Oncolytic Herpesvirus Shows Early Promise in Pediatric Patients with High-grade Glioma
PHILADELPHIA – Treatment with a modified herpesvirus in combination with radiation therapy was well tolerated and showed signs of clinical efficacy in pediatric patients with high-grade glioma, according to data from a phase I clinical trial presented during Week 1 of the virtual AACR Annual Meeting 2021, held April 10-15.
Data from this trial were concurrently published in the New England Journal of Medicine.
“Unfortunately, outcomes are very poor for children with progressive gliomas, and we have not seen a significant improvement in outcomes for this dreadful disease in the last 30 years,” said presenting author Gregory Friedman, MD, professor of pediatrics at the University of Alabama at Birmingham (UAB), research scientist at the UAB O’Neal Comprehensive Cancer Center, and director of developmental therapeutics for the Alabama Center for Childhood Cancer and Blood Disorders at UAB and Children’s of Alabama. “The toxicities associated with the current standard therapies are unacceptably high. There is, therefore, a great need for effective and less toxic targeted therapies for children,” he added.
In this phase I clinical trial, Friedman and colleagues investigated the safety and efficacy of a modified herpes simplex virus type 1 (HSV-1)—a common cause of cold sores—for the treatment of pediatric high-grade gliomas, alone and in combination with radiation therapy. Since HSV-1 naturally infects cells of the peripheral and central nervous system, brain tumors were an ideal target for such a therapy, explained Friedman. Genetic engineering was utilized to generate a modified HSV-1 (called G207) that could infect tumor cells, but not normal cells.
The clinical trial included 12 patients between 7 and 18 years of age with high-grade gliomas that had progressed on prior treatments. G207 was administered to all 12 patients through intratumor catheters. Within 24 hours of G207 infusion, some patients also received a single small radiation dose directed to their tumors, which was designed to enhance virus replication and spread throughout the tumor, Friedman explained.
Treatment response was assessed by imaging, tumor pathology, and the patient’s performance status. Responses were observed in 11 of the 12 patients. Median overall survival was 12.2 months, which was a 120 percent increase over the typical overall survival of 5.6 months seen for progressive pediatric high-grade glioma, Friedman explained. To date, 36 percent of patients have survived longer than the median overall survival of 18 months for newly diagnosed pediatric high-grade glioma, according to Friedman. Patients who had HSV-1 antibodies at baseline had shorter median survival than those who seroconverted after treatment initiation (5.1 months vs. 18.3 months), suggesting that prior HSV-1 exposure may be an important determinant for treatment response.
G207 alone or in combination with radiation therapy was well tolerated, with no dose-limiting toxicities, grade 3/4 treatment-related adverse events, nor evidence of virus shedding into the bloodstream, saliva, or conjunctiva.
“While further investigation in a phase II clinical trial is needed, our findings suggest that oncolytic immunovirotherapy using a modified cold-sore virus is a safe and potentially efficacious approach to target pediatric high-grade glioma,” said Friedman.
In addition, analysis of pre- and post-treatment tumor tissue revealed an increase in the number of tumor-infiltrating immune cells, including CD4+ and CD8+ T cells, within two to nine months of G207 infusion. “These results indicate that this treatment can transform immunologically ‘cold’ pediatric high-grade gliomas with very few immune cells into ‘hot’ tumors with an abundance of immune cells, which is a critical step in the development of an effective immunotherapy for children with brain tumors,” explained Friedman.
Friedman and colleagues have an ongoing phase I trial in progressive pediatric cerebellar tumors, such as medulloblastoma, which is the most common malignant brain tumor in children. Their future work will examine the safety and efficacy of the treatment in a larger phase II clinical trial, which is expected to begin enrollment later this year. In addition, they plan to evaluate G207 in different patient populations, including those with newly diagnosed high-grade glioma. Friedman and colleagues are also investigating whether various combination therapies with G207 could improve the antitumor immune response.
Limitations of the study include the small sample size and the primarily single-institution nature of the study. To address these limitations, the forthcoming larger phase II trial will be conducted through a multi-institutional pediatric consortium.
The study was supported by the United States Food and Drug Administration Orphan Products Clinical Trials Grants Program, Cannonball Kids’ cancer Foundation, the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, St. Baldrick’s Foundation, and the Kaul Pediatric Research Institute. G207 was provided by Treovir LLC.
Friedman is supported, in part, by contracts between UAB and Eli Lilly and Co. and Pfizer.