Gene Therapy Betters Chemotherapy Tolerance, Effectiveness in Small Glioblastoma Study

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Using gene therapy and a combination of chemotherapy drugs, researchers at Fred Hutchinson Cancer Research Center have been able to enhance the tolerance and effectiveness of medications used in treating glioblastoma while also protecting healthy cells from their toxic effects. The report, published this month in the Journal of Clinical Investigations, is based on a study involving seven patients with glioblastoma who survived a median of 20 months, with one-third living up to 2 years.1

Hans-Peter Kiem, MD, PhD, a Stem-Cell Transplant Researcher and Member of the Clinical Research Division at Fred Hutchinson Cancer Research Center, in Seattle and lead author Jennifer Adair, PhD, a Researcher in Dr. Kiem’s Laboratory, expect the stem-cell protocol, once approved, could be used with other malignant solid tumors.

Phase II Study Planned

Based on these results, the researchers are now soon planning to enroll patients in a Phase II clinical trial after having to suspend treatment for a year because of a shortage of a key drug, O6-benzylguanine, or O6BG. The primary treatment for glioblastoma is temozolomide (Temodar), but approximately one-half of patients are resistant to temozolomide. Another drug, O6-benzylguanine, or O6BG, can counter the resistance and permit temozolomide to effectively target the tumors. The combination of O6BG and temozolomide, however, kills bone-marrow cells yielding a potentially deadly side effect.

Conditioning a Key Component to Therapy

Drs. Kiem and Adair developed a method that inserts an engineered gene into the patient’s own cells, shielding them from the O6BG. This method facilitated more effective use of the combination temozolomide and O6BG. 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,” Dr. Adair said. “The gene therapy might not have worked without the conditioning.” ■

Disclosure: Drs. Kiem and Adair reported no potential conflicts of interest.


1. Adair JE, Johnston SK, Mrugala MM, et al: Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J Clin Invest 124(9):4082-4092, 2014.