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Small cells, big hopes

After 40 years, the U continues to lead the charge against cancer and other disorders with lifesaving blood and marrow transplants

Packed into the hollows of your bones, pulsing through your arteries and veins, are millions of immature cells that play a very big role in keeping you alive.

Known as hematopoietic stem cells, or HSCs, these cells produce the blood cells that carry oxygen, keep you from bleeding to death, and defend you against incursions by bacteria, viruses, and other adversaries. HSCs are also the stars of blood and marrow transplantation (BMT), a lifesaving therapy that has given thousands of children and adults a new source of blood cells.

Forty years ago, University of Minnesota pediatrician Robert Good, M.D., Ph.D., made history when he performed the world’s first successful BMT using bone marrow taken from a matched sibling donor, saving the life of a baby boy with an inherited immune deficiency.

Since then, University researchers and clinicians have led the way in applying BMT to a variety of disorders. In 1975 physicians here performed the first successful BMT in a patient with lymphoma. Seven years later, the University was the first to use BMT to treat an inherited metabolic disease. In the 1980s researchers developed a protocol to use a patient’s own marrow to treat chronic myelogenous leukemia. And over the past decade and a half, University physician-researchers have pioneered the use of umbilical cord blood as a source of HSCs for transplant and improved the applicability and success of BMT in both children and adults.

And that’s just the beginning, says Daniel Weisdorf, M.D., professor of medicine and director of the adult blood and marrow transplant program.

“We’re still one of the major centers in the world,” he says. “We have a new generation of very able people in clinical and preclinical research. They’re going to take the program to the next phase of success in the next 10 years.”

Multiple hurdles

In October 2006, Valerie Rosenberg’s immune system gave out. The marrow inside the 27-year-old sculptor’s bones stopped producing sufficient blood cells to carry oxygen, halt bleeding, and fight infection.

The good news? Rosenberg had recently moved to the Twin Cities. Her mom, who lives in Boston, had suggested she go to a clinic attached to a major hospital; her boyfriend happened to have a parking pass for the University of Minnesota Medical Center, Fairview. Seemingly by chance, and certainly by good fortune, Rosenberg ended up at one of the world’s premier BMT centers.

Six weeks after a diagnosis of myelodysplastic syndrome, Rosenberg underwent chemotherapy and total body irradiation to destroy the remnants of her own failing marrow. She then received an infusion of HSCs from her older brother, Mike. That was followed by months of uncertainty as the donated cells and her body struggled to get along. But she made it through—thanks, she says, to the expertise she found at the University.

“I was so lucky to be right where I was,” Rosenberg says.

BMT is conceptually simple: out with the bad HSCs, in with the good. In practice, it’s a complex and uncertain process involving multiple hurdles. Among the first is finding a suitable source of donor cells. Next, doctors must figure out just the right mix of chemotherapy and radiation to destroy the patient’s own HSCs and suppress the immune system (to avoid rejection) while minimizing damage to other tissues. After the transplant, the focus is on coaxing the body and new cells to accept one another. Meanwhile, the body must endure the temporary absence of an innate source of immune, clotting, and oxygen-carrying cells. The process of devising and refining each of these steps has required—and continues to require—enormous amounts of research.

Expanding the universe

One area in which University researchers are making exciting inroads is finding, and fine-tuning the use of, novel sources of HSCs. In some cases, certain of the patient’s own HSCs can be removed and reimplanted after treatment. More often, HSCs come from the bone marrow or blood of a donor whose cells are compatible with the recipient’s. Rosenberg was one of the lucky ones: She had a sibling whose cells matched hers closely enough to serve as a source of HSCs. But one out of four patients needing a BMT can’t find adequately matched blood or marrow from a donor.

John Wagner, M.D., and Daniel Weisdorf, M.D., are breaking new ground in the field of blood and marrow transplantation.

In the 1990s University researchers played a key role in introducing what has become an increasingly important source of HSCs—umbilical cord blood. Recently, research led by John Wagner, M.D., professor and director of pediatric hematology-oncology and blood and marrow transplantation, showed that for some types of leukemia a transplant of imperfectly matched cord blood works as well as, if not better than, matched bone marrow.

“This study suggests that cord blood need not be considered a second-line therapy any longer,” Wagner says. “The fact that cord blood is banked and readily available with little notice is a great advantage. Now, the timing of transplantation can be dictated by the patient’s needs as opposed to the availability of matched bone marrow.”

The University of Minnesota also pioneered the use of blood from two umbilical cords in the treatment of adult patients. The double transplant not only provides the quantity of HSCs an adult needs but also appears to boost the immune system—a bonus doctors had not anticipated, Weisdorf says.

University innovations in the ways patients are prepared for transplant are making BMT an option for more patients. Until recently, individuals who had other illnesses, were elderly, or were weak from cancer therapy were not considered candidates for BMT because of concerns they could not withstand the required chemo- and radiation therapy.

But recent research has led to a reduced-intensity protocol that makes such transplants possible with less severe chemotherapy and radiation therapy preparation. Last fall, Claudio Brunstein, M.D., Ph.D., assistant professor of medicine, reported success using reduced-intensity preparation for transplant with blood from two partially matched umbilical cords to treat patients with leukemia or lymphoma who otherwise might have been in-eligible for transplant. The procedure, known as the “Minneapolis regimen,” will be tested in a national multicenter trial beginning this summer.

