Delivery of Gene Therapy Difficult in Breast Cancer

NASHVILLE—In 1996, delivery difficulties were the major barrier tobreast cancer gene therapy, Jeffrey T. Holt, MD, said at a plenary sessionof the San Antonio Breast Cancer Symposium.

"Since breast cancer is a largely systemic disease, and we can'tdeliver viral vectors systemically, it is difficult to see how we're goingto make any major breakthroughs in breast cancer gene therapy until wecome up with ways to do systemic gene therapy," he said.

In terms of regional gene therapy strategies, two basic protocols havebeen initiated in breast cancer—an antisense protocol in breast cancerpleural effusions and a vector protocol for chest wall recurrences.

"Again, because these treatments are nonsystemic, they are unlikelyto produce any sort of long-term response," said Dr. Holt, associateprofessor of cell biology and pathology at the Vanderbilt University Schoolof Medicine.

Intraperitoneal Administration

Gene therapy is currently a more viable approach in breast cancer'ssister disease, ovarian cancer, he said, because late-stage ovarian canceris predominantly an intraperitoneal disease. "If we can decrease theamount of intraperitoneal disease by a regional gene therapy approach,"he said, "it is possible that we could have some sort of long-termbenefits to the patient."

He noted several other factors that make ovarian cancer a good targetfor gene therapy studies: Retroviral vectors are stable in peritoneal fluid;there are few competing therapies for late- stage ovarian cancer, whichsimplifies patient accrual; and since ovarian cancer can be measured bylaparotomy, the stability of the vector can be assessed.

Finally, he said, there is a constant tumor suppressor defect in thedisease. "Although the BRCA1 gene is mutated in only 5% to 10% ofovarian cancers, we have found that there is decreased expression of BRCA1in the vast majority of ovarian cancers," Dr. Holt explained.

In a phase I trial of patients with stage III/IV ovarian cancer, researchersat Vanderbilt and the University of Washington are currently instillinginto the peritoneal cavity as much as 20 billion vector particles a dayof LXSN-BRCA1, a retroviral vector that expresses BRCA1, in an attemptto in-crease the level of tumor suppressor.

Twelve patients have been treated so far. They are given four dailyinfusions 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 "somewhatidiosyncratic, not dose related," he said, since it was seen at severaldifferent dose levels. Some patients have had fever and myalgias.

The study has also shown that there is a stable vector in some patientseven with repeat administration, suggesting that immune response is notsignificant. "We've only seen antibody formation to retroviral envelopein 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.