LAUSR

Background and Purpose: Radiation therapy is the traditional and only therapy that offers benefits to patients with diffuse intrinsic pontine gliomas (DIPG) which are highly aggressive pediatric central nervous system tumors without known curative therapies. However, unfortunately, efficacy of radiation therapy is transient. Seneca Valley virus-001(SVV-001) is a novel non-pathogenic oncolytic piconavirus that can be systemically administered and pass through brain blood barrier (BBB). Phase I clinical trial of SVV has proven its efficacy in adults patients with cancers with neuroendocrine features and in pediatric patients with non-central nerve system (CNS) tumors. We sought to examine if combining ionizing radiation with an oncolytic virus SVV-001 would lead to synergistically enhanced tumor cell killing and significantly improve therapeutic efficacy in vivo in DIPG patient tumor-derived intra-brain stem orthotopic xenograft mouse models (PDOX). Methods: By infecting PDOX derived tumor cells with green fluorescent protein (GFP)-coupled SVV (SVV-GFP) or SVV-001, in vitro virus infection and anti-tumor activity of SVV were examined by cell viability assay, Western Blotting for apoptosis and autophagy-related protein and immunohistochemistry (IHC) staining or Flow cytometry for cell mitochondria content. In vivo therapeutic efficacy was evaluated by systemic administration of SVV into PDOX derived DIPG xenografts alone or in combination with irradiation. Results: We first had established a novel panel of nine PDOX derived orthotopic xenograft mouse models of DIPG. Our data confirmed that SVV can infect and efficiently kill DIPG tumor cells in vitro by inducing apoptosis and autophagy, leading to improved animal survival in a subset of DIPG xenograft models. We found that the lack of mitochondria in the xenograft tumor cells in vivo impaired the intracellular replication of SVV-001 and subsequently compromised its oncolytic cell killing of tumor cells in vivo. Radiation induced elevated mitochondria biogenesis in tumor cells therefore boosted SVV oncolysis of tumor cells. Moreover, combining fractionated radiation with single i.v.injection of SVV led to significant improvement of animal survival in a subset of DIPG models. Conclusion: SVV-001 killed DIPG xenograft cells in vitro. Radiation activated mitochondria content of tumor cells in vivo, which restored impaired SVV oncolytic function.Combining radiation with single systemic administration of SVV synergistically enhanced animal survival in a subset of DIPG xenograft models. Citation Format: Yuchen Du. Combination ionizing radiation and oncolytic Seneca Valley virus injection enhances tumor cell killing of pediatric gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 706. doi:10.1158/1538-7445.AM2017-706