Scientists View Bone Marrow Xenotransplant With Optimism, Caution

Optimism, Caution Date: March 4, 1996
(The Scientist, Vol:10, #5, pg.3 & 6, March 4, 1996)
(Copyright ©, The Scientist, Inc.)

When Oakland, Calif., AIDS activist-now patient-turned-guinea-pig-Jeff Getty received baboon bone marrow cells in December, doctors gave the daring cross-species experiment little chance of working. Now, three months later, scientists are debating not only whether or not the procedure was a success, but also if it was appropriate in the first place. In question also is what the Food and Drug Administration (FDA), which approved the procedure, should do next.

UNDAUNTED: University of Pittsburgh researcher Suzanne T. Iidstad plans to apply for FDA permission to perform another baboon transplant. To date, there are few signs that the baboon marrow cells transplanted into the bone marrow of the 38-year-old Getty, who was dying of AIDS, have "engrafted," or taken hold in his immune system. Because baboons are resistant to HIV, doctors hoped the baboon cells would spur the development of new, HIV-resistant marrow cells, restoring Getty's devastated immune system. On the other hand, Getty, who asked to undergo the procedure fully aware that it would probably fail, appears by all counts healthier than before the experiment began.

Getty is convinced that "as long as I stay healthy, the field of xenotransplantation [interspecies transplantation] will move forward."

Conducting the experiment were University of Pittsburgh transplant surgeon Suzanne T. Ildstad, along with colleagues Steven Deeks, an assistant professor of medicine at the University of California, San Francisco, and Paul Volberding, a professor of medicine and director of the UC-San Francisco AIDS program at San Francisco General Hospital. They and their coworkers plan to continue the research, monitoring Getty for the rest of his life.

They're also planning to reapply to FDA in four to six months for permission to attempt another baboon marrow transplant in a new patient. Though such procedures normally are controlled by an institution's internal review board, FDA steps in when an experimental therapy carries an infectious disease risk or involves manipulating cells outside the body. FDA asked the transplant team to apply for an Investigational New Drug (IND) approval, as if the bone marrow were an untested new drug.

"We've learned a great deal from the trial," said Ildstad, speaking last month to reporters at the annual meeting of the American Association for the Advancement of Science in Baltimore. "The studies are still under way to see if there was engraftment," she noted. "If there is, it's at a low level. Even if there isn't any [engraftment], I don't think we've failed. We learned that the patient tolerated the level of [pre-transplant radiation and chemotherapy] conditioning very well."

Though the Getty experiment apparently has not promoted bone marrow growth, "a failed clinical experiment is not a failure if it builds on our basic knowledge," contends Jeffrey L. Platt, a professor of experimental surgery, pediatrics, and immunology at Duke University. Though it's too soon to know the final results and what researchers will learn, he adds that applying "rigorous scientific standards to clinical research might be a mistake."

Platt states: "The history of medicine is frequently punctuated by advances in which serendipity plays a role; someone makes a discovery that you rationally couldn't predict." But not everyone is convinced the baboon-to-human marrow procedure was appropriate. Virologist Jonathan Allan of the Southwest Foundation for Biomedical Research in San Antonio and other scientists fear the possibility that Getty will be infected by a potentially dangerous baboon virus. Yet it's not specifically Getty whom Allan and others are worried about. Rather, they are concerned that if tissue and organ xenotransplants -- including those involving temporary heart and liver procedures -- become widespread, they may lead to the spread of animal viruses throughout the population, potentially infecting humans.

Allan believes it's too early to know if a baboon disease was transmitted to Getty. "Viruses -- baboon endogenous viruses, herpesviruses, and retroviruses -- may remain latent for years," he says.

Allan deems the experiment a failure. He doesn't see any reason to believe that the baboon cells will work immunologically and bolster Getty's ravaged immune system.

Ironically, an FDA review committee had concluded that the transplant was safe because the experiment would probably not be successful and the likelihood of spreading potentially lethal baboon viruses was extremely low.

Others argue that the only way to solve the United States' organ shortage -- approximately 50,000 patients currently are waiting for organs -- is to attempt experiments such as this. Cross-species transplants may hold a key to a renewable source of organs, they maintain.

Ildstad, director of the division of cellular therapeutics at the University of Pittsburgh Medical Center, was "heartened" by the unanimous (with one abstention) approval by the FDA panel convened to review the protocol. She says that "in my opinion, the potential benefits [of xenotransplantation] outweigh the risks, though we should proceed with caution." And, alluding to many scientists' concerns, she adds that "all testing has shown to date no evidence of baboon virus infection."

