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Gene therapy boosts chemotherapy tolerance and effectiveness of medications that attack brain cancer

Stem-cell protocol could be used with other malignant solid tumors

Hans-Peter Kiem, M.D., Ph.D., is a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.

Hans-Peter Kiem, M.D., Ph.D., is a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.

Photo by Matt Hagen for Fred Hutch

SEATTLE – Aug. 8, 2014 – Using gene therapy and a cocktail of powerful chemotherapy drugs, researchers at Fred Hutchinson Cancer Research Center have been able to boost the tolerance and effectiveness of medications that attack brain cancer while also shielding healthy cells from their devastating effects.

The report, published today in the Journal of Clinical Investigations, is based on a study involving seven patients with glioblastoma who survived a median of 20 months, with a third living up to two years – all while fighting a disease in which fewer than half of patients can expect to live a year.

“I think this is very promising,” said Hans-Peter Kiem, M.D., a stem cell transplant researcher at Fred Hutch. Kiem, along with lead author Jennifer Adair, Ph.D., a researcher in Kiem’s lab, expect the stem-cell protocol, once approved, could be used with other malignant solid tumors.

Based on these results, the researchers are now soon planning to enroll patients in a Phase 2 clinical trial – after having to suspend treatment for a year because of a shortage of a key drug, O6-benzylguanine, or O6BG.

The top treatment for glioblastoma, which affects about 12,000 to 14,000 patients in the U.S. each year, is temozolomide, or TMZ, a powerful chemotherapy drug. But in about half of all such patients, the tumors produce high amounts of a certain protein, methylguanine methyltransferase, or MGMT, which makes them resistant to the TMZ.

Another drug, the O6-benzylguanine, or O6BG, can turn off the resistance, allowing TMZ to effectively target the tumors. But the combination of O6BG and TMZ kills bone-marrow cells, a potentially deadly side effect.

The challenge facing Kiem and colleagues was to find a way to protect the blood cells from the negative effects of O6BG/TMZ while also allowing the drug to do its job sensitizing the tumor to TMZ. Kiem and Adair developed a method that inserts an engineered gene into the patient’s own cells, shielding them from the O6BG.

This allowed them to use combination TMZ and O6BG more effectively to target the cancer. For example, while most patients might receive one or two cycles of chemotherapy, one patient in the study received nine cycles of chemotherapy.  The researchers also added an extra step to the treatment, conditioning the patients with an additional chemotherapy drug, carmustine, before giving the gene-modified blood cells.

“The drug helped the patients’ bodies accept and use the gene-modified blood cells, but also treated any residual brain tumor,” Adair said. “The gene therapy might not have worked without the conditioning.”

At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch’s pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation’s first cancer prevention research program, as well as the clinical coordinating center of the Women’s Health Initiative and the international headquarters of the HIV Vaccine Trials Network.