The best defense
by Matthew Cyr
With a study that aims to make bone marrow transplantation safer and more accessible, researchers at Children's Hospital Boston are trying to prove the old saying, "The best offense is a good defense."
Eva Guinan, MD, director of the Hematopoietic Stem Cell Transplantation Program, and her colleagues at both Children's and the Dana-Farber Cancer Institute (DFCI), have been working on a method that will blind a donor's immune system and trick it into ignoring differences between a partially matched donor and a transplant recipient. This would help eliminate complications like graft-versus-host disease (GVHD), a potentially fatal condition in which T cells attack the recipient's tissues.
"We've known for many years that there are illnesses, both benign and malignant, that can be treated with hematopoietic stem cell transplantation," says Guinan. "And we saw that the outcome of the transplant was best if you had a matched sibling donor." But around the world, family size is shrinking. Today only one person in four has a family member who can serve as a donor. And despite a worldwide unrelated donor pool that numbers 5 million potential donors, most people in need of a transplant, especially African-Americans, have an extremely difficult time finding a fully matched donor. While a white person of Northern European descent has a better than 50 percent chance of finding a possible donor, African-Americans, due to more diverse transplant-related genetic issues, have only a 10 percent chance of finding a match in time. Combine that with the risk of GVHD and the fact that it takes approximately four months to find a suitable donor, and it's easy to understand why Guinan and her colleagues have pursued this new avenue for treatment.
Traditional bone marrow transplants involve treating the patient with chemotherapy and radiation to kill cancer cells. Healthy bone marrow is then transplanted from a closely matched donor into the patient, and the immune system is suppressed with medication to stave off GVHD. The problem is that immunosuppression leaves the patient open to infection and other types of cancer.
"You're affecting 90-to-99 percent of the immune system's cells when fewer than one in 100 T cells are involved in recognizing these foreigners known as alloantigens," says Guinan. "So we asked ourselves if we could be more specific and target only those cells responsible for recognizing and attacking the recipient."
It was an aggressive goal, but one built on work done by other researchers, including one of Guinan's collaborators, Lee Nadler, MD, chairman of Adult Oncology at DFCI. He and his research team investigated the biological signals involved in determining whether a T cell attacks a cell that appears to be foreign. Donor T cells recognize recipient cells after the T cells are introduced into the body. Through a process known as recognition, T cells seek out specific antigens on the surface of the recipient's cells. If the antigens are significantly different from those found in the donor's body, and the foreign cell sends the correct stimulatory signal, the T cells attack. This is called the costimulatory signal.
While the process is complicated, Guinan's proposed solution was simple, "If we could shut off the costimulatory signal, then the T cells wouldn't attack the foreign cells and the donor's T cells." This process would eliminate the potential for GVHD while leaving the recipient's newly engrafted immune system capable of fighting off infections and further cancers.
Guinan, Nadler and several other researchers put their new system to the test in a human clinical trial that began in 1996. They recruited patients who had unsuccessfully undergone prior treatments, including chemotherapy, radiation therapy or bone marrow transplants, and collected cells from their blood to be used as representatives of foreign recipient antigens.
The patients were given total body irradiation and chemotherapy to destroy the cancer cells and remaining marrow cells, and they were treated with
the traditional immunosuppressants to guard against GVHD. Healthy bone marrow was then removed
from a donor that shared half their genetic material with the recipient. The marrow and the recipient cells were then treated in CTLA-4-Ig, a chemical agent that inhibits the costimulatory response in the donor T cells. After 36 hours, the donor cells were washed
clean and administered to the recipient intravenously.
partial match worked for Sheila Liriano
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Of the original 12 patients, five survived, and four of those patients are currently in remission (the fifth patient recently had the first late relapse), but perhaps the most promising finding was that none of the seven patients who died had succumbed to GVHD. In fact, even though the rate of severe GVHD in traditional mismatched bone marrow transplants is between 70 and 90 percent, only three of the original 12 patients contracted acute GVHD, and these cases were both less severe than expected and easily managed.
The results of the first study were published in the New England Journal of Medicine in June 1999, and the team has recruited seven more patients for the study. A second clinical trial is now under way. They feel that if they can make bone marrow transplantation safer and less toxic, the treatment could be helpful in treating diseases as diverse as breast and colon cancer, sickle cell disease and rheumatoid arthritis. They also think that it could one day allow for a truly universal donor pool and possibly make all types of transplants, not just bone marrow, safer and more accessible. "We may be able to blind a recipient's immune system to a donor organ they've received," says Guinan. "Then we can treat people who have had kidney, liver and lung transplants."
The process of trying to convince an immune system that its traditional enemy should be seen as an ally has undergone, and will continue to undergo, in Guinan's words, "endless tinkering." But, she says, that's not the point of her research. "In the end, it's not just about developing a successful methodology, it's about whether we can cure cancer and whether we can do it the right way."
