• 2009 Fall/Winter Paths of Progress

    Building a Better Stem Cell Transplant
    By Robert Levy

    Doctor and patientVincent Ho, MD, (left) consults with patient Jaime Luo, who received a transplant of stem cells from umbilical cord blood. 

    The only obvious sign that Jaime Luo's stem cell transplant in 2007 was a bit out of the ordinary was that the IV pole beside his hospital bed would hold two bags of blood-making stem cells instead of the usual one.

    The cells that flowed from the bags came not from the bloodstream of an adult donor, as is most often the case, but from the umbilical cords of two newborn babies.

    Years earlier, the babies' mothers had agreed to have the umbilical cord blood collected at birth and stored, frozen, in a public bank, where it would be available for any eligible patient in need.

    Cord-blood stem cell transplants have long been used for treating children with leukemia and other blood disorders, but only recently for adults.

    “When I asked my transplant oncologist, Dr. Vincent Ho [of Dana-Farber/Brigham and Women's Cancer Center] how many patients he has treated with cord blood cells, he said, ‘You'd be the second one,'” Luo recounts.

    “The first patient was doing well, so even though it was based on limited data, the success rate was 100 percent.” Luo, a mechanical engineer from Somerville, Mass., can chuckle at the memory. Two years out of transplant, his leukemia is in remission.

    Although he now requires regular dialysis because of kidney failure that resulted from the pre-transplant chemo and radiation therapy, Luo has returned to work full time.

    “From a big-picture perspective, the transplant allowed me to trade a major problem for a series of smaller ones,” he says. For Luo and other adult patients who need a transplant but do not have a matched donor, an infusion of stem cells from umbilical cord blood can be a life-saver.

    But such transplants come with their own challenges and concerns.

    Making cord blood transplants more effective

    Joseph AntinJoseph Antin, MD, chief of the Adult Stem Cell Transplantation Program 

    For one, cord blood cells are expensive and in short supply. And stem cell transplant patients usually need the cells from two cords. Because cord-blood stem cells take longer to rebuild patients' blood supply and immune system, there is a larger window of time during which infection can set in. And, like all transplants, those involving cord blood sometimes fail.

    This year, physician/scientists at Dana-Farber/Brigham and Women's Cancer Center have begun a clinical trial of a new approach that seeks to make the stem cells more proficient at their job.

    Umbilical cord blood from hospital-based blood banks is currently used in about 20 percent of transplants when a patient lacks a well-matched adult donor. (Because the stem cells in cord blood are more "primitive" than those from an adult donor, they don't need to match the recipient's immunological type quite as closely.)

    The percentage is higher among most ethnic minorities in North America, who have lower odds of finding a compatible match in international donor registries.

    If successful, the approach being tested at Dana-Farber/Brigham and Women's Cancer Center could significantly broaden the availability of cord stem cell transplants.

    "Over the years, researchers have tried a variety of techniques for expanding the number of stem cells in cord blood," says Joseph Antin, MD, chief of the DF/BWCC transplant program.

    "The problem has been that when cytokines [growth-stimulating compounds] are used, the stem cells become more ‘differentiated' – less able to take root in the bone marrow and generate new blood cells. The technique works well at first, patients' blood cell counts come up quickly, but they soon start to drop."

    A different strategy emerged a few years ago from the laboratory of Leonard Zon, MD, director of the Stem Cell Program at Boston Children's Hospital, the pediatric oncology care partner of Dana-Farber.

    Postdoctoral students Trista North, PhD (now at Beth Israel Deaconess Medical Center), and Wolfram Goessling, MD, PhD (now affiliated with Dana-Farber/Brigham and Women's Cancer Center), identified several drugs that could enhance the formation of blood in zebrafish embryos.

    When they did follow-up studies exposing mouse blood stem cells to a drug called prostaglandin E2 (PGE2) – developed years ago to treat stomach acid reflux, but shelved when it proved ineffective – the number of cells grew by 300 to 400 percent.

    It wasn't the increase in numbers per se that intrigued the researchers.

    Researchers and clinicians collaborate to improve cord blood stem cell transplants

    bt-red-blood cells and hematopoietic stem cells.jpgShown here amid red blood cells, hematopoietic stem cells (center) give rise to the cells of the bloodstream. 

    "The stem cells were hardier, they survived better, divided better, and homed in better on the bone marrow," Antin comments. "They were better suited for transplant."

    Zon approached the Center for Human Cell Therapy (CHCT) – a collaborative facility serving Harvard Medical School faculty – for help in adapting his lab's discovery to patient therapy.

    Leslie Silberstein, MD, director of the CHCT, and Jerome Ritz, MD, of Dana-Farber/Brigham and Women's Cancer Center's Adult Hematologic Malignancies program and a codirector of the CHCT, worked with the center's Technical Director Myriam Armant, PhD, and many others to plan how the technique would be tested in patients.

    "With [Dr Zon's] lab, we worked out the proper conditions for incubating cord blood stem cells with PGE2," Ritz says. "Then we brought the technique to the Connell and O'Reilly Families Cell Manipulation Core Facility at Dana-Farber so it could be standardized for patients."

    Next came a green light from the U.S. Food and Drug Administration and approval from Dana-Farber/Brigham and Women's Cancer Center's Institutional Review Board, which evaluates clinical trials for patient safety. The first transplant conducted as part of the clinical trial was performed in late May of this year.

    "We're excited to do this, and we've had an amazing collaboration with the Zon lab to take this research from fish tank to bedside," says Corey Cutler, MD, MPH, a stem cell transplantation specialist at Dana-Farber/Brigham and Women's Cancer Center who is leading the trial.

    The first phase of the trial, undertaken to ensure the technique is safe for patients, is being carried out with individuals who have leukemia or lymphoma. The cord blood units, which come from public international cord blood banks, are processed at Dana-Farber's Cell Manipulation Core Facility.

    The trial is being conducted in groups of six patients. The first group will receive one untreated cord blood unit, followed by another unit treated with PGE2. A second group will receive the units in reverse order – treated blood first, then untreated – to see which, if either, is more effective.

    In a third group, both units will be treated with the drug. The researchers will compare how quickly the new stem cells take hold, or engraft, in patients' bone marrow and bring up blood-cell counts.

    If the method succeeds and is confirmed in larger trials, "it could improve the results of cord-blood transplantation and increase the number of people who have access to it, and with better outcomes," says Cutler.

    It could also increase the number of donated umbilical cords whose stem cells are available for transplant.

    "Only 20 percent of collected cords contain enough stem cells under current practices," Antin remarks. "This technique may make previously unusable or marginal cords usable."

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