Engineered cells beat cancer in human test

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Published September 1, 2006
In a small study of patients with terminal skin cancer, Maryland scientists have demonstrated for the first time that genetically engineered immune cells can kill off large tumors.The research, conducted by a team at the National Cancer Institute in Bethesda, remains highly experimental, and it worked on just two of the 17 patients in the study.But excited government scientists said it is the first time gene therapy has vanquished an advanced cancer. More important, the technique could serve as a potent new assault weapon against breast, lung and other, more common cancers, researchers said."It's a very important study and potentially a major breakthrough in cancer treatment," said Dr. Ephraim Fuchs, an expert on cancer immunology at the Johns Hopkins Kimmel Cancer Center who did not participate in the research.Beyond its direct therapeutic potential, scientists said, the NCI study is a big shot in the arm for the 16-year-old field of gene therapy - the effort to cure or control disease by introducing new DNA into the body, typically using a harmless virus as a delivery vehicle.Once seen as a potential miracle cure for a wide range of ailments, the technique was criticized for not living up to its initial promise and suffered several high-profile setbacks that brought work in the United States nearly to a halt.A 1999 gene therapy trial at the University of Pennsylvania led to the death of an 18-year-old research subject, causing government regulators to step up oversight of the field.A few years later, three children enrolled in a successful French gene therapy trial developed leukemia. One later died. The Food and Drug Administration responded by briefly shutting down more than two dozen gene therapy experiments in the U.S.But in recent years, gene therapy researchers have quietly been making headway. Today nearly 130 U.S. gene therapy trials are actively recruiting patients for diseases as diverse as AIDS, arthritis, cystic fibrosis and heart disease."The general mood in the field is more realistically upbeat than it was in the past," said Dr. Theodore Friedmann, president of the American Society of Gene Therapy. "We now have some very striking results."One application showing the most promise is gene therapy for cancer, says Friedmann.
Deadly skin cancer In the latest study, published yesterday in the online edition of Science, researchers removed white blood cells, lymphocytes, from 17 people with melanoma, the deadliest form of skin cancer. The volunteers had all stopped responding to other treatments and were believed to have six months or less to live.In the lab, scientists inserted genes into each patient's lymphocytes to make them capable of recognizing the tumor cells. The genes essentially acted as a mug shot of melanoma."It gives the cells a new property that they've never had before," said Dr. Steven Rosenberg, who headed the research team.Finally, scientists coaxed the engineered lymphocytes to reproduce and then injected this new billion-cell army back into each patient's body.Mark Origer, 53, was one of two volunteers in the study who learned that their tumors were melting away after the experimental treatment.Origer first received a diagnosis of melanoma in 1999 after noticing a small mole on his back. The tumors spread to his lymph nodes and liver; by summer 2004, doctors said he had less than a year to live. About the same time, his oldest daughter announced she was planning to marry in the fall of 2005."I wanted to be there to walk her down the aisle," said the Watertown, Wis., postmaster.He enrolled in the NCI gene therapy study and received his genetically altered white cells a few weeks before Christmas 2004.


Much to learn He remembers that, at his first follow-up appointment two months later, Rosenberg was beaming as he and colleagues walked into the hospital room to break the good news."Dr. Rosenberg said, 'We're going to learn so much from you,'" he recalled.Both Origer and the other volunteer who responded to the therapy remain cancer-free today, more than 19 months after the trial. Just as important, none of the patients in the study showed signs of side effects from the engineered cells.Rosenberg, a Johns Hopkins University-trained surgeon, has spent more than two decades trying to harness the body's built-in disease-fighting cells against cancerous tumors, an approach called immunotherapy.The body's immune system is designed to repel invaders, and cancer typically doesn't raise an alert because the proliferating cells within each tumor are the body's own. Melanoma, responsible for 8,000 American deaths a year, is a rare exception.By 2002, Rosenberg and his team had made a breakthrough. They discovered a small population of immune cells that can pounce on melanoma tumors. There are too few, however, to make a dent in the disease.So Rosenberg devised a technique to pinpoint these cancer-sensitive cells, remove them from the body and boost their numbers in a lab dish. Later, he reintroduced these tumor-fighters into patients. The technique is known as "adoptive cell transfer" therapy.The technique was a success, shrinking tumors in half of the patients. But Rosenberg says not all melanoma patients naturally produce cancer-fighting immune cells. The technique is also useless against more common cancers of the breast and lung.So Rosenberg and his colleagues set out to genetically engineer cancer killers from scratch, making the technique potentially more widely applicable.He and others stress that significant work remains to be done before the new gene therapy technique is ready for wider use. One big question: Why did only a small percentage of patients in the new study respond to the treatment?"Clearly, we want to do better than this," says Dr. Patrick Hwu, a melanoma specialist at the University of Texas M.D. Anderson Cancer Center in Houston.One clue Rosenberg and his team are examining is that only Origer and his fellow survivor had high levels of genetically altered immune cells in their blood. Moreover, their levels remained high for more than a year.In other patients, the tumor-fighting cells persisted for only a few months. Scientists don't know why.Rosenberg says the genes used in the experiment could also be to blame. The implanted gene was an old one and might have provided immune cells with a murky mug shot of tumor cells.Rosenberg said he and his team have since identified genes that could be up to 100 times more effective at spotting melanoma than the one used in the current study."There are a dozen different modifications that we're now studying," said Rosenberg.He and his lab have also found genes that could be used to attack other cancers. Rosenberg has applied for FDA approval to treat lung and breast cancer patients with genetically engineered immune cells.Mark Origer, meanwhile, who returns to Bethesda every three months for monitoring, said he plans to celebrate his daughter's first wedding anniversary in a few weeks.