Melanoma shrinks from human monoclonals.

Melanoma Shrinks From Human Monoclonals

The first attempt to deploy human monoclonal antibodies in the fight against cancer has resulted in dramatic disappearance of tumors in patients with recurrent, malignant melanoma. Researchers say the experimental therapy--involving antibodies produced by cultured human cells -- proved more effective and had fewer side effects than any current treatment for this tenacious form of skin cancer.

Surgery can cure 90 percent of early-stage melanomas. But when the black growths recur on the skin or the malignancy spreads to a new site, death generally follows within eight to 12 months.

Researchers studying this and other cancers have long sought to use monoclonal antibodies -- biological molecules that bind only to particular target cells -- to attack tumors directly or to shuttle toxins selectively to cancer cells. But most scientists make these antibodies in mouse cells, and the mouse "signature" that remains often triggers an immune reaction in human recipients. This can block the monoclonals' action, and sometimes causes a life-threatening form of immune shock.

Human monoclonal antibodies offer an obvious solution. But researchers who have coaxed human cells to produce such antibodies have obtained only small quantities and at great expense.

Donald L. Morton and Reiko F. Irie of the University of California, Los Angeles, figured that even small quantities of the antibodies might prove useful if applied directly to tumors. They focused on antibodies against gangliosides -- molecular markers found on cancer cells but not on normal cells. Typically, a person with melanoma has only one of three kinds of gangliosides on his or her tumor cells.

The researchers isolated and cultured three kinds of white cells from melanoma patients. Each of these cell lines makes antibodies that bind to a specific ganglioside. When one of these antibodies binds to its matching ganglioside on a cancer cell, it triggers an immune response that kills the cell.

Morton and Irie injected tiny amounts of anti-ganglioside antibodies directly into the cancerous growths of 25 patients with recurrent melanoma. Some of these patients received a randomly assigned antibody. Of those, about 40 percent showed complete loss of skin tumors within days or weeks. For the other patients, the researchers first biopsied and analyzed the tumors to determine which marker the cancer cells bore. All of those patients' tumors disappeared after injection with the appropriate matched antibody, Morton said this week at the annual meeting of the American Society of Clinical Oncology in Washington, D.C.

Carol Westbrook, a University of Chicago oncologist, calls the results "quite impressive" and "very promising." Still, she notes, patients with recurrent melanoma face a high risk of death from metastases to the brain or other vital organs not accesible by direct injection. Indeed, most patients treated with the experimental antibodies have since died from melanoma metastases, although some have survived, including one who has lived three years beyond treatment.

"The desirable thing would be to have enough of the antibody so we could give it systemically and have it go all around the body," Morton says. "Hopefully in a year or so we'll be able to make these things in large quantities at a reasonable cost."

The researchers say they have seen no ill effects from their therapeutic molecules. Oddly, Morton adds, tests indicate that some patients produced significant quantities of their own anti-ganglioside antibodies in response to the injections. "We're activating specific immunity with this treatment," he says. "We don't know how, but we are." In Morton's view, that observation hints that scientists may someday induce the body to make its own supply to these antibodies to fight metastatic melanomas hidden in other organs.