The molecule, developed by a team led by Alan Garen, professor of microbiology and biochemistry at Yale University, will be mass produced at Mount Sinai School of Medicine in New York City for a trial against melanoma, a deadly skin cancer, at the Sidney Kimmel Cancer Center in San Diego.
The treatment has been effective in mice with prostate cancer and melanoma, reports Garen's team in the Oct 2 issue of the Proceedings of the National Academy of Sciences. If further trials are successful, it could be used against a number of cancers, Garen says.The idea of attacking the blood supply of cancers was developed by Dr. Judah Folkman of Harvard University, but his approach using isolated natural molecules to inhibit the growth of blood vessels in cancers has produced only mixed results, Garen says.
So Garen decided to invent a molecule. He started with a natural protein, called tissue factor, which initiates blood clotting. Tissue factor does not circulate in the blood but sits on the inner surface of cells, where it acts as a receptor for another molecule, factor VII, which does circulate in the blood. Tissue factor usually is found only in damaged blood vessels of normal tissue but is present in the fast-growing blood vessels of cancers, Garen says.
When the two molecules combine, with "one of the strongest bonds known in biology," Garen says, blood clots form, a reaction that ordinarily is not damaging enough to kill a cancer. The molecule he has created contains both tissue factor and factor VII and is designed to stimulate an attack by the body's immune defense system.
"Now we have a chimeric molecule with high specificity and sensitivity," Garen says. "When it binds to a blood vessel, it activates the immune response. It will bind to blood vessels in a tumor and not normal cells and will result in an immune response that will destroy them."
Garen calls the molecule an "icon," short for "immunoconjugate." It is delivered by putting the gene that creates it into a harmless virus that is then injected into the body, a technique commonly used in gene therapy. In mice tests, the icon treatment killed not only the main cancer but also the colonies, or metastases, that invade other parts of the body.
"One advantage of this technique is that the blood vessels of all solid tumors express tissue factor, and so this procedure can work for all solid tumors. Other methods have to be tailored for individual tumor cells," Garen says.
For the human tests, "the icon molecules will be derived from human components, and therefore we should have minimal problems," Garen says.
"At this time, the material is being produced in our facility," says Savio Woo, director of the Institute of Gene Therapy and Molecular Medicine at Mount Sinai. "We envision that it will take four to eight weeks for production to be complete, and then a series of tests will have to be done on the product before it can be submitted to the Food and Drug Administration (FDA) for human use."
Those tests will take at least three months, Woo says. "If everything works out, and the FDA gives its blessing, we can then release it to the investigators. Sometime in the spring is a reasonable guesstimate," he says.
The first human trial is planned to include 24 patients with advanced melanoma that has resisted ordinary therapy, says Dr. Albert Deisseroth, president of the Sidney Kimmel Cancer Center. "The trial is slated for late 2001 or early 2002," he says.
What To Do
As with any new concept, the "icon" concept must be shown to be both safe and effective in treating human cancer patients in a limited research setting before more widespread use is possible.
Information about attacking cancer blood vessels is available from the National Cancer Institute.
For more information on blood vessel formation and its role in disease, visit the Angiogenesis Foundation.