Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas

G. K. Friedman, J. M. Johnston, A. K. Bag, J. D. Bernstock, R. Li, I. Aban, K. Kachurak, L. Nan, K. D. Kang, S. Totsch, C. Schlappi, A. M. Martin, D. Pastakia, R. McNall-Knapp, S. Farouk Sait, Y. Khakoo, M. A. Karajannis, K. Woodling, J. D. Palmer, D. S. OsorioJ. Leonard, M. S. Abdelbaki, A. Madan-Swain, T. P. Atkinson, R. J. Whitley, J. B. Fiveash, J. M. Markert

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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 tumorinfiltrating 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 (107 or 108 plaqueforming 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- A nd 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 tumorinfiltrating 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." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).

Original languageEnglish
Pages (from-to)1613-1622
Number of pages10
JournalNew England Journal of Medicine
Volume384
Issue number17
DOIs
StatePublished - Apr 29 2021

Fingerprint

Dive into the research topics of 'Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas'. Together they form a unique fingerprint.

Cite this