The landmark baboon bone marrow transplant undergone by Jeff Getty last month in San Francisco raises the hope--albeit a remote one--of a bold new way to prolong the lives of AIDS patients by increasing their ability to fight off the opportunistic infections that are the cause of most AIDS-related deaths.
But the research behind that controversial transplant may have far broader ramifications. In that work, scientists discovered a so-called facilitator cell that they think allows foreign immune cells to take up residence in a new host. They are pinning their hopes for the 38-year-old Getty's success on the possibility that baboon facilitator cells will allow the transplant to succeed.
Even if the baboon cell experiment fails because of cross-species incompatibility, as most scientists believe it will, four young cancer patients in Houston and Pittsburgh, none of whom has AIDS, are providing evidence that the facilitator cell may make it possible to treat a variety of diseases.
The four men, each in the 35-45 age group, were in the terminal stages of leukemia or lymphoma and in desperate need of a bone marrow transplant to save their lives. As is the case with as many as 70% of all such patients nationwide, no compatible donor was available.
But using the new technology developed by Dr. Suzanne Ildstad of the University of Pittsburgh Medical Center, surgeons there and at M.D. Anderson Hospital in Houston transfused each with mismatched bone marrow from a parent.
In all four cases, the donor marrow did not match the patient's own system in at least two of the six sites immunologists use for gauging compatibility. The sites, called HLA antigens, are found on the surface of every cell in the body. Normally, such a gross mismatch would lead to a catastrophic graft-versus-host reaction in which the donor marrow attacks the recipient's body. Such mismatches are virtually 100% fatal within two weeks after the procedure.
But all four men who received the mismatched grafts are now alive and healthy 10 to 20 weeks after the procedure, Ildstad said, and the grafts have taken hold. A fifth leukemia patient who received a mismatched graft died of a fungal infection unrelated to the donor bone marrow.
"The fact that all of the donor bone marrow has engrafted and none of the patients has had severe graft-versus-host disease, we think, is very encouraging," said Dr. Richard Champlin of M.D. Anderson.
He plans to transplant an additional 35 mismatched patients in the first stage of his study of the technique.
If the technique proves successful, it could have a major impact on cancer therapy. More than 30,000 children and adults annually are found to have diseases such as leukemia and aplastic anemia, and for many of them, their only hope for survival is a bone marrow transplant.
The relatively small doses of chemotherapy and radiation used in conventional leukemia treatments are often not enough to eradicate all cancer cells. Much larger doses will kill the problem cells, but they also kill all the patient's healthy immune cells, leaving them vulnerable to infections.
Bone marrow transplants were devised nearly two decades ago as a way to restore the immune system after such massive therapy.
A recent large study at the Fred Hutchinson Cancer Research Center in Seattle showed that the five-year survival rate for leukemia patients who received a bone marrow transplant was 50%, compared to 20% for those who received chemotherapy or radiation alone.
Surgeons are also increasingly using the technique as a last-ditch treatment for breast cancer and certain other types of solid tumors.
In addition, researchers are experimenting with bone marrow transplants as therapy for a variety of genetic disorders, including sickle cell disease, thalassemia and ADA deficiency.
But only 30% of the patients have matched siblings or other family members who can serve as donors. Success with the new technique could open a new pool of donors, including--if the Getty experiment works--animals.
"We are cautiously very optimistic," Ildstad said recently. Success would affect other types of transplants as well. A growing body of evidence suggests that a successful bone marrow transplant can pave the way for transplants of other organs, inducing a "tolerance" to foreign tissue that might allow drug-free transplants, according to Dr. Nancy Ascher of UC San Francisco.
Ildstad began looking for the facilitator cell, she said, when she first noticed evidence in animals that something in the bone marrow could help make the graft take. She ultimately developed ways to isolate the cell, which accounts for about 0.5% of all the white cells in bone marrow. However, she does not yet know how the facilitator cells work.
Some researchers deny the existence of such cells. In August, the prestigious British journal Lancet ran a scathing review of the then-proposed AIDS experiment, arguing that it was unwarranted and scientifically unjustified.
Among other things, the article charged that the baboon experiment had to be conducted in San Francisco because Ildstad's own institutional review board at Pittsburgh would not approve it, that she had not been able to obtain cross-species engraftment in rodents as she had claimed, and that no one else had been able to isolate the facilitator cell.
In a recent telephone interview, an indignant Ildstad termed the essay "one-sided and inaccurate" and noted that, even though she had tried to ignore the article, she was now going to write a response.
"My own institution did give approval" for the baboon experiment, she said. "We absolutely could not have done it at [UC San Francisco] if we did not have full approval from Pitt."
She also noted that "other people have reproduced" her results, including Champlin, who is isolating the cells for transplants at M.D. Anderson, and Dr. Robert Good of Children's Hospital in St. Petersburg, Fla.
And most important, she concluded, is the human data that has been obtained so far.
"Now that we have transplanted five leukemics, we have very strong human data that supports the rodent data," she said. "I find it amazing that people can claim our data is not good."
Getty, meanwhile, went home from the hospital last week in apparent good health, but it will be weeks to months before the team knows if the baboon cells are doing their job. Getty, however, isoptimistic. "To the naysayers who said I would never recover from this procedure," he said, "well, here I am."
In marrow transplants without facilitator cells, surgeos must find a closely matched donor. There are six HLA sites that immunologists match in identifying compatible donors. The more matches, the greater chances of success.
#of % who get HLA graft- versus- % of mismatches host disease fatalities 0 40 20 1 65 50 2 100 100
Source: Dr. Suzanne IIdstad