139 - Zika Virus as an Oncolytic Treatment for Diffuse Intrinsic Pontine Glioma (DIPG)

Publication Number: 2133.139

Joseph Mazar, Nemours Children's Hospital, Davenport, FL, United States; Emma Sutton, Nemours Children's Hospital, Orlando, FL, United States; Jeanne K. Brooks, Nemours Children's Hospital, Orlando, FL, United States; Rosa Rosario, Nemours Children's Hospital, Orlando, FL, United States; Amanda G. Lasseter, Nemours Children's Hospital, Orlando, FL, United States; Simon P. Cooper, Nemours Children's Hospital, Orlando, FL, United States; Lindsay Poulos, Nemours Children's Hospital, Orlando, FL, United States; Tamarah Westmoreland, Nemours Children's Hospital, Orlando, FL, United States

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem tumor affecting ~300 children in the United States per year. Despite advances in DIPG biology, treatment is ineffective, with a median survival of less than one year. We have previously shown that neuroblastoma cells are permissive to ZIKV infection. Because of the common lineage between neuroblasts and glial cells, we predicted and observed that DIPG cells are permissive as well.

Objective: In this study, we explore the mechanism of action of ZIKV sensitivity as well as a study of the strain-specific effects of ZIKV on DIPG. We also assessed the feasibility of orthotopic intracranial models for the therapeutic treatment of DIPG in its native tumor microenvironment. Validation of tumor elimination after the application of ZIKV could offer a new therapy for the treatment of this deadly disease.

Design/Methods: We performed a comparison of ZIKV-sensitive DIPG (SF8628) cells and ZIKV-resistant neuroblastoma (SK-N-AS) cells to assess expression of the Type I Interferon (IFN-I) pathway. We likewise treated cells with interferon α/β prior to the introduction of ZIKV and measured changes in cell death. A comparative genomic analysis of different ZIKV strains was performed of the primary regions of prevalence: Africa, Central/South America, and Southeast Asia. And finally, DIPG was introduced stereotaxically into the pons of nude mice and treated with ZIKV.

Results: ZIKV-sensitive DIPG cells were found to have systemically poor expression of IFN-I pathway genes compared to ZIKV-resistant cells. Likewise, pre-treatment of cells with INF-I yielded a dose-dependent reduction of cell death following treatment with ZIKV. Comparative genomic analysis of different ZIKV strains generated a phylogenetic tree indicating correlation with geographical location and rate of cell killing. In addition, in vivo intracranial surgery models showed positive engraftment of tumors and treatment with ZIKV yielded elimination of tumor mass.

Conclusion(s): The efficacy of Zika virus as a treatment for human DIPG cells is comparable to results seen in neuroblastoma. Defects identified in the IFN-I pathway provide a possible molecular mechanism for ZIKV susceptibility and a comparison of strain phylogeny optimized the targeted killing of tumor cells, with many strains obtaining ~100% cell death. Most importantly, the establishment of a DIPG intracranial model allowed for an in vivo comparison of strain efficacy, with some strains yielding total elimination of tumor mass.