Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression

Gregory K. Friedman, Joshua D. Bernstock, Dongquan Chen, Li Nan, Blake P. Moore, Virginia M. Kelly, Samantha L. Youngblood, Catherine P. Langford, Xiaosi Han, Eric K. Ring, Elizabeth A. Beierle, G. Yancey Gillespie, James M. Markert

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9 Scopus citations

Abstract

Pediatric high-grade brain tumors and adult glioblastoma are associated with significant morbidity and mortality. Oncolytic herpes simplex virus-1 (oHSV) is a promising approach to target brain tumors; oHSV G207 and M032 (encodes human interleukin-12) are currently in phase I clinical trials in children with malignant supratentorial brain tumors and adults with glioblastoma, respectively. We sought to compare the sensitivity of patient-derived pediatric malignant brain tumor and adult glioblastoma xenografts to these clinically-relevant oHSV. In so doing we found that pediatric brain tumors were more sensitive to the viruses and expressed significantly more nectin-1 (CD111) than adult glioblastoma. Pediatric embryonal and glial tumors were 74-fold and 14-fold more sensitive to M002 and 16-fold and 6-fold more sensitive to G207 than adult glioblastoma, respectively. Of note, pediatric embryonal tumors were more sensitive than glial tumors. Differences in sensitivity may be due in part to nectin-1 expression, which predicted responses to the viruses. Treatment with oHSV resulted in prolonged survival in both pediatric and adult intracranial patient-dervied tumor xenograft models. Our results suggest that pediatric brain tumors are ideal targets for oHSV and that brain tumor expression of nectin-1 may be a useful biomarker to predict patient response to oHSV.

Original languageEnglish (US)
Article number13930
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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    Friedman, G. K., Bernstock, J. D., Chen, D., Nan, L., Moore, B. P., Kelly, V. M., Youngblood, S. L., Langford, C. P., Han, X., Ring, E. K., Beierle, E. A., Gillespie, G. Y., & Markert, J. M. (2018). Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Scientific reports, 8(1), [13930]. https://doi.org/10.1038/s41598-018-32353-x