TMIC-104. Anti-Angiogenic Treatment for Glioblastoma Leads to Molecular Rewiring and an Increased Immune Microenvironment Response – A Transcriptomic Analysis

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Given its highly vascularized nature, anti-angiogenic therapy has been a topic of interest in GBM research, and therapeutic agents targeting various steps of the vascular endothelial growth factor (VEGF) signaling pathway have been evaluated in clinical trials. Bevacizumab, a humanized monoclonal antibody against VEGF is currently in use for the treatment of recurrent GBM, but it unfortunately has not demonstrated a meaningful impact on overall survival in patients. Objective: As there are over forty ongoing trials at various stages in the United States that are exploring the use of biologics such as anti-VEGF and tyrosine kinase inhibitors as mono- or dual therapies, a better understanding of how tumors escape from anti-VEGF therapy will allow the development of more effective combination strategies to improve patient outcomes. METHODS We utilized an intracranial mouse tumor model to investigate mechanisms of resistance to anti-angiogenic therapy. Mice were treated with 25mg/kg weekly injections of aflibercept or control antibodies. Following treatment, tumors were subjected to RNA sequencing, and immune cell recruitment was one of the top differentially expressed pathways found post-aflibercept treatment. Immune cells increased following aflibercept treatment, with high populations of microglia found near the tumor cells. RESULTS Treatment with bevacizumab and aflibercept increased recruitment of immune cell populations, including microglia. These findings were corroborated in patient tumor samples, which showed parallel patterns of immune cell infiltration, suggesting a conserved mechanism of resistance across models. CONCLUSION Anti-angiogenic therapy in an intracranial animal model leads to significant changes in immune infiltration. Staining of patient samples confirms this change, warranting further investigation into the role of microglia in chemoresistance and their potential as a novel therapeutic target.