ENCOURAGED: Rockefeller University's Stephen Morse thinks the experiment "was worth trying". "I think it [the experiment] was worth trying," comments Stephen Morse, an assistant professor of virology at Rockefeller University in New York, and a member of the FDA committee. "It was worth encouraging despite serious reservations. We know the possibility exists of potentially dangerous diseases balanced against an unknown, though real, risk. There are two questions: Are there potential benefits that outweigh the potential disastrous events, and second, are there ways of reducing the risk to make it more practical?" The researchers hoped that at least 10 percent of the baboon bone marrow would take. They worried that pre-treating Getty -- whose immune system is already weak -- with high doses of anti-rejection immunosuppressive drugs, chemotherapy, and radiation might damage the bone marrow and immune system even more, even hastening death.

"The important thing we learned, while some thought the conditioning might hurt Getty, is in fact it might have helped. He feels better than he has in at least four years," Ildstad says, noting that Getty spent three weeks in San Francisco General Hospital after his transplant on December 6. "He's out sailing -- we can't find him sometimes."

According to Ildstad, Getty's T-cell count, which is a measure of immune system health, is 75 cells per cubic millimeter of blood, his highest in four years and nearly four times the count when he had the transplant. "We don't know the mechanism for that -- that's the nature of a clinical research trial; to open up new questions that open up other strategies," she notes.

What the researchers learn about the conditioning process for AIDS patients should also help in gene therapy trials for AIDS, Ildstad remarks. "The intent of gene therapy is to modify a person's cells and return them to the patient," she explains. "A number of gene therapy centers have been readying for trials with AIDS, and now we have some information for a point at which to begin."

Getty, who terms himself an amateur immunologist, says he is "trying to find answers to the pathogenesis of AIDS." Yet "the magic cure for AIDS is not part of what we're doing," notes Getty. He has had HIV since 1980, and has had three bouts of Pneumocystis carinii pneumonia, among other opportunistic infections.

"I'm calling it [the experiment] a success," asserts Getty. "No one in our group has said there's no engraftment -- it's only been a few weeks. Clinically I'm better than ever; the viral load is way down.

"We set out to show that this was a safe procedure. We've shown that. The secondary goal was to achieve marrow engraftment. We doubted that would happen -- we knew it was a long shot," he states.

"People who said this was ill-fated are wrong," he says. "The only thing that was ill-fated was that we didn't hit the home run on the first try.

"One million Americans will die of AIDS in the next seven years," he points out. "To think we would stop this kind of research to answer a question about an unrelated side effect of this science [potentially spreading a virus] is horribly insulting to those of us with AIDS."

Critical: Virologist Jonathan Allan questions the experiment's safety. Virologist Allan is one of the most outspoken critics of the procedure. Baboons harbor potentially lethal viruses that may be transmitted to humans, he argues, and using baboons as a long-term source of organs for human transplant is problematic because baboons are in short supply. They reproduce too slowly, and are expensive and difficult to maintain. On the other hand, industry is already investing in pig donor cell and organ transplant research. He suggests that FDA make separate guidelines for baboons and pigs. The latter are less costly and more easily bred disease-free.

Allan contends that too little of the science behind the experiment is understood, and that it's too soon for Ildstad to reapply to FDA for permission to perform another transplant. "What is the science telling us? The fact is that there's not enough evidence to justify a second patient," he declares.

Philip Noguchi, head of FDA's division of cell and gene therapy -- which oversees the regulation of the experiment -- disagrees. He points out that the issues of patient and public safety have been adequately addressed in the original protocol, and that it is likely that Ildstad's new application, if she were to attempt the procedure on a second patient, would be for an amended IND.

Ildstad notes that subsequent baboon xenotransplants will not require sacrificing the animal. "There are new growth factors available that cause bone marrow stem cells to migrate into the blood, and these stem cells can be collected like a blood donation," she says. "The reason we [sacrificed the animal] in the first place was that the CDC [Centers for Disease Control and Prevention] and the FDA, concerned about infection and public safety, asked us to archive samples of all tissue from the donor.

If a virus resided only in the liver or another organ, and something happened to the donor, we couldn't study the tissue later.

"I agree we should proceed cautiously and we need to study potential transmission of infectious agents," she maintains. "We need to know whether this field should emerge."

New FDA guidelines currently are undergoing review at the National Institutes of Health, CDC, and FDA. According to an article in the Washington Post (R. Weiss, Jan. 9, 1996, page 13), the guidelines will urge xenotransplant teams to take precautions such as testing animals for known viruses and following up patients to watch for disease development.

According to Louisa Chapman, a medical epidemiologist at CDC in Atlanta, the field is "advancing so rapidly that it makes it difficult to draft guidelines. We can't quantitate the risk." Adds Chapman, who helped draft the FDA guidelines: "We don't suggest step-by-step procedures," but rather provide general instructions and advice to research oversight committees in areas such as breeding and screening donor animals, monitoring patients, and recording data. FDA officials hope the guidelines will be printed for public review in the Federal Register within the next few weeks.

