麻豆传媒

Treatment with an oncolytic immunovirotherapy alone or with radiation appeared safe and effective in a phase I study of children and adolescents with heavily pretreated high-grade glioma.

Eleven of 12 patients with progressive or recurrent supratentorial high-grade gliomas achieved radiographic, neuropathological, or clinical responses following treatment with G207, a genetically engineered herpes simplex virus (HSV) delivered intratumorally via catheter, Gregory Friedman, MD, of the University of Alabama at Birmingham, reported at the American Association for Cancer Research virtual meeting.

The treatment was associated with few toxicities, and the median overall survival (OS) reached 12.2 months (95% CI 8.0-16.4), which compares favorably to an established median OS of 5.6 months in the recurrent setting. Four of the 12 patients (36%) have survived beyond 18 months, exceeding the typical life expectancy for newly diagnosed cases.

Additionally, few adverse events occurred (20 in total; all grade 1), and no shedding of the virus was observed.

Findings from the study were published simultaneously in the .

"Oncolytic HSV [herpes simplex virus] immunovirotherapy can overcome challenges to a successful immunotherapy for pediatric high-grade glioma," said Friedman.

"The virus is inoculated intratumorally which overcomes the blood-brain barrier," he continued. "After inoculation, the virus attaches and enters tumor cells and we have shown that the virus can infect a wide variety of pediatric brain tumors, which overcomes tumor heterogeneity."

With deletions of the γ₁34.5 genes, the virus prevents replication in normal cells but maintains replication in cancer cells, explained Friedman, and G207 virus remains sensitive to available antivirals.

In the study, "G207 turned immunologically 'cold' tumors to 'hot,'" he said, noting that increases in tumor-infiltrating lymphocytes were observed in post- versus pre-treatment tissue samples, and that clusters of T cells were seen up to 9 months following the infusions.

From 2016 to 2020, the phase I study enrolled 12 eligible patients (age range: 7-18 years) with progressive or recurrent supratentorial high-grade gliomas, including 10 patients with glioblastomas, one with anaplastic astrocytoma, and one with a high-grade glioma, not otherwise specified.

All tumors were IDH wild-type, and without favorable genetic signatures. Ten of the tumors were large, with a bi-perpendicular tumor of 5.5 cm or more, three patients had multifocal spread, and one had leptomeningeal spread. Eight of the 12 patients had received at least two prior lines of therapy, and four had received at least three.

The primary objective of the study was the safety of G207 alone or combined with a 5-Gy dose of radiation therapy, which was designed to help spread the virus throughout the tumor. The secondary outcome was efficacy and biological response. The study used a 3+3 dose-escalation design using four dose levels (1×10⁷ plaque-forming units; 1×10⁸; 1×10⁷ + 5 Gy; and the planned phase II dose of 1×10⁸ + 5 Gy), delivering the virus in up to 2.4 mL in up to four locations.

Three patients in the study had HSV-1 IgG antibodies at baseline, and while none of four patients treated at the lowest dose seroconverted, three of four treated at the 1×10⁸ dose did. Median OS was superior among those who seroconverted compared with those who had antibodies at baseline (18.3 vs 5.1 months, respectively), though Friedman noted that this would have to be confirmed in a larger group of patients.

Adverse events included diarrhea, nausea and vomiting, chills, fatigue, fever, anorexia, dizziness, headache, seizure, and post-operative hemorrhage, but no serious adverse events were deemed related to G207.

Multiple locations were safely treated, said Friedman, including tumors located in the frontal, parietal, temporal, and occipital lobes, as well as the thalamus, corpus callosum, and insula.

Two types of radiographic response were seen in the study: a "Swiss-cheese" type, where multiple cystic changes increased in size and number over time; and a pseudoprogression associated with lesion enlargement, an increased FLAIR signal, but a decrease in fractional tumor burden.