Epen-09. Targeting Ephb2/Abl1 Restores Anti-Tumor Immunity in a Preclinical Model of Ependymoma

Abstract BACKGROUND Ependymoma (EPN) is a childhood brain cancer that is often resistant to cytotoxic therapies. Molecular profiling has led to a better understanding of unique EPN subtypes and revealed a critical role of EPHB2 in driving disease. With this in mind, new treatments for EPN are desperately needed and should be developed in a molecular subtype-specific fashion. METHODS We developed a syngeneic mouse model of EPHB2-driven genetically engineered EPN tumor cells. We performed transcriptomic profiling and analysis of EPHB2-driven murine EPN tumors and human EPN datasets to reveal multiple protein kinases as potential druggable targets. After identifying the tyrosine kinase inhibitor, Dasatinib, as a potentially effective FDA-approved agent, we measured changes in the murine microenvironment during EPN growth and after Dasatinib treatment. RESULTS We determined that Dasatinib inhibited the growth of EPN both in vitro and in vivo, through blocking EPHB2 and ABL1 signaling. Furthermore, we identified an increased frequency of immunosuppressive M2-like tumor- associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. However, treatment with Dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an anti-tumor M1-like phenotype and increasing CD8 T cell activation. In addition, Dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 T cells compromised the durability of response and reduced overall survival. CONCLUSION In conclusion, these data indicate that Dasatinib may be an effective therapy for EPHB2-driven molecular subgroup of EPN by activating the anti-tumor immune response and support further investigation of Dasatinib in clinical trials.