'Traffic direction' drug linked to reducing transplant hazards
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An existing drug dramatically reduced the most serious complications of bone marrow transplants, University of Pennsylvania researchers are reporting today.
The finding could point the way someday toward an entirely new method of preventing the body from "rejecting" transplanted organs of all kinds in the future, experts said.
The work demonstrates a possible new approach to transplants of donated bone marrow, said Joseph Antin, a professor of medicine at Harvard, who was not involved with the study.
"It is the first time that someone has tried to do this, which makes it fascinating in itself," Dr. Antin said. "Now what we need to do is confirm it" and compare how patients fare with and without the drug in a randomized trial.
Dr. Antin chairs a committee in the Blood and Marrow Transplantation Clinical Trials Network that will design such a trial that could begin in a year or so.
For decades, transplants of nearly all organs have been possible only with the use of powerful medications that suppress the immune system so that it doesn't attack the alien organ. But those immunosuppressant drugs can be toxic to other parts of the body and leave recipients vulnerable to dangerous infections, often for the rest of their lives.
Rather than searching for better immunosuppressant drugs, the Penn researchers asked a different question: "What if we let the immune cells do their job" -- attacking cancers and other diseases -- "and we just tell them where to go and where not to go?" said Ran Reshef, lead author of the paper published today in the New England Journal of Medicine.
It turns out that the traffic signal already exists. It is maraviroc, a drug that has been on the market for five years to treat HIV.
The bone marrow study evaluated only 35 patients, and the first-time finding must be replicated in larger and longer trials. Whether the mechanism would work with transplants of other organs is at this point hypothetical.
Still, several independent researchers said the concept is sound, and the problem it tries to solve -- organ rejection -- is major.
"Transplant surgeons would love to do two things: to operate during the day" and avoid rejection, said Cataldo Doria, director of transplantation at Thomas Jefferson University Hospital, who, like others, praised the study as "promising."
The Penn study tested the HIV drug for prevention of graft-vs.-host disease, the most serious complication of donor bone marrow transplants. About 10,000 Americans a year receive these transplants, often after other treatments for leukemia and other cancers have failed.
Because the bone marrow creates immune cells along with blood cells, a transplant imports a new immune system to use against the cancer. To the donated immune system, the recipient's entire body is alien.
Attacks on organs create graft-vs.-host disease in 30 percent to 70 percent of patients.
After the researchers added maraviroc to the standard immune-suppressing regimen for 33 days, they found that just 6 percent of the patients developed a severe form of the disease; typically, 22 percent would have.
After one year, 15 percent of the patients developed severe disease, compared to the normal 29 percent. There were few side effects.
The early-phase trial had been intended to test only the safety of the drug. "We didn't really expect to see any efficacy results," said Dr. Reshef, who added that the finding "was amazing even to us."
If future trials are successful, he and others predicted that maraviroc could become a supplement to standard therapy for donor bone marrow transplants, probably not a replacement.
Maraviroc is made by Pfizer, which won approval of the drug for HIV in 2007. It did not initiate the Penn study but contributed funding, as did the National Institutes of Health, the Leukemia and Lymphoma Society and other groups. A Pfizer spokeswoman said the company would not speculate about the findings.
The drug treats a specific type of HIV by blocking the path, known as a CCR5 receptor, that the virus uses to enter immune cells.
For graft-vs.-host disease, the researchers took advantage of an entirely different mechanism, known as chemotaxis, which controls where and when cells move around the body.
Just as traffic lights along a street must be turned on by an electrical current before they can direct cars to a location, the CCR5 receptors on cell surfaces must receive specific chemical signals called chemokines to direct the immune cells to the liver.
Maraviroc is known as a CCR5 antagonist because it attaches to the same receptors and blocks the chemokines, leaving the cells without direction and protecting the liver from attack.
Graft-vs.-host disease is most severe in the liver and gut; CCR5 is involved with trafficking immune cells to those same organs.
After a donor bone marrow transplant, immunosuppressive drugs typically are tapered off as the body adapts. By contrast, transplants of "solid" organs -- such as the liver, kidney and heart -- require lifelong suppression of the immune system to avoid attacks on the new organs.
The trial did not investigate whether using a drug to block the CCR5 or other receptors would work with those organs, but researchers said the concept would be the same.
"There have been laboratory experiments that suggest that that's true," said David L. Porter, a senior author of the Penn paper and director of Penn's blood and marrow transplantation program. And studies have found that people with a particular deletion in their CCR5 receptor are less likely than others to reject a transplanted kidney, he said.
In an unrelated study published last month, researchers at Thomas Jefferson University used maraviroc to prevent highly aggressive breast cancer cells from being trafficked -- in this case, metastasizing -- to other organs in mice, where they can kill.
Marcel van den Brink, the head of hematological oncology at Memorial Sloan-Kettering Cancer Center in New York, noted that the concept of "blocking trafficking" has been pursued since the 1990s but this is the first trial that appears to have had success.
For solid organs, "I think it is possible," he said, "maybe for the same organs that showed [positive results] here, such as the gut and liver."
Daniel Weisdorf, director of the adult bone marrow transplantation program at the University of Minnesota Medical Center, said research still needed to prove that it was the trafficking mechanism rather than something else that caused what he termed "very interesting and promising" findings for bone marrow transplants.
"If there is directed signaling that tells lymphocites to go to a kidney and attack a transplanted kidney," he said, then something like this "might work really well."
First Published July 12, 2012 12:00 am