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Tumor Suppressor Gene Therapy Moves to Phase I Trials

Tumor Suppressor Gene Therapy Moves to Phase I Trials

SEATTLE—Targeted Genetics Corporation’s tumor suppressor gene product, tgDCC-E1A, is currently being tested in two phase I trials.

The company uses a nonviral vector, a cationic lipid called DC-cholesterol, to deliver the gene. Cationic lipids are well suited to gene therapy because they do not generate a specific immune response or produce any major toxic effects, H. Stewart Parker, president and CEO of the company, said in an interview with Oncology News International.

Both trials are expected to enroll about 24 patients with advanced cancer. In one study, the drug is being given as an intra-cavitary infusion into the pleural cavity of breast cancer patients and the peritoneal cavity of ovarian cancer patients whose tumors overexpress HER-2/neu.

The other trial involves direct intra-tumoral injections of the product in patients with breast, head and neck, or small-cell lung cancer. In both trials, patients receive weekly doses of tgDCC-E1A for up to six months.

The intracavitary trial is being conducted at The University of Texas M.D. Anderson Cancer Center; Rush Presbyterian-St. Luke’s Medical Center, Chicago; and the Virginia Mason Medical Center, Seattle. The direct injection trial is taking place at Wayne State University, Detroit; The M.D. Anderson Cancer Center; and Rush Presbyterian-St. Luke’s.

In addition to testing tgDCC-E1A for safety, both trials are designed to demonstrate E1A transfer into tumor cells, determine the optimum dose, and measure tumor regression. “So far, everything is on track, and we have not seen any untoward effects,” Ms. Parker said. The company expects to complete the trials by the end of this year or early 1998.

The E1A gene product physically targets tumor cells via direct intratumoral delivery. “The product doesn’t have molecular targeting capability at this point,” Ms. Parker said, “but we’re working on delivery systems that would incorporate molecular targeting for use at a later stage.”

Mechanisms of Action

In mouse studies, the cationic lipid-E1A gene product has been shown to suppress HER-2/neu function in breast and ovarian cancer models, and to significantly increase the long-term survival of the animals.

The company believes, however, that the E1A gene may have potential beyond its effects on the HER-2/neu oncogene (see figure). “We think E1A works in a number of different pathways,” Ms. Parker said. “We know from animal models that it down-regulates HER-2/neu, but it seems to have some broader effects as well, related to cycling tumor cells into apoptosis.”

In a preclinical study using tumor cell lines that did not overexpress the HER-2/neu gene, E1A was found to reduce tumor growth in mice. In this same study, E1A was shown to sensitize tumor cells to killing by chemotherapeutic agents.

“There seems to be a variety of mechanisms for E1A’s tumor-suppressing activity,” Ms. Parker said, “and we’re still tracking those down. But we had a premise for moving to human clinical trials based on very good animal data showing tumor regression with E1A.”

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