Summary
Background
The outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical average survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or “cold,” with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are very sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which has no genes necessary for replication in normal brain tissue.
Methods
We conducted a phase 1 study of G207, which used a 3 + 3 design with four dose groups of children and adolescents with biopsy-confirmed recurrent or progressive supratentoral brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The next day they received G207 (107 of 108 plaque-forming units) by infusion at a controlled rate over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after administration of G207. Viral poisoning of saliva, conjunctiva and blood was assessed by culture and polymerase chain reaction test. Adapted tissue samples before and after treatment were examined on immunohistological analysis for lymphocytes infiltrating tumors.
Results
Twelve patients aged 7 to 18 years with high-grade glioma received G207. No dose-limiting toxic effects or serious side effects were attributed to G207 by the investigators. Twenty grade 1 side effects may be related to G207. No virus shedding was detected. Radiographic, neuropathological or clinical reactions were observed in 11 patients. The mean overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); On 5 June 2020, a total of 4 out of 11 patients were still alive 18 months after G207 treatment. G207 significantly increased the number of tumor-infiltrating lymphocytes.
Conclusions
Intratumoral G207 alone and with radiation had an acceptable side effect profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunological “cold” tumors into “warm” ones. (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.)