Spring 2003

"There is such a big difference in my life now"

Patients with autoimmune diseases are finding success with treatments originally developed to fight cancer




At first, Sandra Seymour paid little attention to the tingling sensation in her toes. But when it became difficult to grip a frying pan while cooking breakfast for her children, she decided her odd symptoms warranted a visit to her doctor. There, Seymour learned the startling news that she had an autoimmune disease called scleroderma.

Like other autoimmune diseases, scleroderma results from an immune system that turns against the body's healthy tissue. In Seymour's case, which eventually progressed to a more severe form known as systemic sclerosis, the disease attacked her skin, joints and later, her lungs.

"Within a year or two after my symptoms began, I could hardly move my arms and the disease moved into my lungs," said Seymour, a data-billing clerk from Inchelium, Washington, a small town on the Colville Indian Reservation. "I couldn't even make it up a flight of stairs."

With no known cures for systemic sclerosis, Seymour's doctor could only prescribe medications to relieve her symptoms, such as anti-inflammatory agents and drugs to suppress the abnormal immune response. When these proved ineffective, Seymour was referred to doctors at Fred Hutchinson Cancer Research Center, where research was under way on experimental therapies for patients with severe autoimmune diseases. By that time, Seymour had quit her job and was unable to care for her four children.

"None of the medications I had tried was working," she said. "The treatment at Fred Hutchinson was my last chance."

Dr. Richard Nash and his colleagues at Fred Hutchinson treated Seymour with a stem-cell transplant, a technique originally developed for patients with leukemia, a cancer of the blood. During the procedure, she received an infusion of healthy stem cells from her brother, Douglas. Within six months of her therapy, the range of motion in her arms dramatically improved and her lungs began to heal. Today, more than three years post-treatment, the scleroderma-hardening of the skin-has almost gone away, except for the skin on her fingers. And she has regained enough energy to return to work.

Seymour is one of many patients with autoimmune disease who benefit from the diverse research conducted at Fred Hutchinson, where studies of cancer often spawn unanticipated benefits for those with other diseases. In turn, research on immune-system disorders - including scleroderma, lupus and AIDS - often yields new insight into cancer, a disease that researchers suspect results from an immune system that has failed to do its job.

For Nash and colleagues, using stem-cell transplantation to treat autoimmune disease was a logical extension of what they had learned while working with leukemia patients. When patients undergo this procedure, they are treated with high-dose chemotherapy, sometimes in conjunction with intensive radiation, to destroy their cancerous immune system. Shortly thereafter, they are "rescued" with a transfusion of blood-forming stem cells, which hopefully regenerate a healthy new blood and immune system. The stem cells come from a tissue-compatible donor or the patient, who has previously stored them.

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For weeks after a transplant, until a new immune system is established, even a sneeze from a hospital visitor can be enough to put a transplant patient's outcome in peril. Yet the researchers realized that this vulnerable state may have untold benefits for people who suffer from autoimmune diseases, Nash said.

"It was clear to many doctors early on that the immune system is severely affected by the transplant-conditioning regimen," he said. "With that observation, the logical question is: Can we use the same treatment for other diseases which are immune-mediated, such as autoimmune diseases?"

Based on the successful outcomes of patients like Seymour, Nash and his colleagues believe they can. Fred Hutchinson is one of only two institutions in the country to lead clinical trials that use stem-cell transplantation to treat autoimmune disease. Northwestern University Medical School in Chicago is the other.

Autoimmune diseases, which are much more likely to occur in women than men, include about 50 ailments whose symptoms range from mild rashes to life-threatening conditions that attack major organ systems. Disease symptoms differ depending on which tissue is targeted for destruction. In multiple sclerosis, for example, the immune system reacts against myelin, a protein that coats nerve fibers. Loss of myelin leads to neurological symptoms ranging from weakness to paralysis.

Currently, Nash said, treatment at Fred Hutchinson is targeted toward particularly severe autoimmune diseases, including multiple sclerosis, systemic sclerosis and systemic lupus.

"These are considered pilot studies and are for patients who have failed other therapies and otherwise probably would have a 50 percent risk of mortality or severe disability," Nash said.

Other autoimmune patients, he said, exhibit much milder symptoms.

"These diseases don't look the same in all patients," he said. "For example, there are some multiple sclerosis patients who, just by looking at them, you'd never know they had the disease. They might go 20 or 30 years without serious symptoms. We're trying to choose patients who have severe disease, have clearly progressed and have failed other therapies."

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In developing their approach, doctors reasoned that compromising the immune system with high-dose therapy or immunosuppressive drugs would eliminate not only the patient's ability to fight infection, but also the ability to attack itself.

Most patients in these studies have undergone a procedure called autologous transplantation, in which their own blood-forming stem cells are collected prior to a pre-transplant conditioning regimen and transfused back after most remaining immune cells have been weakened by immunosuppressive drugs.

"We are investigating whether patients can be transplanted with their own stem cells and be induced into a sustained remission if the mature types of immune cells, known as T cells, are removed from the graft," Nash said. "It is the T cells in patients with autoimmune diseases that react against their tissue, not the stem cells."

Seymour and one other systemic sclerosis patient have received what is known as an allogeneic transplant, a procedure that relies on stem cells donated by a tissue-matched relative. Before infusion of the cells, the patients' immune systems are destroyed with high-dose therapy.

The first patients underwent the procedure in 1997 with promising results.

"Initially, we thought transplants would prevent the disease from worsening," Nash said. "But to see some of the disease symptoms of the skin actually reverse, as in some of the patients with systemic sclerosis, is especially exciting."

The treatment's ultimate success awaits longer follow-up. But with no known cure for any autoimmune disease, transplants ultimately may be the best hope for patients with extreme symptoms.

For patients like Seymour, the treatment's success is evident each morning when she wakes up and goes to work.

"There is a such a big difference in my life now," she said. "I feel very lucky."

Barbara Berg, Ph.D., is a science writer for Fred Hutchinson.

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