Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas Journal Article
| Authors: | Friedman, G. K.; Johnston, J. M.; Bag, A. K.; Bernstock, J. D.; Li, R.; Aban, I.; Kachurak, K.; Nan, L.; Kang, K. D.; Totsch, S.; Schlappi, C.; Martin, A. M.; Pastakia, D.; McNall-Knapp, R.; Farouk Sait, S.; Khakoo, Y.; Karajannis, M. A.; Woodling, K.; Palmer, J. D.; Osorio, D. S.; Leonard, J.; Abdelbaki, M. S.; Madan-Swain, A.; Atkinson, T. P.; Whitley, R. J.; Fiveash, J. B.; Markert, J. M.; Gillespie, G. Y. |
| Article Title: | Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas |
| Abstract: | 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." |
| Journal Title: | New England Journal of Medicine |
| Volume: | 384 |
| Issue: | 17 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2021-04-29 |
| Start Page: | 1613 |
| End Page: | 1622 |
| Language: | English |
| ACCESSION: | WOS:000640368200001 |
| DOI: | 10.1056/NEJMoa2024947 |
| PROVIDER: | wos |
| PUBMED: | 33838625 |
| PMCID: | PMC8284840 |
| Notes: | Article -- Source: Wos |
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66Farouk Sait
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