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.
Highlights
Compared to GM-CSF alone in advanced melanoma[5]
These viruses were chosen because of their clinical relevance; G207 is currently in a phase I clinical trial in children with recurrent or progressive supratentorial malignant brain tumors (NCT02457845), and M002 is identical to M032, which is currently in a phase I clinical trial in adults with recurrent malignant high-grade glioma (NCT02062827), except M002 expresses the murine IL-12 transgene and M032 expresses the human IL-12 transgene[10,11]
The pediatric tumor cells were highly sensitive to both G207 and M002; at 3.3 plaque-forming units (PFU)/cell, only 2.1–31.1% (Fig. 1A) and 1.2–34.8% (Fig. 1B) of cells were alive at 72 hours after infection, respectively
Summary
Compared to GM-CSF alone in advanced melanoma[5]. Deletion of the γ134.5 gene prevents a productive infection in normal brain cells through PKR-mediated translational arrest while maintaining the virus’ oncolytic activity against cancer cells which harbor defective signaling pathways or activating ras mutations that suppress cellular host antiviral responses[6,7,8]. Two γ134.5-deleted viruses, G207, which contains a lacZ insertion within the UL39 gene that encodes viral ribonucleotide reductase, and M032, which expresses human IL-12, are currently being studied in a phase I brain tumor clinical trial in children (clinicaltrials.gov NCT02457845) and adults (NCT02062827) respectively[10,11]. In the current study, we sought to define and compare sensitivity patterns of a panel of patient-derived xenografts including pediatric embryonal brain tumors, pediatric high-grade glial tumors, and adult glioblastoma, using clinically relevant oHSVs G207 and M002 (differs from M032 only by expressing murine IL-12 transgene instead of the human transgene) and to determine if the primary HSV-1 entry molecule nectin-1 (CD111) may be a useful biomarker to predict the response of malignant brain tumors to oHSV
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