Possible new therapy for lymphoma and leukemia patients

Marty Holmes, a landscaper from Stockton, Calif., had never heard of a regulatory T cell before his doctor suggested that it could be the key to helping him survive his cancer.

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

Findings published in the Sept. 29 issue of the New England Journal of Medicine suggest that the new therapy pioneered at Stanford University School of Medicine has paid off for Holmes and other lymphoma and leukemia patients. Holmes became the 40th person to undergo this procedure after Stanford researchers had shown that it could boost the relative levels of regulatory T cells in the immune system of mice - an effect that turned out to be beneficial before undergoing a hematopoietic (blood) stem cell transplantation, a common treatment for blood cancers.

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

The new method tested at Stanford appears to retain the desired result of the transplantation - killing the cancerous cells - without inducing the acute form of graft-versus-host disease. "It allows you to throw out the one effect but not the other," said Samuel Strober, MD, professor of medicine (immunology and rheumatology) and the senior author of the study.

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

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

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

The treatment was not as effective in stemming the less-serious, chronic form of graft-versus-host disease. The study found no apparent difference in the typical rates of the chronic form of the condition among the patients who survived more than 100 days after transplantation.

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

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

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

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

It makes sense that the regulatory T cells - a tiny subset of immune cells - could play such a vital role in stemming graft-versus-host disease: These cells appear to act as the immune system's peacekeepers, signaling to other immune cells to hold off from attacking an intruder. Thus, it seemed promising to use them to stop the 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 that regulatory (formerly called suppressor) T cells even existed. Through the years, he fine-tuned a method to harness the elusive cells' immune system-soothing abilities in mice. Using a combination of irradiation and antibodies, he was able to preferentially boost the mice's regulatory T cells from about 1 percent of the total T cells to more than 90 percent. The treated mice had a dramatic reduction in acute graft-versus-host disease compared with untreated mice following a blood 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 strategies for improving blood stem cell transplantations as director of the blood and marrow transplantation program of the Saskatchewan Cancer Agency until moving to Stanford in 2001. Together, Lowsky and Strober modified the 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.

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

In Holmes' case, the incoming cells - shipped from Germany - were from an unrelated donor who was not completely matched. Lowsky explained that without using the regulatory T cell-boosting procedure, Holmes would have been likely to experience a great deal of graft-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 chronic graft-versus-host disease - skin rashes and sores in his mouth - he has gone from a partial remission to complete remission. Indeed, Holmes said he noticed an immediate improvement following transplantation. "I was gaining weight and getting my energy level back," he said, "but I thought the only way to know for sure was to test myself, to force myself to do something really challenging."

A few months ago, Holmes, who refers to himself as "The Cancer Challenger," decided to do a marathon without any prior training just 10 days before the event and less than a year after his transplant. At a follow-up clinic visit after he had completed the race, Holmes said Lowsky was amazed to hear that he had undertaken such a challenge at that stage of his recovery. Lowsky immediately looked up the race results online. Sure enough, he found that Holmes had placed 15,354th.

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