PCM-09COMPARISON OF THE SENSITIVITIES OF PEDIATRIC HIGH-GRADE BRAIN TUMOR VERSUS ADULT GLIOBLASTOMA XENOGRAFTS TO ENGINEERED ONCOLYTIC HERPES SIMPLEX VIROTHERAPY

Abstract

Outcomes for a subset of children with malignant high-grade brain tumors are unacceptably dismal. Children who survive often suffer lifelong neurotoxicities from current therapies. Oncolytic herpes simplex virus (oHSV) G207 has been successfully engineered to contain deletions of both copies of the γ134.5 neurovirulence gene to abrogate infection in normal cells while maintaining the virus' ability to kill cancer cells. Three phase I trials of G207 given alone or with radiation in adults with recurrent glioblastoma conclusivelydemonstrated safety, and17 of 35 subjects had radiographic evidence of tumor response, including two long-term survivors. We compared sensitivities of 8 patient-derived pediatric high-grade tumor xenografts (4 medulloblastoma, 2 glioblastoma, 1 supratentorial PNET, and 1 ependymoma) to G207 with that of 6 adult glioblastoma xenografts. Disaggregated xenograft tumor cells were examined for expression of the primary HSV entry molecule CD111 by flow cytometry and were tested for in vitro sensitivity to G207 by alamarBlue assay. On average, pediatric tumor cells expressed CD111 in significantly greater amounts than adult glioblastoma cells (83.0±15.3 versus 26.9±10.9; p < 0.0001) and were 22-fold more sensitive than adult tumor cells with significantly lower lethal doses required to kill 50% of the cells (p = 0.0006). These data suggest that pediatric brain tumors are more likely to be sensitive to oHSV than adult glioblastoma, and pediatric patients may be the ideal candidates for this therapy. A phase I trial of G207 in children with recurrent supratentorial malignant tumors (NCT02457845) is ongoing at Children's of Alabama.