HG-22: TREATMENT OF INTRA-BRAIN STEM XENOGRAFT MOUSE MODELS OF DIPG WITH COMBINED RADIATION AND ONCOLYTIC VIRAL THERAPY

BACKGROUND AND PURPOSE: Radiation is the only therapy that offers clinical benefits to patients with diffuse intrinsic pontine glioma (DIPG), although these effects are not curative. Seneca Valley virus-001 (SVV-001) is a non-pathogenic oncolytic piconavirus able to penetrate the blood-brain barrier. A phase I clinical trial of SVV-001 showed efficacy in adults with neuroendocrine tumors and children with extra-CNS solid tumors. We examined if combining radiation with SVV-001 would enhance tumor cell killing and prolong survival in DIPG patient tumor-derived intra-brain stem orthotopic xenograft (PDOX) mouse models. METHODS: PDOX-derived DIPG cells were infected in vitro with SVV-001. Viral infection and SVV-001 activity were examined by cell viability assay, apotosis and autophagy with western blotting, and cell mitochondrial content with immunohistochemical staining and flow cytometry. In vivo therapeutic efficacy was evaluated by systemic administration of SVV-001 into DIPG PDOX models alone or combined with radiation. RESULTS: SVV-001 infected and efficiently killed DIPG cells in vitro through induction of apoptosis and autophagy. In vivo, a lack of tumor cell mitochondria impaired SVV-001's intracellular replication and compromised its oncolytic cell killing of target tumor cells. Radiation induced mitochondrial biogenesis in tumor cells and consequently boosted SVV-001's in vivo oncolytic effects. Combining radiation with SVV-001 injection improved animal survival in a subset of DIPG models. CONCLUSION: SVV-001 killed DIPG xenograft cells in vitro. Radiation increased mitochondria content of tumor cells in vivo, restoring impaired SVV-001 oncolytic function. Combining radiation with systemic administration of SVV-001 synergistically enhanced animal survival in DIPG xenograft models.