NASHVILLEIn 1996, delivery difficulties were the major barrier to
breast cancer gene therapy, Jeffrey T. Holt, MD, said at a plenary session
of the San Antonio Breast Cancer Symposium.
"Since breast cancer is a largely systemic disease, and we can't
deliver viral vectors systemically, it is difficult to see how we're going
to make any major breakthroughs in breast cancer gene therapy until we
come up with ways to do systemic gene therapy," he said.
In terms of regional gene therapy strategies, two basic protocols have
been initiated in breast canceran antisense protocol in breast cancer
pleural effusions and a vector protocol for chest wall recurrences.
"Again, because these treatments are nonsystemic, they are unlikely
to produce any sort of long-term response," said Dr. Holt, associate
professor of cell biology and pathology at the Vanderbilt University School
Gene therapy is currently a more viable approach in breast cancer's
sister disease, ovarian cancer, he said, because late-stage ovarian cancer
is predominantly an intraperitoneal disease. "If we can decrease the
amount of intraperitoneal disease by a regional gene therapy approach,"
he said, "it is possible that we could have some sort of long-term
benefits to the patient."
He noted several other factors that make ovarian cancer a good target
for gene therapy studies: Retroviral vectors are stable in peritoneal fluid;
there are few competing therapies for late- stage ovarian cancer, which
simplifies patient accrual; and since ovarian cancer can be measured by
laparotomy, the stability of the vector can be assessed.
Finally, he said, there is a constant tumor suppressor defect in the
disease. "Although the BRCA1 gene is mutated in only 5% to 10% of
ovarian cancers, we have found that there is decreased expression of BRCA1
in the vast majority of ovarian cancers," Dr. Holt explained.
In a phase I trial of patients with stage III/IV ovarian cancer, researchers
at Vanderbilt and the University of Washington are currently instilling
into the peritoneal cavity as much as 20 billion vector particles a day
of LXSN-BRCA1, a retroviral vector that expresses BRCA1, in an attempt
to in-crease the level of tumor suppressor.
Twelve patients have been treated so far. They are given four daily
infusions and examined after a month. If their disease has progressed,
treatment is stopped; if they have stable disease or an objective response,
treatment is continued.
Three patients have developed peritonitis, but it appears to be "somewhat
idiosyncratic, not dose related," he said, since it was seen at several
different dose levels. Some patients have had fever and myalgias.
The study has also shown that there is a stable vector in some patients
even with repeat administration, suggesting that immune response is not
significant. "We've only seen antibody formation to retroviral envelope
in one patient to date," Dr. Holt said, "and in this patient,
even though antibody was present, it didn't appear to affect stability."
Stability is affected by complement level within the peritoneal fluid;
patients with stable vector tend to have low complement levels.