“We are getting good engraftment and survival in people we would have turned down a few years ago,” Weisdorf says.

Researchers are also stretching the boundaries of BMT by using natural killer (NK) cells to knock stubborn cases of leukemia into remission so the patient can undergo transplant. NK cells cruise the bloodstream killing viruses and cells that seem foreign to them. Because cancerous cells are actually “self” cells gone bad, NK cells don’t always recognize them as invaders.

“About 10 years ago I was thinking about these cells, and I realized that NK cells from a partially matched donor might be able to do the job on leukemic cells that a person’s own NK cells can’t,” recalls Jeffrey Miller, M.D., professor of medicine and associate director of the Masonic Cancer Center, University of Minnesota.

He began testing his hypothesis, with promising results. Eight years ago, after extensive research, Miller and colleagues began clinical trials using donor NK cells to prepare patients with acute myelogenous leukemia for BMT.

“So far, 10 of the 32 patients receiving NK therapy have gone into remission,” Miller says. Buoyed by the success, researchers are now developing protocols for mobilizing donated NK cells against other cancers, including non-Hodgkin’s lymphoma and breast and ovarian cancer. They also have completed the first clinical trial using NK cells from cord blood, are looking at ways to combine NK treatment with BMT in a single procedure, and are working to increase the sensitivity of cancers to NK cells.

“Our goal is to take what we learn in patients back to the research laboratory to test new ideas that optimally exploit NK cells as cancer therapy,” Miller says.

Safer transplants

A major complication of BMT is graft-versus-host disease (GVHD), in which donor cells attack the recipient’s tissue. Occurring in about two-thirds of BMTs, GVHD is responsible for one-third of deaths after transplant.

In hopes of reducing GVHD, Bruce Blazar, M.D., professor and section chief of pediatric blood and marrow transplantation, has turned his attention to regulatory T cells, or T-regs. Present in the blood in minute quantities, T cells act as a natural brake on immune reactions.

“The idea arose from rodent studies in our laboratory that showed donor T-regs could control adverse immune response,” says Blazar, holder of the Andersen Chair in Transplantation Immunology.

Jeffrey Miller, M.D., began testing the application of natural killer cells to treat leukemia eight years ago. Today he’s developing protocols for using those cells to treat other types of cancer as well.

Researchers led by Brunstein recently began a clinical trial to find out whether infusing T-regs with BMT diminishes GVHD. So far, the results are promising.

“If [the use of T-regs] reduces the prevalence of GVHD and doesn’t blunt the transplant effect, it would make transplant substantially safer,” Weisdorf says. “This is the first trial actually testing how to do this in people. We’re leading the pack because of work in Bruce Blazar’s lab.”

Blazar hopes to improve BMT in other ways as well. “We would like to find new approaches to reduce … injury to critical organs, such as the thymus and lung, and reduce relapse rates after BMT,” he says. “In addition, we plan to examine new approaches to preventing or repairing tissue injury using protein-, gene-, or cell-based therapies.”

Meanwhile, Jakub Tolar, M.D., Ph.D., assistant professor of pediatrics, is studying ways to use selected HSCs to boost recovery from the chemotherapy and radiation patients must undergo to prepare for BMT.

Beyond cancer

Cancers are the conditions most commonly treated with BMT. But physicians also use BMT to treat patients with genetic disorders characterized by the inability to make certain proteins. Known as inherited metabolic and storage diseases, these rare ailments cause bodily functions to deteriorate as toxic substances build up in the absence of the enzymes that Break them down. Depending on the enzyme involved, these diseases can lead to lethal dysfunction of various organs, including the brain.

Researchers discovered in the 1980s that, in some cases, transplanted HSCs can supply the missing enzyme. Today University physicians perform nearly two transplants a month for a variety of metabolic and storage diseases, including osteopetrosis, which causes debilitating thickening of the bones; inherited leukodystrophies, which damage the brain; and Hurler syndrome, which affects a number of organs.

The availability of cord blood is a boon to this type of treatment because these diseases are often rapidly progressive—tragic deterioration can occur in the time it takes to find and obtain cells from a suitable marrow donor.

“We’ve made a lot of recent advances in how we’re doing transplants, so the outcomes have improved,” says Paul Orchard, M.D., associate professor of pediatrics and medical director of the inherited metabolic and storage disease bone marrow transplantation program.

The University’s BMT program made national news last fall when Wagner treated Nate Liao, a toddler from New Jersey, with stem cells to correct a life-threatening skin disease called recessive dystrophic epidermolysis bullosa (EB). EB is a genetic disorder in which the protein that anchors skin and lining of the gastrointestinal tract to the body is missing, so the tissues come off with minimal trauma—just coughing or walking, for example. Tolar, Blazar, and Wagner had previously demonstrated in animal studies that BMT might be able to help correct the disorder. In just one year, Wagner and colleagues translated this novel approach into a treatment for people with EB.

“This is just one more example of how basic investigators and clinicians can work together to develop life-saving new therapies,” says Wagner, who holds the Variety Club Chair in Molecular and Cellular Therapeutics, the Children’s Cancer Research Fund Hageboeck Chair in Pediatric Oncology, and the McKnight Presidential Chair in Hematology and Oncology. “While not all such treatments will work in humans, stem cell research brings hope to hundreds of thousands of children and adults with life-threatening, debilitating diseases. We are on the verge of a medical revolution.”

By Mary Hoff

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