Gene therapy, the radical but unproven strategy of scientifically manipulating genes to combat disease, cleared one of its biggest hurdles yesterday when the government gave researchers permission to use the technique for the first time to treat cancer.
In a matter of weeks, researchers at the National Institutes of Health plan to inject genetically altered white blood cells into three patients with advanced melanoma, a malignant skin cancer for which there is no effective treatment once the cancer has spread from the skin to other organs.
The scientists hope the altered blood cells will find their way to the patient's tumors and will begin churning out a potent cancer-busting compound that could shrink or even destroy the growths.
"What we're trying to do is produce an effective treatment for cancer," said Steven Rosenberg of the National Cancer Institute, who is leading the study. "We're trying to kill cancer cells using the tools of gene therapy."
"It is an important project," said Gerald Quinnan, acting director of the Food and Drug Administration's Center for Biologics, Evaluation and Research, which approved the experimental use of gene therapy for melanoma yesterday.
FDA approval of the radical new technique marks the second time gene therapy will be tried in humans and the first time it will be used to treat a common cancer.
"The principle sounds great," said Dusty Miller, a leading gene therapy researcher at the Fred Hutchinson Cancer Research Center in Seattle. "But in this particular case, whether it works or not is unclear."
The American Cancer Society reports that there will be 27,600 new cases of melanoma in 1990 and that 6,300 people will die. In recent years, the incidence of melanoma has been rising faster than that of any other cancer in the United States.
In September, NIH researchers used gene therapy for the first time to treat an extremely rare disorder of the immune system. The patient, a 4-year-old girl, is being monitored and researchers say it is too early to tell whether the therapy had any effect.
In the next six weeks, Rosenberg and his colleagues will give three melanoma patients transfusions of their own white blood cells, which have been genetically altered to fight cancer. Eventually, as many as 50 patients may be treated. To enter the study, all patients must have advanced melanoma and must be expected to live for no longer than three months without the treatment.
Rosenberg said he and colleagues Michael Blaese of the National Cancer Institute and French Anderson of the National Heart, Lung and Blood Institute are getting about 20 or 30 calls a day from patients desperate for the experimental therapy.
To treat the patients, the researchers will remove special cancer-killing cells called tumor-infiltrating lymphocytes (TILs) from the patient's tumors. These lymphocytes are white blood cells that migrate from all over the body to attack cancer cells.
Tumor-infiltrating lymphocytes naturally produce a powerful compound called tumor necrosis factor (TNF), which eats away at cancer cells. In mice, scientists have observed remarkable improvements following treatment with tumor necrosis factor. Unfortunately, human lymphocytes produce only a tiny amount of the anti-cancer compound, apparently not enough to destroy large or rapidly growing tumors.
So the researchers will insert a pair of genes into the patient's lymphocytes, which increases each cell's production of TNF by a hundred-fold. The gene package includes a bit of DNA called a promoter, which essentially flips the switch that turns on the production of tumor necrosis factor and keeps it on.
The patients will get 3 billion altered cells in their first dose. At the end of 15 weeks of therapy, they will be getting about 300 billion cells per dose. Rosenberg said the first patient already has had cells harvested from his tumors and that in the next few days, the researchers will begin inserting new genes into that batch of cells in preparation for the first injections.
The experiment is an attempt to improve upon mixed results obtained in earlier studies in which cancer patients were treated with unaltered tumor-infiltrating lymphocytes with high doses of a cell-stimulating substance called interleukin-2.
Researchers also have tried injecting patients directly with tumor necrosis factor, but the treatment failed. Rosenberg said that, in humans, high doses of the anti-cancer agent cause shock and body wasting.
He said he hopes that by delivering a large amount of tumor necrosis factor directly to the tumors, the substance's toxicity will be reduced and the tumors will be flooded with the anti-cancer agent.
A piece of malignant tumor containing defensive white blood cells called TILs (tumor-infiltrating lymphocytes) is removed from the patient's skin.
Using the growth-promoter interleukin-2, laboratory scientists stimulate the TILs to grow and divide.
The scientists then insert the gene for a natural anti-cancer substance called TNF into he TILs. At the same time they add a "promoter" that helps cells switch on the cancer-fighting gene, and a "marker" that identifies cells in which the gene has been incorporated.
After the genetically-altered TILs with enhanced cancer-fighting capabilities have multiplied in the laboratory, they are returned to the patient through a transfusion.
If the experiment succeeds, the altered cells will fight the cancer and increase a patient's chances of survival.