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Harnessing crucial cells to save lives

Heather Stefanski, M.D., Ph.D., is conducting research focused on boosting children's immune systems after a blood or marrow transplant. (Photo: Richard Anderson)

It has been more than 40 years since University of Minnesota physicians performed the world’s first successful pediatric bone marrow transplant, and researchers here have never stopped trying to find better ways to secure long and healthy lives for children who have cancer.

Physician-scientist Heather Stefanski, M.D., Ph.D., echoes the dedication of her colleagues past and present when she says of her young patients, “I have to make life better for them.”

Today two major research efforts are exploring how to manipulate immunity-boosting T-cells—before and after an umbilical cord blood or bone marrow transplant—to save a child’s life.

Helping the body do its job

When a child receives a blood or marrow transplant, immune system T-cells play a central role. These sophisticated cells are educated as youngsters in the thymus—the “T” in T-cell—and develop into mature T-cells ready to protect the body against invaders.

One of the things to guard against after a transplant is graft-versus-host disease (GVHD), which occurs when T-cells in the graft (the transplanted blood or bone marrow) attack the patient’s body (the host) as “foreign.”

Bruce Blazar, M.D., director of the University’s Clinical and Translational Science Institute, wants to find a way to thwart GVHD by boosting a child’s supply of a type of cell called regulatory T-cells, whose job is to suppress fellow T-cells if they become too aggressive.

Growing regulatory T-cells in a lab is difficult, but Blazar’s research—supported by the National Institutes of Health (NIH), Leukemia and Lymphoma Society, and Children’s Cancer Research Fund—has replicated these cells in vitro up to 50-million-fold compared with only 70-fold previously. In animal models and limited human trials, University studies have shown that fortifying the body with these cells before a transplant is effective against GVHD.

“The ability to deliver such large quantities of these cells to patients before they undergo transplantation significantly reduces the chances of graft-versus-host disease,” says Blazar.

John Wagner, M.D., director of the University’s Blood and Marrow Transplantation Program, is now evaluating the promise of Blazar’s work through a clinical trial.

No time to spare

If overactive T-cells in the graft pose a threat to the child, not having enough T-cells in the host—the child’s body—can be lethal.

“Until a year after a transplant, children don’t have enough of their own T-cells,” says Stefanski, an assistant professor of pediatrics in the Division of Hematology, Oncology, and Blood and Marrow Transplantation. “Our patients can be cured of their leukemia and yet die from a common cold.”

Stem cells in the transplanted blood or marrow will, over time, develop into a child’s own protective T-cells, but these patients cannot afford to wait that long, Stefanski says. To better defend children against infections in that critical first year, she is looking for a way to augment their immune systems with young T-cells.

Working under an NIH project grant secured by Blazar and Wagner, Stefanski is growing these cells in her lab until they are strong enough to be delivered to a child. The hope is that enough of them will then migrate to the child’s thymus and grow more quickly into protective T-cells.

In a year or two, Stefanski believes she’ll be ready to transplant umbilical cord blood into mice and then introduce enough budding T-cells to prevent life-threatening infections. If her methods are successful, a human clinical trial may be possible in five years.

“One of the most heartbreaking aspects of my job is when a child dies because of an overwhelming infection due to the transplant,” she says. “We do everything we can, and it’s still not good enough. This is unacceptable to me and the reason that I’m doing my research.”

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