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SEATTLE-Targeted Genetics Corporation’s tumor suppressor gene product, tgDCC-E1A, is currently being tested in two phase I trials.
SEATTLETargeted 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 becausethey do not generate a specific immune response or produce any major toxiceffects, H. Stewart Parker, president and CEO of the company, said in aninterview 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 intothe pleural cavity of breast cancer patients and the peritoneal cavityof ovarian cancer patients whose tumors overexpress HER-2/neu.
The other trial involves direct intra-tumoral injections of the productin patients with breast, head and neck, or small-cell lung cancer. In bothtrials, patients receive weekly doses of tgDCC-E1A for up to six months.
The intracavitary trial is being conducted at The University of TexasM.D. Anderson Cancer Center; Rush Presbyterian-St. Luke’s Medical Center,Chicago; and the Virginia Mason Medical Center, Seattle. The direct injectiontrial is taking place at Wayne State University, Detroit; The M.D. AndersonCancer Center; and Rush Presbyterian-St. Luke’s.
In addition to testing tgDCC-E1A for safety, both trials are designedto demonstrate E1A transfer into tumor cells, determine the optimum dose,and measure tumor regression. “So far, everything is on track, and we havenot seen any untoward effects,” Ms. Parker said. The company expects tocomplete the trials by the end of this year or early 1998.
The E1A gene product physically targets tumor cells via direct intratumoraldelivery. “The product doesn’t have molecular targeting capability at thispoint,” Ms. Parker said, “but we’re working on delivery systems that wouldincorporate molecular targeting for use at a later stage.”
Mechanisms of Action
In mouse studies, the cationic lipid-E1A gene product has been shownto suppress HER-2/neu function in breast and ovarian cancer models, andto significantly increase the long-term survival of the animals.
The company believes, however, that the E1A gene may have potentialbeyond its effects on the HER-2/neu oncogene (seefigure). “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 tumorcells into apoptosis.”
In a preclinical study using tumor cell lines that did not overexpressthe HER-2/neu gene, E1A was found to reduce tumor growth in mice. In thissame study, E1A was shown to sensitize tumor cells to killing by chemotherapeuticagents.
“There seems to be a variety of mechanisms for E1A’s tumor-suppressingactivity,” Ms. Parker said, “and we’re still tracking those down. But wehad a premise for moving to human clinical trials based on very good animaldata showing tumor regression with E1A.”