Allan was a member of the FDA panel that ultimately unanimously approved the experiment (though he abstained). He notes that the procedure was allowed based not on the science involved but rather on humanitarian considerations.

Ralph Dell, a professor of pediatrics at the Columbia University College of Physicians and Surgeons and chairman of the Columbia University Health Sciences Institutional Animal Care and Use Committee, helped organize an Institute of Medicine (IoM) workshop in late June on xenotransplantation. Dell has spoken to more than 50 immunologists and virologists about xenotransplants, and he claims that only two -- Allan included -- saw imminent public health danger from spreading infectious animal diseases. He believes that most scientists support careful monitoring of both animal and patient, as does he.

However, Dell, who also observed the FDA hearings on the procedure, notes that several immunologists challenged Ildstad's experiment, calling for further scientific proof of her theory that certain bone marrow cells called facilitator cells would promote engraftment.

The IoM committee plans to release a report, currently under internal National Academy of Sciences review, in the next month or so on the scientific, ethical, and public policies of xenotransplantation.

Ildstad is excited about the possibilities for the field of xenotransplantation as a solution to alleviate part of the organ-shortage problem.

HOPEFUL: Duke University's Jeffrey Platt believes xenotransplants may circumvent human organ shortages. Duke's Platt agrees. He sees such experiments as "driven by serious clinical needs -- most obviously the organ shortage. We have the ability to help patients, but we don't have the organs." Xenotransplantation, he believes, has a bright, albeit uncertain, future.

At least four small biotechnology companies also agree, including Nextran Corp., a Princeton, N.J.-based company with which Platt is working to develop pig organs compatible with the human immune system (F. Hoke, The cientist, Aug. 21, 1995, page 4). In July, Platt and his coworkers received FDA approval to use livers from transgenically altered pigs for bridges in 10 liver-failure patients awaiting human transplants.

Xenotransplantation has many advantages over allotransplantation (transplants between members of the same species). "You could rationally plan a procedure with the kind of organ you want to put in a patient," Platt points out. "With allotransplantation you're stuck with happenstance. You're on a waiting list for an organ, which come from patients who frequently may carry diseases. There's all this hoopla about worrying about transmitting primate diseases to humans, but we transplant diseases from humans to humans all the time -- you can't characterize donors ahead of time." The downside is organ rejection, he says, though he's optimistic about scientists resolving such difficulties.

"Xenotransplantation is ready now for a few appropriately designed studies," remarks Keith Reemtsma, a professor of surgery at Columbia University. In 1963 and 1964, Reemtsma performed several chimpanzee-to-human kidney transplants. Today, he is involved in efforts to transplant pancreatic islet cells from other species to humans to treat diabetes. He agrees that "there's no scenario in which [there are] enough human organs to meet the demand today for placement." Another advantage, he adds, is the possibility of stockpiling animal donors in a "xenograft room."

Intrigued: Researcher David Sachs calls for more animal tests Some researchers, such as David Sachs, a professor of surgery and immunology at Harvard Medical School and director of the Transplantation Biology Research Center at Massachusetts General Hospital, call for more animal testing to better understand the science behind xenotransplantation.

Sachs, whose own work involves pig-primate transplants, acknowledges that he is intrigued by what scientists may ultimately learn from the experiment about xenotransplants and the immune system. However, he regards the Getty case as unique and favors "exploring these kinds of questions [regarding cross-species bone marrow engraftment] in animal models in the future." His approach is "to get a certain procedure working in animal models to where we feel confident that it will be successful. We know that the immune systems of other primates are similar to humans, but when we show this works conclusively there will be more enthusiasm for clinical applications."

Yet Ildstad argues that at some point, for progress to occur, researchers must decide when it is appropriate to do parallel animal and human studies. Infectious disease specialist and team member Marian Michaels agrees.

"I think it's dangerous for science not to move forward because of potential risk," says Michaels, an assistant professor of pediatrics and surgery at the University of Pittsburgh.

"Infectious disease is an issue with any kind of transplant," she notes. "The major risk is to the individual patient. I think it's real [in the Getty case], but how tangible is it? This is only one case."

When considering the experiment, Michaels says she "felt that xenotransplantation, whether involving HIV, or even in a heart transplant, would be in limited number, and that the only way to learn [whether and how xenotransplants work] is with [carefully designed] human experiments."

Sachs acknowledges that the field of transplantation "is in a paradoxical situation."

He comments: "It has worked so well that the need for organs has outstripped availability. To move forward we need another source of organs. That's why xenotransplants are so attractive. The world is ready for xenotransplants, but we have to show it will work as an effective, long-lasting treatment."

Undaunted: University of Pittsburgh researcher Suzanne T. Ildstad plans to apply for FDA permission to perform another baboon transplant.