Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas

N Engl J Med. 2021 Apr 29;384(17):1613-1622. doi: 10.1056/NEJMoa2024947. Epub 2021 Apr 10.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / pathology
  • Brain Neoplasms / radiotherapy
  • Brain Neoplasms / therapy*
  • Child
  • Child, Preschool
  • Combined Modality Therapy
  • Female
  • Glioma / diagnostic imaging
  • Glioma / pathology
  • Glioma / radiotherapy
  • Glioma / therapy*
  • Humans
  • Kaplan-Meier Estimate
  • Killer Cells, Natural
  • Leukocyte Count
  • Male
  • Oncolytic Virotherapy* / adverse effects
  • T-Lymphocytes

Associated data

  • ClinicalTrials.gov/NCT02457845