A modified herpes virus, alone and when combined with radiation, has shown early signs of clinical effectiveness in a small group of pediatric patients with high-grade gliomas, according to data presented April 10 at the virtual American Association for Cancer Research Annual Meeting 2021 (Abstract CT018).
Not only did the combination indicate clinical efficacy, but it was well-tolerated in the study, which involved 12 patients between 7 and 18 years of age with high-grade gliomas that had progressed on prior treatments.
The researchers used a modified herpes simplex virus type 1 (HSV-1), a common cause of cold sores, said Gregory Friedman, MD, Professor of Pediatrics at the University of Alabama at Birmingham (UAB), and a research scientist at the UAB O'Neal Comprehensive Cancer Center.
When injected into a malignant brain tumor via a catheter, the virus enters the tumor cells and replicates, killing malignant cells and hunting out other tumor cells. The virus also triggers a strong immune response to attack the tumor.
"Pediatric high-grade glioma is a devastating disease that lacks effective, targeted therapies and results in high morbidity and mortality. Since HSV-1 naturally infects cells of the peripheral and central nervous system, brain tumors were an ideal target for such a therapy," he told a pre-conference media briefing.
"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," noted Friedman, who is also Director of Developmental Therapeutics for the Alabama Center for Childhood Cancer and Blood Disorders at UAB and Children's of Alabama.
"This is the first study utilizing delivery of a viral immunotherapy directly into the tumor of children with brain tumors, and the results indicate the engineered herpes virus can be delivered safely into tumors located in all areas of the cerebrum in children," said Friedman.
About 8-10 percent of pediatric brain tumors are malignant high-grade gliomas, most are fatal, and most follow a rapid course. Survival rates have not improved in 30 years; the 3-year event-free survival among patients treated with standard radiation and chemotherapy is 11-22 percent. At recurrence, the median life expectancy is only 5.6 months. Moreover, for the few children cured of high-grade glioma, conventional therapies can irreversibly injure the developing brain.
"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."
In an effort to reduce this risk, the researchers used genetic engineering to generate a modified HSV-1 called G207, the product of more than 30 years of research. The trial used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Treatment response was assessed by imaging, tumor pathology, and the patient's performance status.
Out of 12 children, 11 responded to treatment and median overall survival was 12.2 months-a 120 percent increase over the typical overall survival of 5.6 months seen for progressive pediatric high-grade glioma, Friedman said. To date, 36 percent of patients have survived longer than the median overall survival of 18 months for newly diagnosed pediatric high-grade glioma.
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.
"The key findings thus far are that the approach is safe and well-tolerable, and the preliminary evidence of efficacy is promising," noted Friedman.
G207, alone or in combination with radiation therapy, was well-tolerated with no dose-limiting toxicities, grade 3/4 treatment-related adverse events, or evidence of virus shedding into the bloodstream, saliva, or conjunctiva. In addition, pre- and post-treatment tumor tissue examination revealed an increase in the number of tumor-infiltrating immune cells, including CD4+ and CD8+ T cells, within 2-9 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.
As in previous trials of G207 involving adults with high-grade glioma, no evidence of peripheral viral shedding was found. Most patients had a strong response to G207 despite many being heavily pretreated and having large tumors. Thus, unlike traditional therapies, patients may benefit from G207 months after receiving it even after another therapy is initiated, resulting in improved overall survival.
"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."
Friedman and his colleagues have an ongoing Phase I trial in progressive pediatric cerebellar tumors, such as medulloblastoma, the most common malignant brain tumor in children. In the future, they plan to 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, the team plans to evaluate G207 in different patient populations, including patients with newly diagnosed high-grade glioma. They are also investigating whether various combination therapies with G207 could improve the antitumor immune response.
Limitations of the study included its relatively 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, Friedman noted, adding that the next steps are to determine the ideal timing to treat patients and what therapies can be used with viral immunotherapy to maximize the antitumor immune response.
Based on the encouraging Phase I trial results, he said that he and his team are working with the Pediatric Brain Tumor Consortium to develop a multi-institutional Phase II trial of G207 for progressive pediatric high-grade glioma, which they hope to initiate later this year.
Data from this trial were concurrently published in the New England Journal of Medicine (2021; doi: 10.1056/NEJMoa2024947).
Kurt Samson is a contributing writer.