Oncolytic Virotherapy ‘Potential’ Demonstrated For Paediatric High-Grade Glioma

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Oncolytic virotherapy using a genetically engineered form of herpes simplex virus type 1 (HSV-1), given alone or with radiotherapy, has shown promise in a phase I trial as a novel treatment for recurrent or progressive paediatric high-grade glioma. 

Study findings for 12 children were presented at the virtual AACR Annual Meeting 2021 by Gregory Friedman, from the University of Alabama at Birmingham, USA, and simultaneously published in The New England Journal of Medicine. 

The authors believe that the oncolytic HSV-1 agent G207 “has the potential to overcome many treatment challenges posed by pediatric high-grade glioma”, such as delivery through the blood–brain barrier, a lack of actionable genetic alterations and immunological “cold” status with few tumour-infiltrating lymphocytes (TILs). 

The trial recruited patients aged 3–18 years old with a supratentorial high-grade glioma at least 1.0 cm in diameter after at least two (n=8) or three (n=4) treatments with chemotherapy, radiotherapy or surgery. 

The tumours included 10 glioblastomas, one anaplastic astrocytoma and one nonspecified high-grade glioma; 10 patients had tumours larger than 5.5 cm at screening, three had multifocal tumours and one patient had leptomeningeal spread. 

The participants were assigned to receive 107 (n=6) or 108 (n=6) plaque-forming units (PFU) of G207 given in 2.4 mL total volume over 6 hours via three or four intratumoural catheters. Half the patients in each PFU cohort also received 5 Gy of radiotherapy to the gross tumour volume within 24 hours of G207 delivery, explain Gregory Friedman and team. 

The surgical procedure was not associated with any neurological sequelae but there were two minor complications, a small catheter tract haemorrhage that did not require treatment and one cerebrospinal fluid leak at a catheter and biopsy site that required oversewing on day 8. 

All 20 reported adverse events (AEs) considered to be possibly attributable to G207 within 30 days of the procedure occurred at grade 1 and there were no dose-limiting or serious AEs, nor evidence of peripheral G207 shedding or viremia, the researchers say. 

The median overall survival (OS) after G207 treatment was 12.2 months, with four patients alive after 18.0 months of follow-up. 

While acknowledging the difficulty of direct comparisons with earlier treatments, the investigators point to a previously reported median OS of just 5.6 months for children who progressed after initial treatment of high-grade glioma. 

“As with other immunovirotherapies, determination of the timing of progression was difficult owing to pseudoprogression and mixed responses except when disease was stable”, observe Gregory Friedman et al. 

Nevertheless, they report that 11 of the 12 patients showed a radiographical, neuropathological or clinical response to treatment. 

Stable disease was detected at 1, 3, 5 and 12 months in 58%, 36%, 27% and 18% of patients, respectively. 

Imaging of two patients with stable disease showed “polycystic degradation” over time, say the researchers, corresponding with an improvement in performance score over time in one patient, accompanied by a response lasting 42 months, and stable disease for 12 months in the second patient. A third patient remained asymptomatic but showed clinical changes believed to be pseudoprogression, and this appeared to be confirmed by biopsy after 3 months. 

The researchers also compared T lymphocyte counts in four patients who underwent biopsy or resection following indeterminate imaging (n=3) or new-onset neurological symptoms (n=1). While pretreatment biopsies showed few TILs, biopsy samples taken 2–9 months after treatment showed “brisk infiltration of CD8+ cells”, indicating “an immune response to G207 and a shift to immunologically ‘hot’ tumors”, they say. 

There were also “substantive increases” in CD3+ and CD4+ TILs, as well as increases in CD138+ plasma cells in two patients, one of whom also had increases in CD20+ B lymphocytes. 

“Although rare subtypes of pediatric high-grade glioma may response to immunotherapy (e.g., hypermutated), pediatric high-grade gliomas are largely immunologically silent”, the authors note. 

“The informative difference in this trial is the large number of [TILs] induced by intratumoral G207 inoculation, although it remains unclear whether the infiltrates reflect a general inflammatory response or the response is indeed related to virus antigen or tumor antigen recognition.” 

A multi-institution phase II trial of G207 in paediatric high-grade glioma is now planned, Gregory Friedman et al say. 

References 

Friedman GK, Johnston JM, Bag AK, et al. Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas. N Engl J Med; Advance online publication 10 April 2021. DOI: 10.1056/NEJMoa2024947

Abstract CT018. Friedman GK, Johnston Jr JM, Bag AK, et al. Phase I immunovirotherapy trial of oncolytic HSV-1 G207 alone or combined with radiation in pediatric high-grade glioma. AACR Annual Meeting 2021; 10–15 April.