rGBM model does not fully resemble the entire treatment regimen offered to GBM patients. Thus, our future aim is to further refine this resection model and assess adjuvant therapies at different time points along disease progression without needing to sacrifice the animal for analysis of tissue.