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

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

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 chil...

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Published in:Scientific reports Vol. 8; no. 1; pp. 13930 - 10
Main Authors: Friedman, Gregory K., Bernstock, Joshua D., Chen, Dongquan, Nan, Li, Moore, Blake P., Kelly, Virginia M., Youngblood, Samantha L., Langford, Catherine P., Han, Xiaosi, Ring, Eric K., Beierle, Elizabeth A., Gillespie, G. Yancey, Markert, James M.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 17-09-2018
Nature Publishing Group
Subjects:
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59/5
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692/4028/67/1922
Brain cancer
Brain tumors
Children
Clinical trials
Glioblastoma
Herpes simplex
Humanities and Social Sciences
Interleukin 12
Morbidity
multidisciplinary
Nectin
Oncolysis
Patients
Pediatrics
Science
Science (multidisciplinary)
Tumors
Xenografts
Adult Tumor Cells
Herpes Virus Entry Mediator (HVEM)
Adult Glioblastoma
Pediatric Embryonal Tumors
Brain Tumor Xenografts
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Summary: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-32353-x