Plans to carry out the first attempt at human gene therapy -- the long-awaited attempt to cure diseases by inserting foreign genes into a patient's cells -- received a green light yesterday from a key federal review panel.
The first patients to undergo the ground-breaking procedure, probably this fall, will be people with a lethal form of skin cancer and children with an inherited illness that robs them of an immune system.
The approval was granted by a special panel of experts convened by the Recombinant DNA Advisory Committee of the National Institutes of Health. Although the full committee is to meet today to consider the plans, its approval is considered a virtual certainty.
In one set of experiments, a gene for a powerful hormone will be put in the white blood cells of people dying from advanced malignant melanoma, a skin cancer for which there is no effective treatment.
The white blood cells, called tumor-infiltrating lymphocytes, or TIL, normally attack the cancer, but not well enough to destroy the tumor. The gene to be inserted into the cells will command them to secrete a substance, called tumor necrosis factor (TNF), that kills tumors by preventing them from developing a blood supply.
Physicians at the National Cancer Institute have learned to remove the TIL cells, grow billions of them in the laboratory and return the cells to the body to attack the cancer.
About half the patients improve after treatment with massive amounts of TIL cells; some completely recover. But the rest get worse and die.
"There is a need to improve this form of therapy," said NCI's Steven A. Rosenberg. "One way to improve it is to alter the TIL to improve their killing capacity."
The technique was developed in mice by Rosenberg, along with W. French Anderson of the National Heart, Lung and Blood Institute, and NCI's R. Michael Blaese.
"There is no more effective agent for tumor dissolution in mice than TNF," Rosenberg said. People, however, cannot tolerate injections of large quantites of TNF, so another way is needed to get high concentrations of the hormone to the cancer cell.
Genetically altering white blood cells to produce TNF inside the tumors should solve that problem and produce dramatic results, Rosenberg predicted.
Blaese and Anderson also received approval to treat 10 children suffering from an inherited malfunction of their immune systems that leaves them susceptible to every passing germ. The best known case involved a boy known only as David who spent his life in a sterile plastic bubble in Houston to protect him from infections.
The disease is caused by the victim's cells being unable to make a key enzyme. Children with the disease now receive regular injections of the missing enzyme, but it does not always rebuild their immune system. In the gene therapy experiments, these children will have some of their white blood cells removed each month and given the gene to make the missing enzyme inside the blood cells, Blaese said.
Although the gene-repaired cells will produce the enzyme, treatment is not yet considered a cure since most of the white blood cells will die after a few weeks, Blaese said. Enough of them may persist long enough, however, to restore a normally functioning immune system.
Gene therapy is the result of more than a decade of work to develop techniques to splice specific bits of genetic material -- individual genes that command cells to make specific substances -- into human cells. The treatment turns cells into factories that can manufacture certain needed proteins anywhere in the body. Genes provide the blueprints cells need to guide their protein-making apparatus. The proteins function as enzymes that control chemical reactions, or as powerful hormones that signal cells to carry out some action, or, in still other cases, the proteins act like the girders of a building.
Anderson said patients probably will not begin receiving the gene-altered cells until sometime in the fall, though Rosenberg said he is ready to start tomorrow.