Vaccine Extends Glioblastoma Patients' Survival in Phase II Trial
MD Anderson News Release 10/05/10
A vaccine that turns the immune system against brain tumor cells bearing a genetic mutation that drives the most aggressive form of glioblastoma multiforme improved survival of patients in a phase II clinical trial, researchers at Duke University and The University of Texas MD Anderson Cancer Center reported today in the Journal of Clinical Oncology.
Eighteen newly diagnosed patients who were vaccinated after undergoing standard treatment - surgery followed by radiation and chemotherapy - had median overall survival of 26 months compared with 15 months for 17 patients in a control group who received standard treatment. Median survival for newly diagnosed patients with glioblastoma multiforme is 14.6 months.
Vaccinated patients also experienced a longer period before their disease progressed, 14.2 months, compared with 6.3 months for the control group. Side effects were limited mainly to irritation at the injection site.
"This promising targeted therapy blocks a key molecular signal that drives the malignant features of these tumors," said Amy Heimberger, M.D., associate professor in MD Anderson's Department of Neurosurgery and co-lead author of the paper. "If a patient's tumor expresses the target of this vaccine, she usually has only a 5 percent chance to live for two years."
All patients in the trial had the target variation, called epidermal growth factor receptor variant III (EGFRvIII), which occurs in about a third of glioblastomas and also is found in breast, lung and head and neck cancers. The flawed gene produces a protein that aids tumor development, migration and resistance to chemotherapy and radiation. It is not found in normal tissue.
Out of 11 tumor recurrences analyzed from vaccinated patients, the EGFRvIII cells were completely gone in nine, indicating that the vaccine had done its job eliminating the most aggressive cells, said co-lead author John Sampson, M.D., Ph.D., professor of Neurosurgery at Duke.
Other findings hint at the vaccine's likely effectiveness against EGFRvIII. Of six patients who had an immune response to the vaccine as indicated by blood tests, overall survival was 47.7 months compared with 22.8 months for those lacking a response. Median survival had not been reached after 50 months among three patients who had a T cell response to the vaccine.
However, the limited size of the sample calls for cautious interpretation of these results, Heimberger said. The next step for the vaccine, known as CDX-110, is a large phase III clinical trial, Heimberger said, which is in the planning stage.
The EGFRvIII variant was co-discovered by Bert Vogelstein, M.D., and Albert Wong, M.D., at Johns Hopkins University and Darrell Bigner, M.D., Ph.D., director of the brain tumor center at Duke and corresponding author of the JCO paper.
Glioblastomas have other molecular drivers, so tumors come back, which the authors say points to a need to develop vaccines that address more than one target.
Heimberger sees the addition of vaccines to glioblastoma treatment as one more way to convert the deadly tumors more of a chronic disease. Developments in recent years, including approval of the chemotherapy drug temozolomide, have extended expected survival from around seven months to 14.
Funding for the work came from the National Institutes of Health, the American Brain Tumor Association, Accelerate Brain Cancer Cure, the Brain Tumor Society, the Commonwealth Cancer Foundation, the Adam Singer Foundation, the Dr. Marnie Rose Foundation and Golfers Against Cancer.
Co-authors are Kenneth Aldape, M.D., of MD Anderson’s Department of Pathology; Raymond Sawaya, M.D., and Mark Gilbert, M.D., of MD Anderson’s Department of Neurosurgery, and Weiming Shi of the Office of Performance Improvement at MD Anderson; and Gary Archer, Ph.D., Allan Friedman, M.D., Henry Friedman, M.D., James Herndon II, Ph.D., Robert Schmittling, Roger McLendon, M.D., Duane Mitchell, M.D., Ph.D., David Reardon, M.D., and James Vredenburgh, M.D. from Duke.
Bigner, Heimberger and Sampson, along with Duke University and MD Anderson report potential conflicts of interest from consulting agreements, stock options and potential further licensing fees. The institutions have plans in place to manage them. 10/05/10