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
(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
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.
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.