Combination Therapy Knocks Out Glioblastoma

Study reveals targets on the tumor cell that can be recognized by killer T-cells.

Scientists at UCLA have developed a promising new combination therapy for glioblastoma (GBM) that could give patients with the deadliest form of brain cancer hope for their future.

GBM, known in oncological circles as grade IV glioma, is the most aggressive form of brain cancer in humans. It is estimated that 23,000 people are newly diagnosed each year in the United States with GBM.

Treatment options include surgery, chemotherapy, and radiation, but these treatments are not very effective; an estimated 50% of GBM patients die within 1 year and 90% die within 3 years.

UCLA Jonsson Comprehensive Cancer Center members Drs. Robert Prins and Linda Liau led the study, which evaluated the impact of a combined treatment using a chemotherapy drug called decitabine and genetically modified immune cells or T-cell immunotherapy. The study acts as a continuation of another study conducted in 2011 that focused on the effect of decitabine on GBM human cell cultures.

In the current study, researchers used a technique called adoptive cell transfer that involved extracting and growing immune cells outside of the body, then reprogramming them with a gene known as New York Esophageal Squamous Cell Carcinoma, or NY-ESO-1. They then inject it back into mouse models with tumors to produce and immune response that targets the brain cancer.

GBM cells do not naturally produce NY-ESO-1, so in order for the cells to express the gene they must first be treated with decitabine before injecting the NY-ESO-1 targeting T-cells.

“The lymphocytes will seek out and find the glioblastoma cells in the brain,” Dr. Prins said. “They can cross different fiber tracts in the brain to reach tumor cells that have migrated away from the main tumor mass. These factors are important in the treatment of invasive tumors, such as glioblastoma. While surgery to remove the main tumor mass can be done, it is not possible to then locate the tumor cells that get away and this ultimately leads to a nearly universal tumor regrowth.”

According to the study results, the treatment method was 50% effective in curing GBM.

“Brain cancer cells are very good at evading the host immune system, because they do not express specific targets that can be recognized by immune cells,” Dr. Liau said. “By treating glioblastoma cells with decitabine, we found that we can unmask targets on the tumor cell that can be recognized by killer T-cells. Once these targets are uncovered, we can then administer T cells that are genetically programmed to attack tumor cells with the new targets.”

Researchers plan to continue their efforts by confirming these findings in other brain tumor models before proceeding with clinical trial testing.