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Immunovirotherapy Shows Promise in Pediatric High-Grade Glioma

Treatment with oncolytic immunovirotherapy alone or with radiation was shown to be safe and effective in a phase I study in 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 after treatment with G207, a genetically engineered herpes simplex virus (HSV) administered intratumorally via catheter, Gregory Friedman, MD, of the University of Alabama in Birmingham, reported at the American Association for Cancer Research Virtual Meeting.

Treatment was associated with few toxicities and the median overall survival (OS) reached 12.2 months (95% CI 8.0-16.4), comparing favorably with an established median OS of 5.6 months in the relapsed setting. . Four of the 12 patients (36%) survived more than 18 months, exceeding normal life expectancy for newly diagnosed cases.

In addition, there were few side effects (20 in total; all grade 1) and no virus shedding was observed.

The study’s findings were simultaneously published in the New England Journal of Medicine.

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

“The virus is inoculated intratumorally, overcoming the blood-brain barrier,” he continued. “After inoculation, the virus attaches to and enters tumor cells and we have shown that the virus can infect a wide variety of brain tumors in children, overcoming tumor heterogeneity.”

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

In the study, G207 immunologically turned ‘cold’ tumors to ‘warm,’ ” he said, noting that increases in tumor-infiltrating lymphocytes were seen in tissue samples after versus pretreatment, and that clusters of T cells were observed. months after the infusions.

From 2016 to 2020, 12 eligible patients (age range: 7-18 years) with progressive or recurrent supratentorial high-grade gliomas were enrolled in the Phase I study, 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 goal of the study was the safety of G207 alone or in combination with a dose of 5 Gy radiation therapy, which was designed to help spread the virus through the tumor. The secondary result 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) , deliver the virus in up to 2.4 ml at up to four sites.

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

Adverse reactions included diarrhea, nausea and vomiting, chills, fatigue, fever, anorexia, dizziness, headache, seizures and postoperative bleeding, but no serious adverse events were considered to be related to G207.

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

Two types of radiographic response were observed in the study: a “Swiss cheese” type, in which multiple cystic changes in size and number increased over time; and a pseudo-progression associated with lesion enlargement, an increased FLAIR signal, but a decrease in fractional tumor burden.

Ian Ingram joined MedPage Today in 2018 as a deputy editor in chief and covers oncology for the site.

Disclosures

The study was funded primarily by the FDA. Aettis / Treovir provided the G207.

Friedman disclosed support from the government and foundations.

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