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 (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.).

Copyright © 2021 Massachusetts Medical Society.

Figures

Figure 1.. Enrollment, Treatment, and Analysis.

PFU denotes plaque-forming units.

Figure 2.. Kaplan–Meier Curve of Overall Survival Probability among Patients Treated with G207.

The median survival was 12.2 months (95% confidence interval, 8.0 to 16.4). Circles represent patients with censored data.

Figure 3.. Response in Patient 002 Treated with G207.

In the top row, post-gadolinium sagittal T1-weighted images show the decreased size of the enhancing component of the tumor with interval development of numerous enlarging cystic spaces where G207 was inoculated. In the bottom row, sagittal fluid-attenuated inversion recovery (FLAIR) images show an interval decrease in the size of the FLAIR hyperintense component of the tumor in the frontal and temporal lobes after G207 treatment. These changes corresponded with an increase in the performance score from 80 before treatment to 100 by 12 months after treatment (on a scale from 0 to 100, with higher scores indicating better function). The patient had a continuous response 42 months after G207 treatment without any additional therapy

Figure 4.. Immunohistologic Staining for CD8+ Cytotoxic T Lymphocytes in Matched Pre- and Post-treatment Tissue from Four Patients.

The left column shows the initial core biopsies before G207 administration; there were few immune-related cells, a finding consistent with immunologically silent or “cold” tumors. The other three columns show tumor tissues between 3 and 9 months after G207 administration from these same four patients. Post-G207 tissue revealed a brisk infiltration of CD8+ cells, which indicates an immune response to G207 and a shift to immunologically “hot” tumors. Photomicrographs were taken at low, medium, and high magnifications. Doses are in plaque-forming units (PFU) of G207 and in grays (Gy) of radiation.