Poster Presentation Advances in Neuroblastoma Research Congress 2016

Increasing NAT (noradrenaline transporter) expression to enhance ¹³¹I-mIBG therapy is a targeted approach to improving survival and outcomes in children with high-risk neuroblastoma. Seprehvir (HSV1716) is a Δγ₁34.5 attenuated HSV currently in a pediatric phase 1 clinical trial (NCT00931931). HSV1716/NAT is a derivative of Seprehvir constructed to deliver NAT cDNA to cancer cells. Previous studies show increased antitumor effects in glioma and melanoma xenografts exposed to ¹³¹I-mIBG and HSV1716/NAT.¹ We sought to determine the antitumor efficacy of the oncolytic virus HSV1716/NAT in combination with ¹³¹I-mIBG in preclinical models of neuroblastoma. We determined endogenous NAT expression in 12 neuroblastoma cell lines and in xenograft tumors grown in athymic nude mice by qRT-PCR. Gene transfer, viral production, and cytotoxicity assays demonstrated each cell lines’ response to HSV1716/NAT. We exposed neuroblastoma cells and xenografts in mice to HSV1716NAT and/or ¹³¹I-mIBG to determine differences in cytotoxicity and ¹³¹I-mIBG uptake. We found variation in endogenous NAT mRNA expression, in HSV1716/NAT susceptibility and permissivity, in effective NAT production, and in radiation sensitivity among the neuroblastoma cell lines. Neuroblastoma cells and xenograft tumors infected with HSV1716/NAT showed increased NAT mRNA expression, increased specific uptake of ¹³¹I-mIBG via NAT (see Fig 1), and increased cytotoxicity with ¹³¹I-mIBG. We are currently evaluating animal survival in mice with neuroblastoma xenografts exposed to HSV1716/NAT, ¹³¹I-mIBG, and the combination of HSV1716/NAT and ¹³¹I-mIBG. We aim to translate this project into a clinical trial with potential to expand to other pediatric tumor types.