A step to freedom in transplants

Advance may allow patients to stop taking harsh drugs

By MARILYNN MARCHIONE of the Journal Sentinel staff

May 13, 2001

Surgeons at the University of Wisconsin-Madison and the National Institutes of Health have achieved a breakthrough that's a key step toward freeing transplant patients from the harsh drugs they now take to keep their bodies from rejecting their new organs.

Researchers say that if the early results bear out in larger tests, it's potentially one of the biggest developments since cyclosporine came out in the 1980s and made transplants possible.

"It's phenomenally valuable, and a great advance in the current standard of care. It may avoid or eliminate the need for immune suppression," said Allan Kirk, a transplant surgeon and researcher for NIH and the Navy, who led one of the two studies.

Results were reported Sunday at a transplant surgery conference in Chicago.

People who get new organs usually take a steroid, such as prednisone, and one or two other drugs, such as cyclosporine or tacrolimus, which are called calcineurin inhibitors, for the rest of their lives.

The drugs work in different ways to keep the immune system from attacking the new organ, but they often lead to kidney failure, high blood pressure, heart disease, diabetes or other potentially fatal complications.

"Patients run into very serious long-term risks from their medicines," said Christian Larsen, director of the transplant center at Emory University in Atlanta and an expert on immune suppression research. Finding ways to avoid or reduce these drugs "has been a major focus of the field for the last several years," he said.

But so far, researchers have had only limited success cutting back on either steroids or calcineurin inhibitors and have not been able to discontinue the drugs without organ rejection occurring.

Now the UW and NIH experiments have achieved that and have substituted a low dose of a different type of anti-rejection drug with less severe side effects.

Antibody kills killer cells

Campath-1H kills most of these cells, thereby preventing the initial assault on the new organ. The theory is that as such cells slowly grow back over the next few months, tolerance of the organ gradually develops, and less drugs are needed to prevent rejection than would have been if a full-fledged attack had occurred at the outset.

Kirk explained it this way: "If you remove the cells that could cause rejection at the time the organ is placed, allow the organ to heal and then allow the cells to come back naturally, there is very little rejection response and many times, no rejection response."

UW surgeon Stuart Knechtle did pioneering work over the last few years that showed the concept worked in primates. He started the first human experiments in August under a 20-person pilot study approved by the U.S. Food and Drug Administration.

So far, seven kidney recipients have gotten two doses of Campath-1H, one at the time of transplant and another a day later, and then were put on low doses of the anti-rejection drug sirolimus, sold as Rapamycin or Rapamune.

With an average of six months follow-up, the first six patients show no signs of rejection. The seventh just started showing some signs and is being treated, Knechtle reported.

"It's a significant step forward. It will improve the quality of life of transplant patients" if current results last for many years, he said.

Kirk's study involves eight patients, four of whom got three doses of Campath-1H just before their transplants, and four who got two doses before and one dose afterward.

Results are promising

After that two-week window, some early signs of potential rejection were observed, so patients were given modest doses of Rapamycin and kept on it as their sole drug therapy.

Now, with follow-up ranging from one to 16 months, "all patients are alive and well and at home," Kirk said.

He predicted that transplant patients someday soon will not have to take drugs for the rest of their lives to prevent organ rejection.

"I'm positive of it," he said. "We are very close to understanding the keys to immune tolerance" of foreign organs.

Campath-1H is made by Millennium Pharmaceuticals of Cambridge, Mass. The company is in the final stages of testing it as a treatment for leukemia and lymphoma and is expected to seek U.S. Food and Drug Administration approval for that purpose later this year, the researchers said.

Larsen at Emory said it would be the first time that a drug developed for a completely different purpose - cancer treatment - "was looking extremely promising" and likely to be widely used for transplantation "without a single published clinical trial" on that type of use.

Although this research has been done on kidney recipients, there is no reason to think it wouldn't work for other organs as well, especially since kidneys "are very unpleasant characters when it comes to rejection," said Hans Sollinger, chairman of UW's transplant program.

The UW transplant program performs more than 450 transplants a year, the second-largest volume in the country, behind the University of California at Los Angeles. It has long been a pioneer in organ transplantation, such as developing an organ preservative solution that's widely used today. It also has been a national leader in getting organ donations.