Modified marrow cells may resist chemotherapy’s toxic effects

Chemotherapy kills cancer cells, but its toxic effects on normal cells such as bone marrow and blood cells limits its use. Hutchinson Center researchers have found a possible approach to reduce this toxicity: modify the bone marrow cells with a gene that makes them resistant to chemotherapy.

The Clinical Research Division’s Dr. Hans-Peter Kiem and colleagues reported the findings at the American Society of Gene and Cell Therapy’s annual meeting on May 20 in Seattle. Kiem, along with Dr. Jennifer Adair, also of the Clinical Research Division, and Dr. Maciej Mrugala, a neuro-oncologist at Seattle Cancer Care Alliance and the University of Washington, presented data from a clinical trial in which bone marrow stem cells from brain tumor patients were removed and modified with a retrovirus vector to introduce the chemotherapy-resistant gene. The cells were then reinfused into the patients. In the trial, which was designed to evaluate safety and feasibility, patients were safely administered gene-modified blood stem cells that persisted for more than one year and did not show any apparent harmful effects. 

This approach was first attempted in patients with a terminal form of brain cancer called glioblastoma. Currently, median survival for glioblastoma patients is just 12 to 15 months. The prognosis for these patients is poor not only because no curative treatment is available but because doctors cannot effectively use the treatment that does exist.

Glioblastoma cells make a large amount of a protein called MGMT that makes them resistant to chemotherapy, so doctors use a second drug, benzylguanine, to knock down MGMT and make the tumor cells susceptible to the chemotherapy. However, this potent one-two punch is not limited to the brain tumor cells. Benzylguanine also disables MGMT in normal blood and bone marrow cells, leaving them susceptible to the effects of chemotherapy. The effects on patients’ blood and bone marrow can be pronounced and often limit the ability to effectively administer the chemotherapy.

“Our initial results are encouraging because our first patient is still alive and without evidence of disease progression almost two years after diagnosis,” Kiem said.

The results of the trial suggest the administration of the modified cells represents a safe method for protecting marrow and blood cells from the harmful effects of chemotherapy in brain tumor patients. Future clinical trials will determine whether this combination chemotherapy improves survival.