Gene therapy shows hope vs. skin cancer


Published: Friday, September 1, 2006 at 6:01 a.m.
Last Modified: Thursday, August 31, 2006 at 11:33 p.m.
WASHINGTON - A team of researchers from the National Cancer Institute reported Thursday they have successfully treated two cancer patients using "gene therapy," the introduction of genes into the human body for medical purposes.
Two men, both with the rapidly growing skin cancer melanoma, were given immune system cells taken from their own blood and engineered to attack their tumors. They are alive, with no evidence of cancer, 18 months later. Fifteen other patients who got the same treatment died.
The report, published online by the journal Science, is the latest result of a three-decade effort by surgeon Steven Rosenberg to find ways to manipulate the human immune system to fight cancer.
Four years ago, Rosenberg and his colleagues treated a group of melanoma patients with naturally occurring anti-cancer cells extracted from their tumors, and some of those patients also have had long-term disappearance of their cancers. The new report, however, is believed to be the first time that genetically engineered immune system cells - specifically, T lymphocytes - have produced the same effect.
Neither Rosenberg nor others would describe the two patients as "cured." At least five years would need to pass before such a declaration would be considered. And cancer sometimes returns even after that much time has lapsed.
Gene therapy was once viewed as the great hope for treating, or even curing, a long list of diseases. But tests of the concept since the late 1980s have been overwhelmingly disappointing.
"I do consider this a proof of the principle that it can work." Rosenberg said Thursday. "I have every expectation that we can get it to work better."
Response by others in the field was positive but not effusive.
"I think it is an important landmark to see some cancer patients respond to a gene therapy - finally," said Patrick Hwu, a physician and gene-therapy researcher at University of Texas M.D. Anderson Cancer Center in Houston, who was not involved in the new study. "I think that clearly all of us want to do better than two out of 17."
Michael Lotze, professor of surgery and bioengineering at the University of Pittsburgh, said that "the work is heroic. The question is, does it advance the field in a major way?"
While the good response in two patients is encouraging, "in terms of response rates, the overwhelming data is that T cells, even in high numbers, are inadequate to mediate sufficient anti-tumor effects," Lotze said.
In the study, Rosenberg and his colleagues took lymphocytes from the blood and inserted into them genes for a receptor capable of "recognizing" a protein on melanoma cells called MART-1. This would allow the lymphocyte to attach to a tumor cell and kill it.
The patients, all of whom had previously undergone surgery and immune-based treatments, got chemotherapy to temporarily wipe out their immune system. The engineered cells were then re-injected, with the hope they would proliferate as the immune system recovered. The patients also received interleukin-2, which is a cytokine, or immune-system hormone.
One of the patients, a 52-year-old man, had melanoma in his neck, armpit, liver and armpit. It disappeared everyplace but one spot in the liver; surgeons removed that area. The other man, age 30, had tumor in his lungs and just outside them in the middle of the chest. His cancer disappeared also.
The paper published Thursday provided few details of previous treatment the men had received. Rosenberg also did not analyze any of the re-introduced lymphocytes to see if, in fact, they had the ability to kill cancer cells.
Because of that, it is difficult to say with certainty that the engineered cells were responsible for the tumors' disappearance. However, Lotze, the Pittsburgh expert, said "it is unlikely" that it was due to other treatments.
Rosenberg said he and his colleagues have engineered lymphocytes to recognize tumor markers, or antigens, found in about half of all cancers, including breast, colon and lung cancer. He said many of the modified cells have a much better ability to bind to tumor cells than the anti-melanoma cells he used in the study reported Thursday, which was conducted two years ago.
The research team recently applied to the Food and Drug Administration to try the new cells in about a hundred patients. The FDA is expected to respond to the request by mid-September.
Other researchers are working on similar strategies. Hwu, of M. D. Anderson, is engineering lymphocytes that have receptors for substances called chemokines that some tumors put out. This will help the lymphocytes home in on the cancer.
"We need to figure out how to get the T cells to migrate into the tumor more efficiently," he said. "If the T cells are able to recognize the cancer, but are circulating in the bloodstream, then they are not on the battlefield where they need to be."

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