Cancer war escalates to genetic weapons.

Cancer war escalates to genetic weapons

Two terminally ill cancer patients this week received infusions of genetically engineered white blood cells designed to attack their intractable tumors, marking the first attempt to use gene therapy against cancer, federal scientists announced. The event comes four months after the first human gene therapy experiment, in which researchers added a missing gene to the blood cells of a child suffering from a deadly immune deficiency (SN: 9/22/90, p.180).

Both cancer patients -- a 29-year-old woman and a 42-year-old man -- have advanced melanoma, a deadly form of skin cancer that had failed to respond to traditional therapies. The experimental approach, which received the final go-ahead from the Food and Drug Administration on Jan. 8, seeks to enhance the tumor-fighting power of the patients' own white blood cells by boosting production of tumor necrosis factor (TNF), a potent cancer-shrinking compound normally secreted in small quantities by those cells. The work is led by Steven A. Rosenberg, R. Michael Blaese and W. French Anderson of the National Institutes of Health in Bethesda, Md.

Several weeks ago, the researchers removed white blood cells called tumor-infiltrating lymphocytes from each patient's tumors. These cells naturally home in on tumors but often lack the power to kill them. The team cultured the lymphocytes in the laboratory, mixing them with partially disabled viruses loaded with extra copies of the TNF gene. The viruses acted as delivery trucks, dropping their TNF-gene packages into the lymphocytes' DNA. This week, after tests showed that the cultured cells had incorporated the TNF genes, the researchers returned the cells to the patients.

"This is an attempt to use genetic techniques to improve medical treatment for cancer patients," says Rosenberg. He adds, however, that "it's going to be a long time" before researchers refine the technique into a commonly available treatment with predictable results. Rosenberg spearheaded the four-year effort that led to federal permission to try the novel therapy on 50 patients.

He and his colleagues remain uncertain whether the current experiment will elicit therapeutic effects. This week's starting infusions of 100 million cells into each patient represent one-tenth the dosage initially proposed by Rosenberg. But FDA regulators, concerned about TNF's potentially toxic effects, limited the number of cells per infusion and disallowed the concurrent infusion of interleukin-2, which the researchers had wanted to add to their experimental cocktail. Interleukin-2 increases TNF secretion in cells bearing the TNF gene and increases their survival in the body. Without it, the engineered cells "don't proliferate and will die off fairly quickly," says Jay Greenblatt of the National Cancer Institute's drug regulatory affairs section.

The gene-altered cells produce less TNF than some nonengineered cells used in other cancer treatments. But if all goes well, additional infusions will boost patients' TNF levels significantly. The researchers have permission to pack larger and larger numbers of engineered cells into the twice-weekly infusions, Rosenberg says. Moreover, the experiment's protocol allows for the addition of some interleukin-2 later in the trials, depending on initial TNF-toxicity findings.

Rosenberg says he and his colleagues continue to look for particular subtypes of tumor-infiltrating lymphocytes that migrate to tumor sites more efficiently than others. By adding the TNF gene only to the more efficient subtypes, they hope to increase TNF's anticancer effects while minimizing its toxicity to healthy tissues.