NASHVILLE--Researchers at the National Institutes of Health have seen objective responses in some of the 15 patients treated to date in the first clinical trial of gene therapy in brain tumors, Michael Blaese, MD, said at the scientific subcommittee session on gene therapy at the American Society of Hematology (ASH) meeting.
Although the results are encouraging, "we're not curing anyone with this strategy at the moment," said Dr. Blaese, chief of the Clinical Gene Therapy Branch, National Center for Human Genome Research (NCHGR). "But I think we're getting closer, and eventually this might be an effective treatment for a variety of localized cancers," he continued.
The trial, launched about 2 years ago, involves an approach designed to make brain tumors sensitive to the antiviral drug ganciclovir(Drug information on ganciclovir) (Cytovene). In the protocol (developed by Dr. Blaese and his colleagues, Drs. Kenneth Culver, Edward Oldfield, and Zvi Ram), genetically altered mouse cells that produce retroviral vectors carrying the herpesvirus thymidine kinase gene are injected into the tumor. The tumor cells are genetically modified by the retroviral vectors to produce herpes thymidine kinase and thus become targets for ganciclovir.
The patients in the study had all failed surgery and radiotherapy, and most had also failed chemotherapy. Responses were evaluated in a variety of ways, including PET scans and MRI scans prior to therapy and 2 weeks following therapy.
Dr. Blaese showed MRI scans from one of the first patients in the study who had relapsed with two brain lesions following primary surgery and radiotherapy. "We have been following this patient now for 23 months after treatment with vector-producer cells and ganciclovir without having seen a recurrence," he said. Three of the responses seen were sustained for at least a few months, but in many patients who showed an initial response, the tumor quickly returned, and some patients had no response at all, Dr. Blaese said.
He noted that the results appear to be due to the actual transfer of the gene and not just the initial injection of altered cells. In a study of a patient on another arm of the protocol in which tumors were injected with vector-producer cells and resected on day 7 without ganciclovir therapy, the researchers showed that the cells in the tumor had been transduced, "so one can transfer genes effectively to tumor cells in the vicinity of the injection using this kind of strategy," he said.
Dr. Blaese emphasized the importance of the "bystander effect," in which the ganciclovir treatment kills both tumor cells containing the gene and neighboring tumors that had not been gene modified. He believes there may also be an immune component to this effect, because in some clinical situations, the researchers have seen very substantial reductions in volume in tumors in which less than 1% of tumor cells were effectively transduced with the gene.