April 14, 2003
The state of the art in stem cell transplantation
Fine-tuning the response
Wendy Haskell and Jerome Ritz, MD, handle a bag of stem cells.
Efforts to tame GVHD are, in fact, following several tracks, some based in the clinic, some in the lab, some shuttling between the two.
New medications are a prime area of study. One of the most promising is a natural antibiotic called rapamycin, produced by a soil organism on Rapa Nui (Easter Island), off the coast of Chile. Attempts to use the compound as an antibiotic for humans didn't have much success, but Joseph Antin, MD, conceived of another use while attending a seminar on kidney transplants a few years ago.
"A physician reported that patients treated with low doses of cyclosporine [a standard anti-GVHD drug] and rapamycin had low rates of graft rejection and did not experience kidney problems," says Antin, chief of stem cell transplantation at Dana-Farber and medical director of bone marrow transplantation at BWH. "I inferred that if it works so well in kidney transplants, it may have similar benefits for stem cell transplant patients."
Recent clinical trials are bearing out those hopes. A three-drug regimen of rapamycin, tacrolimus, and methotrexate has produced a better than 50-percent reduction in the risk of graft-versus-host disease among transplant patients at the greatest risk for this condition, Antin and his colleagues have found.
Both rapamycin and tacrolimus bind to proteins inside cells, altering the proteins' physical structure. When T cells try to use these reshaped proteins, they're prevented from responding to signals that would ordinarily cause them to storm the body's normal tissue. Because these two drugs achieve the same effect by different routes, lower doses of them can be as potent against GVHD, with fewer side effects, than large doses of either one.
"The early results from our trials are very exciting," Antin reports. "We have been looking for ways to reduce transplant-related side effects for many years, and these data tell us we are on the right track."
Another strategy for disarming donated tissue has been studied at Dana-Farber for more than 15 years. Researchers reasoned that if it were possible to remove T cells from donor marrow before it was infused into patients, the marrow's ability to mount a harmful assault on its new host would be diminished.
In the 1980s, Institute investigators were the first to demonstrate that the technique, called "T-cell depletion," could be done safely and reduce GVHD, even as it lowered the level of antirejection drugs needed by patients.
"T-cell depeletion is not necessarily a panacea," notes Dana-Farber's Robert Soiffer, MD. "There is the potential that, along with removing the T cells that cause graft-versus-host, we're also removing the T cells responsible for the graft-versus-leukemia effect."
For patients, no less than for doctors, the goal is to have the best of both worlds: a way to shut down GVHD without weakening the GVL benefit. Researchers have tried several approaches. One is to follow the transplant with an injection of cytokines, natural substances that can restrain a T-cell attack. The results of studies using this method have been heartening, Soiffer remarks.
Equally promising is a technique that seeks to sift out only those T cells thought to be involved in graft-versus-host disease. "We found over time that patients who developed GVHD had a disproportionately large number of the CD8 type of T cells," Soiffer says. So he, Ritz, Alyea, and physician assistant Christine Canning began a clinical trial in which CD8 T cells were purged from donor tissue before being implanted in patients. "We found that it was possible for patients to have anti-leukemic activity without necessarily developing GVHD," he adds.
Researchers then undertook a much larger study of the procedure in patients who received stem cells from a relative. The results of that trial, which has just ended, are so encouraging, Soiffer says, that it has spawned a similar study for patients whose transplants come from unrelated donors.
Ideas from the lab Along with these main currents in transplant research are a variety of other studies aimed at boosting the procedure's advantages while reducing its risks. Jerome Ritz and his laboratory team are leading efforts to pinpoint genes involved in GVHD and the GVL effect and to identify the minute insignia on normal cells that mark them for attack by donor T cells. A recent gift from the Pasquarello family of Sudbury, Mass., has enabled the Institute to set up a system for collecting and analyzing blood samples for genes associated with GVHD.
Other researchers are seeking ways to diminish infection risk among transplant recipients. Many patients are now vaccinated against infectious agents before undergoing transplants. A clinical trial is also under way of a new antibiotic designed to prevent fungal infections. And a novel medication is successfully being tested for an infrequent, but potentially fatal, aftereffect of transplantation called hepatic veno-occlusive disease.
All these efforts are resulting in real, palpable progress and growing hope for transplant patients. Translating those advances into statistics, however, is difficult because much of the work is very recent and because researchers are sorting out the combinations of treatments that work best for specific diseases.
"We know that GVHD rates have dropped among those receiving related donor transplants from 60 to 70 percent 15 years ago to 10 to 30 percent today," Soiffer notes. "We're confident that the advances we're making now, because they're coming in so many different areas, will improve the outlook for transplant patients even more in the years ahead."
(This story first appeared in the Winter/Spring 2003 issue of Paths of Progress.)
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