One Root, Many Shoots
Dr. Irwin Bernstein, head of Seattle Children’s Division of Hematology/Oncology and leader of the Bernstein laboratory at the Hutchinson Center.
The potential of bench research is that a single advance in basic scientific knowledge will spur inquiry along multiple lines and ultimately lead to a variety of new clinical applications.
Such translational research — applying fundamental scientific discoveries to clinically relevant questions — has long been the hallmark of the pediatric cancer program at Seattle Children’s and Fred Hutchinson Cancer Research Center.
2006 saw several clinical advances whose origins can be traced back to basic research in stem cell development begun more than 25 years ago by Dr. Irwin Bernstein, head of Seattle Children’s Division of Hematology/Oncology and leader of the Bernstein laboratory at the Hutchinson Center.
This work identified several proteins, known as antigens, that are expressed during both the normal and abnormal development of stem cells. This fundamental finding provided the basis for a number of important clinical breakthroughs that are improving treatment options and outcomes throughout the world.
Antigen Marks the Cancer Cell
Bernstein’s initial research on stem cell development led to the identification of a protein, known as CD33, on the surface of most acute myeloid leukemia (AML) cells. This research on abnormal stem cell development ultimately led to the creation of Mylotarg, one of the new generation of targeted cancer treatments that employs monoclonal antibodies to deliver chemotherapy directly to specific cancer cells, sparing healthy cells from damage. In collaboration with Wyeth Pharmaceuticals, members of the Bernstein lab linked a highly toxic poison to an anti-CD33 antibody that delivers the toxin directly to the cancer cell.
Since receiving FDA approval for older adults with relapsed AML in 2000, Mylotarg has had several clinical trials to better understand its effectiveness as a single chemotherapeutic agent, as part of a multidrug regimen, and for use in additional patient populations. In 2006, Seattle Children’s began leading a large international study for the Children’s Oncology Group to test the effectiveness of Mylotarg in initial therapy of pediatric patients with AML.
On the Cusp of a Cord Blood Breakthrough
Bernstein’s work in stem cell biology also opened the potential for a breakthrough in cord blood transplantation.
Umbilical cord blood has several distinct advantages as a source of stem cells for transplant. It is readily available, retrieving the cells isn’t invasive to the infant and it carries fewer infectious viruses than cells obtained in other ways. Its biggest advantage, however, is that it doesn’t require the close genetic matching needed for other types of bone marrow transplants. This makes it especially promising for the 16,000 patients diagnosed with leukemia each year who cannot find a suitable bone marrow donor — many of whom have mixed ethnic or racial ancestry.
The drawback is that each unit of cord blood has a limited number of stem cells, and the resulting slow engraftment process leaves patients more susceptible to potentially fatal infections.
Early work in the Bernstein lab determined that hematopoietic stem cells express the CD34 antigen, and these cells also express the Notch1 receptor, suggesting a role for Notch in regulating stem cell development.
This finding led to development of methods for activating the Notch receptor using a protein called Delta1. By exposing cord blood stem cells to Delta1, the lab was able to increase the number of CD34+ cells more than a hundredfold. (Other labs throughout the country have only been able to achieve a tenfold increase in CD34+ cells.) In addition, a preclinical mouse model showed that the cells cultured in Delta1 provided rapid marrow engraftment.
Dr. Colleen Delaney, a faculty member in the Division of Pediatric Hematology/Oncology, has taken these initial preclinical findings from the bench to the bedside, developing clinically required methods for applying this work to the cord blood transplant setting. In 2006, after several years of preclinical development, Delaney introduced a cord blood expansion protocol in which two units of cord blood are transplanted — one unit of noncultured cord blood stem cells that lead to long-term engraftment and one unit of the cultured cells to overcome the problem of prolonged recovery of white blood cells.
The hypothesis that the cells cultured in the lab will engraft quickly in the patient and decrease the period of neutropenia (when a patient’s white blood count is so low that there is little resistance to infection) has borne out in the initial patients treated. Although very preliminary, early data are encouraging, showing an average time to engraftment of 15 days, as opposed to the 23 or more days reported in the cord blood literature. Delaney is enrolling more patients in this phase I clinical trial.
“We believe that using Delta1 turns on the stem cell’s own Notch signaling and enables us to manipulate the decision-making of the stem cell toward self-renewal rather than differentiation,” says Delaney. “Culturing cord blood stem cells in the presence of a Notch ligand prior to transplant allows us to expand the number of cells available for transplant that give rise to more rapid recovery of white blood cells when infused in the patient — at least for a short period of time until the unmanipulated unit begins producing cells.”
Moving Cancer Treatment Forward
The fertile ground of stem cell development continues to produce new growth. In late 2006, members of the Bernstein lab, including Dr. Jessica Pollard, Dr. Soheil Meshinchi and others, published an article in Blood that explored how mutations in different AML progenitor cell types affect whether the cancer will respond to current treatment protocols or prove resistant. This knowledge could lead to a clinical paradigm that will help determine treatment protocols and more exact prognoses.
“Insights like these change the nature of how we approach therapy,” says Bernstein. “It’s this type of higher-level thinking that move cancer treatment forward.”