Research Profile - When good grafts go bad

A BC researcher is working to spare leukemia survivors from a life-long debilitating disease triggered by the very treatment that saved them.

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The easiest way to understand graft-versus-host disease (GVHD) is to think about Friedrich Nietzsche's notion that "that which does not kill us makes us stronger." Except in reverse.

With GVHD, that which saves someone – a bone marrow transplant – makes them weaker.

Bone marrow transplants are commonly used to treat leukemia to rebuild the blood supply and create a brand new immune system capable of attacking the cancer. GVHD occurs when this new immune system turns against its host's body and starts attacking organs.

"The new immune system is the graft," explains Dr. Kirk Schultz, Director of Childhood Cancer and Blood Research at the BC Children's Hospital and the Child and Family Research Institute. "But sometimes it reacts to the entire body as, 'This isn't me!' It rejects the body and causes a multi-system disease."

GVHD is a new malady, the cruel byproduct of a lifesaving procedure that only came into major clinical use after years of Nobel-Prize-winning research in the 1960s and '70s by America's Dr. E. Donnall Thomas. Prior to Thomas' advances, bone marrow transplantation was reserved largely for identical twins.

There are two types of GVHD: an early-onset form, called acute, and a chronic kind. Medical science has had good success in controlling the acute form and it usually goes away within three months of the bone marrow transplant. With the chronic kind, however, a person often survives their cancer only to live long-term with the potentially fatal complications of GVHD.

"It's similar to an autoimmune disease called scleroderma in which a person's immune system will go out and attack various parts of their body," says Dr. Schultz. "It can go on for years and years and people can be very debilitated and not able to lead a normal life, even though they've been cured of their cancer."

Dr. Schultz estimates there are about 900 allogenic bone marrow transplants (using donated marrow from a friend, relative or stranger) in Canada every year. In adults, the odds of getting chronic GVHD are about 50-50. "In kids, it's a little bit lower," says Dr. Schultz. "With children, we can get at least half of them to become tolerant over time. With adults, many people have lifelong disease requiring immune suppressing drugs."

A clinician-scientist who spends about 70% of his time in the lab and 30% working with patients, Dr. Schultz focuses much of his attention on blood-derived biomarkers for GVHD.

"The term 'biomarker' is trendy right now, but really it can be applied to just about any type of medical test – a urine test or a saliva test – that tells a doctor what's going on. We chose blood because the immune system circulates through the blood and it's easy to get at."

While the acute form of GVHD comes on fairly quickly and dramatically and is easier to diagnose, the chronic kind takes hold with insidious changes that are easy to miss. It would be helpful if physicians had simple blood test biomarkers to diagnose the disease earlier and jump on treatments more quickly, says Dr. Schultz.

"That's one of the goals of our work. We also think that the biomarkers will allow us to classify the chronic form of GVHD. We think it has multiple factors or contributing components. Once we get better at knowing the biomarkers, we could be able to say, 'This is the major thing that's going on and it's being caused more by factor A versus factor B.'"

Biomarkers also could help doctors know when treatments are working – and when they're not. "If we could do a test that allows us to see if the blood markers have changed, indicating the patient is responding to treatment, we'd know we should continue doing what we're doing. That would be incredibly useful in treating a disease that comes on slowly and goes away slowly."

The Study

Dr. Schultz is leading a five-year study, funded by the Canadian Institutes of Health Research, to investigate blood-based biomarkers to better understand, diagnose and treat GVHD.

"We have five biomarkers that we have published in the literature. One is a marker of B cells and we call them RLR9 high expressing B cells. We know that one of the effective treatments for chronic GVHD is an antibody that attacks these cells, and it works about half the time."

Dr. Schultz's team is currently collecting samples from 500 to 600 participants in two studies with the Canadian Bone Marrow Transplantation Group, a national volunteer organization promoting excellence in patient care and research, and a Seattle-based study.

"That will take two to three years. It's not fast, which is one of the frustrations of research. The funding is allowing us to really start looking at larger populations, particularly in adults, to try to validate some of these markers."

He hopes the work will help people who have overcome leukemia avoid having to face a lifelong health hardship.

"We hope to change the field actually," says D. Schultz. "Eventually, what we hope to do is identify high-risk groups and do interventions before they get GVHD to try to decrease their risks. That is our big dream."

"Biomarkers can help us better understand the underlying mechanisms of the disease. We understand some of the basic mechanisms going on, but we don't understand the whole thing very well. If we can understand the underlying mechanisms, we can design better treatments."