In a phase I trial reported at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract CT018) and simultaneously published in The New England Journal of Medicine, Friedman et al found that oncolytic virotherapy with genetically engineered herpes simplex virus-1 (HSV-1) G207 produced responses and had manageable toxicity in pediatric patients with high-grade gliomas. 

Genetic engineering of G207 includes deletion of the diploid γ134.5 neurovirulence gene and disabling of viral ribonucleotide reductase via insertion of Escherichia coli lacZ. These alterations prevent productive infection in normal cells and permit replication in tumor cells.

As related by the investigators, pediatric high-grade gliomas are characteristically immunologically silent, or “cold,” containing few tumor-infiltrating lymphocytes. In addition to infection and direct lysing of tumor cells, G207 can reverse tumor immune evasion, increase cross-presentation of tumor antigens, and promote an antitumor immune response. In animal models, a single dose of radiation has been found to increase G207 efficacy by increasing replication and spread of the virus. The investigators stated that the hypothesis for the study was that “intratumoral G207 would increase the amount of tumor-infiltrating lymphocytes and thereby convert immunologically ‘cold’ pediatric brain tumors to ‘hot’ and ‘inflamed.’”

Study Details

In the study, 12 patients aged 7 to 18 years with recurrent or progressive high-grade gliomas underwent stereotactic placement of up to four intratumoral catheters. The following day, the patients received G207 in four dose cohorts at 10⁷ or 10⁸ plaque-forming units via 6-hour infusion. One cohort at each dose level received radiation at 5 Gy to the gross tumor volume within 24 hours after G207 administration.

Toxicity

G207 delivery was not associated with any dose-limiting toxicity or serious adverse events. The most common adverse events of any grade observed within 30 days after G207 treatment  irrespective of cause were postoperative hemorrhage (6 patients, all grade 1), vomiting (5 patients, all grade 1 or 2), fever (4 patients, all grade 1), and diarrhea (3 patients, all grade 1).

A total of seven grade 3 adverse events were observed (no grade 4 events), consisting of one case each of anemia, perirectal abscess, increased alanine transaminase, decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and obesity. A total of 20 adverse events considered possibly related to G207 were observed in 11 of the 12 patients, with all being grade 1. No evidence of peripheral G207 shedding or viremia was observed in any patient.

Responses

Radiographic, neuropathologic, or clinical responses were observed in 11 patients (92%). At first radiographic evaluation, imaging responses consisted of stable appearance and pseudoprogression; stable disease was observed in 7 (58%) of 12 patients at 1 month, 4 (36%) of 11 at 3 months, 3 (27%) of 11 at 5 months, and 2 (18%) of 11 at 12 months.

Median overall survival was 12.2 months (95% confidence interval = 8.0–16.4 months); as of June 2020, 4 (36%) of 11 patients remained alive at 18 months after G207 treatment. As noted by the investigators, historical median overall survival in this setting is 5.6 months.

Comparison of pretreatment and posttreatment T-lymphocyte levels was performed in tissue from four patients (1 from each dose group) who had undergone posttreatment biopsy or resection. Pretreatment tissue showed few tumor-infiltrating lymphocytes. At 3 to 9 months after treatment, tissue showed marked increases in CD8-positive tumor-infiltrating lymphocytes (as well as CD4-positive T lymphocytes), indicating the presence of an immune response to G207 and conversion of the tumors to immunologically “hot” tumors.

The investigators concluded, “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.’”

Disclosure: For full disclosures of the study authors, visit nejm.org.