New blood transplant method stops fatal side effect
Sep 29, 2005 - 8:34:38 PM
Findings published in the Sept. 29 issue of the New England Journal of Medicine suggest that the new therapy pioneered at Stanford University School of Medicine has paid off for lymphoma and leukemia patients. Marty Holmes, a landscaper from Stockton, Calif., became the 40th person to undergo this procedure after Stanford researchers had shown that it could boost the relative levels of regulatory T cells in the immune system of mice - an effect that turned out to be beneficial before undergoing a hematopoietic (blood) stem cell transplantation, a common treatment for blood cancers.
Blood stem cell transplantation replaces the cancerous blood cells of a leukemia or lymphoma patient with those from a healthy donor. The transplantation cures the cancer, but in up to 80 percent of the cases there is a potentially deadly side effect: The donor's incoming immune cells attack the patient's body as "foreign" in what is known as graft-versus-host disease.
The new method tested at Stanford appears to retain the desired result of the transplantation - killing the cancerous cells - without inducing the acute form of graft-versus-host disease. "It allows you to throw out the one effect but not the other," said Samuel Strober, MD, professor of medicine (immunology and rheumatology) and the senior author of the study.
Among the 37 study participants included in the National Institutes of Health-funded clinical trial, there was more than a tenfold reduction in the incidence of acute graft-versus-host disease. Only 5 percent, or just two patients, experienced the acute form of the disease.
"You would have expected something in the order of 30 to 60 percent incidence of severe graft-versus-host disease in these patients, according to conventional methods," said Strober. "And it didn't look like there was a price to be paid for this major reduction," he added, explaining that the patients did not have any higher rate of infections or relapse.
The majority of patients who were in partial remission went into complete remission, and those who were in complete remission didn't relapse over the course of the three-year study.
The treatment was not as effective in stemming the less-serious, chronic form of graft-versus-host disease. The study found no apparent difference in the typical rates of the chronic form of the condition among the patients who survived more than 100 days after transplantation.
Acute graft-versus-host disease occurs within 100 days of transplantation and involves the donor immune cells attacking the host's skin, intestines and liver. It is lethal in up to 40 percent of the cases. Chronic graft-versus-host disease is characterized by such long-term problems as dryness of the eyes and mouth, skin rashes, stiff joints, weight loss caused by intestinal scarring, and more infections due to a weakened immune system.
"We didn't seem to impact much on the incidence of chronic graft-versus-host disease, maybe a bit," said the paper's first author, Stanford assistant professor of medicine Robert Lowsky, MD. "With the acute form we did wonders, and acute is often the more worrisome complication."
Robertson Parkman, MD, an immunologist who was not involved in the study, said that the new procedure "is definitely a significant improvement" over the existing methods. He did, however, find it a bit problematic that the patients continue to show some chronic graft-versus-host disease. "Reducing acute graft-versus-host disease is a good thing, but this approach may not be as much of a total panacea as we'd like it to be," said Parkman, professor of pediatrics in the Division of Research Immunology/Bone Marrow Transplant at Children's Hospital Los Angeles.
The Stanford researchers said that more research is needed, and they hope to begin testing their method with other cancer centers soon.
It makes sense that the regulatory T cells - a tiny subset of immune cells - could play such a vital role in stemming graft-versus-host disease: These cells appear to act as the immune system's peacekeepers, signaling to other immune cells to hold off from attacking an intruder. Thus, it seemed promising to use them to stop the newly transplanted cells from attacking the host.
Strober has studied regulatory T cells for more than 25 years. He weathered through a time when many immunologists doubted that regulatory (formerly called suppressor) T cells even existed. Through the years, he fine-tuned a method to harness the elusive cells' immune system-soothing abilities in mice. Using a combination of irradiation and antibodies, he was able to preferentially boost the mice's regulatory T cells from about 1 percent of the total T cells to more than 90 percent. The treated mice had a dramatic reduction in acute graft-versus-host disease compared with untreated mice following a blood stem cell transplantation.
But would the strategy be as successful in humans? To find out, he teamed up with Lowsky, who had experience trying novel strategies for improving blood stem cell transplantations as director of the blood and marrow transplantation program of the Saskatchewan Cancer Agency until moving to Stanford in 2001. Together, Lowsky and Strober modified the mouse protocol to be used in humans.
"The beauty of this study is that it is a practical example of translating an animal model to the clinic," said Lowsky.
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