A novel virus engineered to target malignant gliomas, which are particularly aggressive brain tumors, may prolong survival, according to a recent phase 1 study.
The findings, published June 29 in The Lancet Oncology, show early promise in targeting malignant gliomas, which have been notoriously difficult to treat. Only 1 in 4 patients are alive 2 years after diagnosis. The median overall survival from diagnosis is 14.6 to 16.7 months.
In a study of a novel therapy called NSC-CRAd-S-pk7 — an oncolytic adenovirus delivered across the blood-brain barrier by neural stem cells — overall survival improved by several months for patients with malignant gliomas.
“To my knowledge, this is the first time neural stem cells have been used as a delivery strategy for an oncolytic virus,” said Terence Burns, MD, PhD, associate professor of neurosurgery at the Mayo Clinic, Rochester, Minnesota, who was not involved in the research.
In this open-label, dose-escalation trial, researchers enrolled 12 patients with newly diagnosed malignant gliomas between April 2017 and November 2019. After neurosurgical tumor resection, patients were placed in one of three cohorts distinguished by dose of NSC-CRAd-S-pk7. Three patients received the lowest dose of 6.25×1010 viral particles administered by 5.00×10⁷ neural stem cells (NSCs), three received a more moderate dose of 1.25×10 viral particles administered by 1.00×108 NSCs, and remaining six patients received a dose of 1.875×1011 viral particles administered by 1.50×108 NSCs. Within 10 to 14 days, the investigators also initiated treatment with temozolomide and radiotherapy.
The investigators report that after a median 18-month follow-up period, median progression-free survival was 9.1 months, and median overall survival of 18.4 months. In a subgroup of patients with unmethylated MGMT promoters — DNA repair enzymes that make tumor cells more resistant to treatment — median progression-free survival was 8.8 months, and median overall survival was 18.0 months.
There was no dose-limiting toxicity, and there were no treatment-related deaths. One patient developed viral meningitis, owing to the inadvertent ventricular injection of NSC-CRAd-S-pk7, and fully recovered after hospitalization.
Patients tolerated the treatment well, which is critical because “drugs that could fight gliomas might also have serious adverse effects,” first author Jawad Fares, MD, a postdoctoral fellow in neurological surgery at Northwestern University Feinberg School of Medicine, Chicago, Illinois, said in an interview with Medscape Medical News.
A Novel Approach
A significant challenge to delivering drugs to the site of malignant gliomas is the blood-brain barrier, which blocks entry of many chemotherapeutic drugs.
“Because of this barrier, physicians often employ other strategies, such as direct injection in the brain cavity, but even with an injection, it is problematic to disseminate the drug so that the medication spreads throughout the tumor mass,” said Fares. “Our innovative approach, which employs the use of neural stem cells as shuttles to deliver viruses, seeks to address this problem. Neural stem cells tend to travel within hours to areas of injury, areas of stroke or brain tumors, and could disperse the oncolytic virus.”
Gliomas create an immunosuppressive tumor microenvironment, which uses tissue cells, blood vessels, immune cells, and other parts of the body to blunt antitumor immune responses. Using NSCs to deliver NSC-CRAd-S-pk7 directly to the tumor has the advantage of “giving the virus more time to replicate and kill tumor cells,” said Marta Alonso Roldán, MD, Clinica Universidad de Navarra, in Spain, in an interview.
Although NSC-CRAd-S-pk7 appeared to improve survival in this cohort by a few months, follow-up trials with larger sample sizes and control groups are necessary to demonstrate efficacy.
Moreover, patients in this trial may not be representative of the average patient, said Burns. “For instance, three of the patients had relatively small tumors in nicely operable areas with a high likelihood of getting a gross total resection. These things do stack your odds in favor of having a longer survival.”
Moving forward, “this trial sets the stage for a phase 2/3 study in which the efficacy of NSC-CRAd-S-pk7 in eliciting an anti-glioma immune response and prolonging survival in a larger cohort of patients with controlled conditions can be explored,” Fares said.
The study was funded by the US National Institutes of Health. Fares, Burns, and Roldán have disclosed no relevant financial relationships.
Lancet Oncol. Published online June 29, 2021. Abstract
Anna Goshua is a reporting intern with Medscape. She is a dual medical and journalism student who has previously written for STAT, Scientific American, Slate, and other outlets. She can be reached at [email protected] or @AnnaGoshua.
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