Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 384, Issue 17, Pages 1613-1622Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa2024947
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Funding
- Food and Drug Administration [R01FD005379]
- National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) [UL1TR003096]
- Cannonball Kids' Cancer Foundation
- Rally Foundation for Childhood Cancer Research
- Department of Defense [W81XWH-15-1-0108]
- Andrew McDonough B+ Foundation
- Kaul Pediatric Research Institute
- NIH/National Cancer Institute Cancer Center Support Grants [P30CA013148, P30CA008748]
- Kelsie's Crew, Eli's Block Party Childhood Cancer Foundation
- Eli Jackson Foundation
- Jaxon's F.R.O.G. Foundation
- Battle for a Cure Foundation
- Sandcastle Kids
- Hyundai Hope on Wheels
- St. Baldrick's Foundation
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The study conducted a phase 1 trial of G207 in children and adolescents with recurrent or progressive supratentorial brain tumors, showing an acceptable adverse-event profile and evidence of responses. G207 was able to convert immunologically cold tumors to hot.
BACKGROUND Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall 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 highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10(7) or 10(8) plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically cold tumors to hot.
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