New Blood Transplant Method Stops Fatal Side Effect, Stanford Study Finds

Holmes recalled that he didn't bat an eye when the doctors proposedan experimental radiation and drug procedure to help boost these cells,even though it had been tested almost solely in mice. "As long as therewas any percentage of hope, I just shot for that," he said of thedecision he made last year. "I felt privileged to be a human guineapig."

Findings published in the Sept. 29 issue of the New EnglandJournal of Medicine suggest that the new therapy pioneered at StanfordUniversity School of Medicine has paid off for Holmes and otherlymphoma and leukemia patients. Holmes became the 40th person toundergo this procedure after Stanford researchers had shown that itcould boost the relative levels of regulatory T cells in the immunesystem of mice - an effect that turned out to be beneficial beforeundergoing a hematopoietic (blood) stem cell transplantation, a commontreatment for blood cancers.

Blood stem cell transplantation replaces the cancerous bloodcells of a leukemia or lymphoma patient with those from a healthydonor. The transplantation cures the cancer, but in up to 80 percent ofthe cases there is a potentially deadly side effect: The donor'sincoming immune cells attack the patient's body as "foreign" in what isknown as graft-versus-host disease.

The new method tested at Stanford appears to retain the desiredresult of the transplantation - killing the cancerous cells - withoutinducing the acute form of graft-versus-host disease. "It allows you tothrow out the one effect but not the other," said Samuel Strober, MD,professor of medicine (immunology and rheumatology) and the seniorauthor of the study.

Among the 37 study participants included in the NationalInstitutes of Health-funded clinical trial, there was more than atenfold reduction in the incidence of acute graft-versus-host disease.Only 5 percent, or just two patients, experienced the acute form of thedisease.

"You would have expected something in the order of 30 to 60percent incidence of severe graft-versus-host disease in thesepatients, according to conventional methods," said Strober. "And itdidn't look like there was a price to be paid for this majorreduction," he added, explaining that the patients did not have anyhigher rate of infections or relapse.

The majority of patients who were in partial remission wentinto complete remission, and those who were in complete remissiondidn't relapse over the course of the three-year study.

The treatment was not as effective in stemming theless-serious, chronic form of graft-versus-host disease. The studyfound no apparent difference in the typical rates of the chronic formof the condition among the patients who survived more than 100 daysafter transplantation.

Acute graft-versus-host disease occurs within 100 days oftransplantation and involves the donor immune cells attacking thehost's skin, intestines and liver. It is lethal in up to 40 percent ofthe cases. Chronic graft-versus-host disease is characterized by suchlong-term problems as dryness of the eyes and mouth, skin rashes, stiffjoints, weight loss caused by intestinal scarring, and more infectionsdue to a weakened immune system.

"We didn't seem to impact much on the incidence of chronicgraft-versus-host disease, maybe a bit," said the paper's first author,Stanford assistant professor of medicine Robert Lowsky, MD. "With theacute form we did wonders, and acute is often the more worrisomecomplication."

Robertson Parkman, MD, an immunologist who was not involved inthe study, said that the new procedure "is definitely a significantimprovement" over the existing methods. He did, however, find it a bitproblematic that the patients continue to show some chronicgraft-versus-host disease. "Reducing acute graft-versus-host disease isa good thing, but this approach may not be as much of a total panaceaas we'd like it to be," said Parkman, professor of pediatrics in theDivision of Research Immunology/Bone Marrow Transplant at Children'sHospital Los Angeles.

The Stanford researchers said that more research is needed, andthey hope to begin testing their method with other cancer centers soon.

FROM MICE TO MEN

It makes sense that the regulatory T cells - a tiny subset ofimmune cells - could play such a vital role in stemminggraft-versus-host disease: These cells appear to act as the immunesystem's peacekeepers, signaling to other immune cells to hold off fromattacking an intruder. Thus, it seemed promising to use them to stopthe 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 thatregulatory (formerly called suppressor) T cells even existed. Throughthe years, he fine-tuned a method to harness the elusive cells' immunesystem-soothing abilities in mice. Using a combination of irradiationand antibodies, he was able to preferentially boost the mice'sregulatory T cells from about 1 percent of the total T cells to morethan 90 percent. The treated mice had a dramatic reduction in acutegraft-versus-host disease compared with untreated mice following ablood 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 strategiesfor improving blood stem cell transplantations as director of the bloodand marrow transplantation program of the Saskatchewan Cancer Agencyuntil moving to Stanford in 2001. Together, Lowsky and Strober modifiedthe 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.

THE MARATHON MAN

Holmes is certainly glad that he could benefit from the trial.He had been referred to Stanford for a blood stem cell transplantationin July 2004. It had been six years since, at age 38, he had noticed agolf-ball-sized lump in his armpit and found out that he non-Hodgkinlymphoma. Doctors at Stanford identified him as a good candidate forthe new transplantation procedure.

In Holmes' case, the incoming cells - shipped from Germany -were from an unrelated donor who was not completely matched. Lowskyexplained that without using the regulatory T cell-boosting procedure,Holmes would have been likely to experience a great deal ofgraft-versus-host disease because of the differences between Holmes'cells and the donor's that could have triggered immune responses.

Although Holmes has experienced some of the effects of chronicgraft-versus-host disease - skin rashes and sores in his mouth - he hasgone from a partial remission to complete remission. Indeed, Holmessaid he noticed an immediate improvement following transplantation. "Iwas gaining weight and getting my energy level back," he said, "but Ithought the only way to know for sure was to test myself, to forcemyself to do something really challenging."

A few months ago, Holmes, who refers to himself as "The CancerChallenger," decided to do a marathon without any prior training just10 days before the event and less than a year after his transplant. Ata follow-up clinic visit after he had completed the race, Holmes saidLowsky was amazed to hear that he had undertaken such a challenge atthat stage of his recovery. Lowsky immediately looked up the raceresults online. Sure enough, he found that Holmes had placed 15,354th.

"I won't say it wasn't painful," said Holmes, who finished themarathon in seven hours and 13 minutes, mostly walking, "but it doesn'tcompare to some of the things I went through having cancer."