Targeting High-Risk Neuroblastoma Patient-Derived Xenografts with Oncolytic Virotherapy

SIMPLE SUMMARY: More than half of children with high-risk neuroblastoma will not survive despite aggressive treatment regimens. The discovery of suitable novel therapies that target high-risk disease remain limited. Oncolytic virotherapy employs common viruses, such as herpes simplex virus. These viruses are modified to solely target cancer cells and avoid damage to healthy cells. The previous work of others and ourselves has shown oncolytic herpes simplex viruses (oHSVs) are effective in targeting cultured neuroblastoma cancer cell lines, but to our knowledge, no one has demonstrated the effects of oHSV in neuroblastoma patient-derived xenograft cells. Herein, we show that oHSV works well in high-risk neuroblastoma patient-derived xenografts and provide critical preclinical evidence to translate this therapy to a clinical setting. ABSTRACT: Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution. Oncolytic viruses attack tumor cells in two ways: direct infection of tumor cells leading to cytolysis, and production of a debris field that stimulates an anti-tumor immune response. Our group has previously shown that M002, an oncolytic herpes simplex virus (oHSV), genetically engineered to express murine interleukin-12 (mIL-12), was effective at targeting and killing long term passage tumor cell lines. In the current study, we investigated M002 in three neuroblastoma patient-derived xenografts (PDXs). PDXs better recapitulate the human condition, and these studies were designed to gather robust data for translation to a clinical trial. We found that all three PDXs expressed viral entry receptors, and that the virus actively replicated in the cells. M002 caused significant tumor cell death in 2D culture and 3D bioprinted tumor models. Finally, the PDXs displayed variable susceptibility to M002, with a more profound effect on high-risk neuroblastoma PDXs compared to low-risk PDX. These findings validate the importance of incorporating PDXs for preclinical testing of oncolytic viral therapeutics and showcase a novel technique, 3D bioprinting, to test therapies in PDXs. Collectively, our data indicate that oHSVs effectively target high-risk neuroblastoma, and support the advancement of this therapy to the clinical setting.