Experimental Gene Therapy Protects Normal Cells from Toxic Effects of ChemotherapyIn a proof-of-concept study, a gene therapy technique designed to protect normal blood stem cells from the toxic effects of chemotherapy allowed three patients with glioblastoma to tolerate high doses of an experimental drug. All three patients survived longer than the median time for patients with this type of brain cancer, which has a poor prognosis. One patient remained alive without the disease progressing for more than 2 years after diagnosis. Dr. Hans-Peter Kiem of Fred Hutchinson Cancer Research Center and his colleagues published the findings May 9 in Science Translational Medicine.
The three patients had tumors that overexpressed a gene called MGMT. An experimental drug called O6-benzylguanine (O6-BG) inhibits the protein produced by MGMT and makes tumors more sensitive to anticancer drugs such as temozolomide, but it also increases the toxicity of chemotherapy to normal blood cells, including blood-forming stem cells. To make treatment with O6-BG tolerable, the researchers inserted a mutant MGMT gene called P140K, which makes cells resistant to O6-BG, into the patients’ blood stem cells.
The patients first underwent surgery to remove as much of their tumor as possible, followed by radiation therapy. Then stem cells were collected from their blood. The researchers cultured the stem cells in the lab and used a virus to deliver the mutant gene to the cells, in a process known as transduction. Next, the patients received the chemotherapy drug carmustine. Finally, the researchers infused the transduced stem cells into the patients, and the patients then received additional chemotherapy with O6-BG and temozolomide.
Each patient tolerated at least three cycles of combined drug treatment, and one patient received nine cycles. Normal blood cells containing the mutant MGMT gene were detected in the patients up to 14 months after stem cell transplantation. The researchers did not see any changes in the bone marrow indicative of leukemia during the study, although they plan to monitor the transduced stem cells in the remaining patient during follow-up. (One concern with gene therapy is that the foreign genes might insert themselves into the normal genome at a location that triggers a second cancer.)
The lack of toxicity seen in these patients and their relatively good survival “suggests that this approach will allow for administration of multiple cycles of this chemotherapy, possibly at higher, more-effective doses, potentially leading to better treatment outcomes,” concluded the authors.