Duke Brain Tumor Research Scientists Develop a New Drug Shown to More Than Double Progression-Free Survival in Glioma Patients
In 2024, the FDA approved a new targeted drug specifically for brain tumors called low-grade gliomas. The drug, vorasidenib, was shown in clinical trials to delay progression of low-grade gliomas that had mutations in the IDH1 or IDH2 genes.
“Although there have been other targeted therapies for the treatment of brain tumors with the IDH mutation, [this one] has been one of the most successful in survival prolongation of brain tumor patients,” said Darell Bigner, MD, PhD, the E. L. and Lucille F. Jones Cancer Distinguished Research Professor and founding director of the Preston Robert Tisch Brain Tumor Center at Duke.
In clinical trials, progression-free survival was estimated to be 27.7 months for people in the vorasidenib group versus 11.1 months for those in the placebo group.
Bigner, Katherine Peters, MD, PhD, professor of neurology and neurosurgery, and others at the Duke Brain Tumor Center played pivotal roles in the development and approval of the drug: Bigner in the early collaborations with Johns Hopkins University that led to the discovery of the IDH mutation, and Peters, more recently, as a lead investigator in the clinical trial.
Patents developed from the early collaborations were licensed to industry through the Duke University Office for Translation & Commercialization, making this the seventh drug currently on the market with Duke intellectual property roots.
New Study Disrupts a Long-Held Paradigm for Tumor Resistance to Immunotherapy
A study published in Nature Cancer describes how tumors previously thought to be unresponsive to immunotherapy are responsive through a novel mechanism.
The paper was authored by Duke MD/PhD student Emily Lerner, and co-author Peter Fecci, MD, PhD, Duke professor of neurosurgery.
Anti-tumor immunotherapies such as immune checkpoint blockade have revolutionized cancer treatment. Unfortunately, many solid tumors, including glioblastoma (GBM), have thus far failed to respond. Researchers are therefore investigating the mechanisms underlying tumor resistance to immunotherapy.
One such proposed mechanism is tumor mutations leading to decreased or absent major histocompatibility complex I (MHC-I) expression. MHC-I proteins are normally found on the surface of all nucleated cells. MHC-I complexes present antigens to CD8 T cells, the main effector cells of the adaptive anti-tumor immune response. Cells that do not express MHC-I are therefore thought to be invisible to CD8 T cells. Downregulation of MHC-I by tumor cells has been suggested as a major mechanism of tumor resistance to CD8 T cell killing, and by extension, CD8 T cell-dependent immune checkpoint blockade therapy.
“In this study, we found that CD8+ T cells can still kill tumor cells that are entirely devoid of MHC-I expression, a function previously thought to be restricted to the innate immune system,” said Lerner. “We show that CD8 T cells can recognize tumor cells via the NKG2D receptor. This receptor binds to cell surface proteins that are upregulated in the setting of cellular stress and are highly expressed in tumor cells.”
These findings bridge the gap between the adaptive and innate immune response in cancer and challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape.
Engineered Herpes Virus to Combat Recurrent High-Grade Glioma
Mustafa Khasraw, MD, professor of neurosurgery, is leading a new study of an oncolytic herpes simplex virus as a treatment for recurrent high-grade glioma.
The PuMp Trial is a multi-stage, multi-center, phase 1, open-label study evaluating the safety, tolerability, and preliminary efficacy of MVR-C5252, when delivered directly into tumors via convection-enhanced delivery (CED), bypassing the blood-brain barrier.
The trial is a large collaborative effort involving a multidisciplinary team of experts at Duke. Additionally, the Duke team is facilitating the trial's expansion to six cancer centers: New York University, St. Luke's Health in Kansas, University of California San Francisco, University of California Los Angeles, Huntsman Cancer Institute in Utah, and Memorial Sloan Kettering in New York.
The PuMP Trial introduces several novel elements. First, it employs a genetically engineered oncolytic herpes simplex virus type 1 designed with dual payload genes:
one encoding human IL-12, which enhances immune activation, and another encoding an anti-PD-1 antibody fragment, which helps counteract immune suppression in the tumor microenvironment.
This dual mechanism is intended to convert "cold" tumors (immune-suppressive) into "hot" (immune-active) tumors, a significant challenge in glioblastoma treatment. Second, while many CED trials have been conducted before, the novelty here is the implantation of a pump that enables repeated doses, allowing both priming and boosting doses of the immunotherapeutic agent. This approach aims to enhance repetitive tumor targeting while reducing systemic exposure and associated toxicity. Together, these innovations address the immune-evasive nature of glioblastoma and the challenges of effective drug delivery within the brain, presenting a potentially impactful approach for recurrent high-grade gliomas.
New Report Examines Brain Tumor Prevalence Among Adolescents
A report from Duke Neurosurgery scientists sheds light on the prevalence of primary brain and other central nervous system (CNS) tumors among adolescents and young adults (AYAs).
The study revealed that brain and other CNS tumors are the second most common cancer type among people between the ages of 15 and 39, with an average of 12,848 individuals diagnosed annually. Over 90 percent survived for at least five years, with approximately 208,620 AYAs expected to be living with a history of brain or other CNS tumor diagnosis in 2024.
Quinn Ostrom, PhD, assistant professor in the Duke Department of Neurosurgery, was senior author of the report. Duke Neurosurgery’s Mackenzie Price and Corey Neff were lead authors.
“This is the first statistical report to analyze this unique population while incorporating current tumor classifications based on recent molecular data,” said Ostrom. “Understanding the burden of disease and knowing the molecular makeup of tumors is different within this population is a significant step towards improving health outcomes and care.”
Kyle Walsh, PhD, neuro-epidemiologist and associate professor in the Duke Department of Neurosurgery, emphasized the importance of the new report. “These registry data cover the entire U.S. over a five-year period (2016–2020), totaling 64,238 new brain and CNS tumor diagnoses in persons ages 15–39 years (approximately 27% malignant, 73% benign),” he said. “This epidemiologic report supersedes all previous reports in terms of both completeness and accuracy; it is a huge service to the research community.”
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