Stem Cells Found to Protect Against Chemo Side Effects

Hans-Peter Kiem (Fred Hutchinson Cancer Research Center)

Researchers at the Fred Hutchinson Cancer Research Center in Seattle and four other institutions have developed a method for transplanting brain cancer patients’ own gene-modified blood stem cells to protect their bone marrow against the toxic side effects of chemotherapy. Their findings appear in this week’s issue of the journal Science Translational Medicine (paid subscription required).

The team led by Hans-Peter Kiem (pictured right) at the Hutchinson Center reported the results of a small, ongoing clinical trial of patients with glioblastoma, a common and aggressive brain cancer; the late Senator Ted Kennedy died from the disease. Of the three patients reported from the trial, two patients survived longer than predicted if they had not been given the transplants, and a third patient remains alive with no disease progression almost three years after treatment.

Kiem says a barrier to the use of chemotherapy to treat cancers like glioblastoma has been the toxicity of chemotherapy drugs to bone marrow and other organs. This toxicity decreases blood cell counts, and increases susceptibility to infections and other side effects. Discontinuing, delaying, or reducing the dose of chemotherapy is often required under these circumstances, but that often results in less effective treatment.

The task for Kiem’s team — that includes colleagues from the Hutchinson Center, Washington State University, University of Washington, Dana Farber/Children’s Hospital Cancer Center, and Harvard Medical School — was to devise a method for decreasing the toxicity of chemotherapy to the patients, while maintaining the treatment’s effectiveness. They focused on a gene, labeled MGMT, found in glioblastoma patients.

MGMT is a DNA repair enzyme that counteracts the toxic effect of some chemotherapy agents, but in glioblastoma patients the promoter of this gene is unmethylated, a condition that alters the gene’s expression pattern. A drug called benzylguanine can block the MGMT gene and make tumor cells receptive to chemotherapy. When given with chemotherapy, however, the toxic effects of benzylguanine and chemotherapy can take their toll on bone marrow cells, resulting in marrow suppression.

In the trial, the researchers tested P140K, a modified version MGMT, which was transplanted into the bone marrow of the patients. The modifications in P140K maintain the sensitivity to chemotherapy, while protecting against the effects of the benzylguanine and chemotherapy combination. “P140K can repair the damage caused by chemotherapy,” says Kiem, “and is impervious to the effects of benzylguanine.”

The three patients reported in this study survived an average of 22 months after receiving transplants of their own circulating blood stem cells. One of the patients remains alive 34 months after treatment. The median time of survival for patients with this type of glioblastoma without a transplant is just over one year.

The Hutchinson Center estimates that as many as 50 to 60 percent of glioblastoma patients have chemotherapy-resistant tumors, which makes gene-modified stem cell transplant therapy applicable to a large number of these patients. In addition, brain tumors such as neuroblastoma and other solid tumors with MGMT-mediated chemo resistance, could benefit from this approach.

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• University, Company Test Gene Transfer Cancer Treatment

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