The Program in Transplantation Biology combines basic and translational research directed at understanding and eliminating major barriers to successful allogeneic hematopoietic stem cell transplantation; these include host-versus-graft reactions, graft failure, acute and chronic graft-versus-host disease (GVHD), regimen-related toxicities, and induction of graft-versus-tumor reactions. The program’s goal has been to use stem cell transplantation to treat patients with malignant and nonmalignant hematologic diseases.
Specific research goals include:
A new direction includes investigations of the “plasticity” of stem cells which might be used to regenerate epithelial and muscle cells. For the latter studies, a canine model of Duchenne’s muscular dystrophy has been developed. The program’s preclinical studies are done in a canine model which has proven to be reliable for quick extrapolation to humans. The choice of this model has necessitated the development of canine molecular immunogenetics and the cloning of many canine genes to produce reagents analogous to those used in humans, e.g. CD34 monoclonal antibodies, hematopoietic growth factors, anti-T and -B cell reagents, microsatellite polymorphism markers, and so forth. This effort to optimize the canine model has allowed the program to play a leading role in canine “genome” and disease gene mapping projects.
Finally, our experience in hematopoietic stem cell transplantation has prompted increased referrals of human patients with genetic and other nonmalignant diseases. This has led to research in gene therapy.
It’s called a “mini-transplant” but there’s nothing diminutive about this innovative and lifesaving therapy. First developed at Fred Hutchinson Cancer Research Center in 1997, the mini-transplant is offering new hope for older patients with leukemia, lymphoma and other serious blood diseases — a population that is often medically unfit to withstand the rigors of a conventional blood (hematopoietic) stem-cell transplant. And, the therapy shows promise for treating some solid tumor cancers.
Traditional bone-marrow or peripheral-blood stem-cell transplant regimens include high doses of radiation and/or chemotherapy to destroy a patient’s diseased bone marrow, followed by transfusion of donor cells to reconstitute a healthy blood and immune system. Although it cures many patients with life-threatening diseases, the process requires weeks of hospitalization and is poorly tolerated by patients older than 50 and younger patients with additional medical complications.
In contrast, the mini-transplant, developed at the Hutchinson Center by Rainer Storb, M.D., and colleagues, uses a minimal dose of radiation, such that the patient’s own immune system is not destroyed. Patients then receive a transfusion of donor cells and drugs to suppress the patient’s immune system to prevent graft rejection or other complications. Mini-transplant recipients often require no hospitalization — and don’t even lose their hair.
The key to a mini-transplant’s curative powers are donor immune cells, known as T lymphocytes or T cells, which recognize the patient’s cancer cells as foreign and target them for destruction — a property known as the graft-vs.-tumor effect.
The mini-transplant is not without risks. Some cells in the mixture given to patients also recognize healthy cells, thus triggering an undesired immune response called graft-vs.-host disease, in which donor cells recognize the patient’s healthy cells as foreign, sometimes resulting in destruction of healthy tissue. This can occur in transplants involving non-twin siblings or unrelated individuals.
Survival rates among patients who receive a mini-transplant range from 30 percent to 70 percent, depending on the underlying disease, disease stage and whether the patient has other illnesses at the time of treatment, according to Storb.
Hundreds of mini-transplants have been done at the Hutchinson Center and at more than a dozen other centers around the country that are collaborating with Hutchinson Center researchers to further refine the procedure. For example, the first mini-transplants were done only with donor cells from a patient’s sibling; now unrelated donor cells are being transplanted as researchers find better ways to minimize graft-vs.-host disease.
Hutchinson Center researchers are now trying to improve the cancer-fighting immune response while minimizing side effects.
“The initial regimen has been slightly modified by adding a drug and we are focusing right now on graft-vs.-host-disease prevention,” Storb said. “For example, we are conducting a randomized, phase II study in which we are testing three preventive regimens in order to decrease the mortality associated with this complication.”
Hutchinson researchers also are studying the effectiveness of anti-tumor therapy by giving patients certain antibodies, including those that work against a protein called CD45, which is expressed in all hematopoietic cells, and CD20, which is expressed on lymphoma cells. They are also linking a short-lived radioactive isotope to these antibodies with the hope of targeting the therapy to the tumors and thereby decrease the tumor burden.
In order to use the mini-transplant to treat more cancers, Storb and colleagues are developing a protocol for patients with acute myeloblastic leukemias and advanced myelodysplasias with a focus on patients younger than 65.
Continuing research into the uses of mini-transplants has found that the therapy may be effective for some solid-tumor cancers. In a recent study, Hutchinson Center researchers, as well as researchers at the National Institutes of Health, found that mini-transplants show initial promise as a therapy for an aggressive form of kidney cancer. The transplant eliminated or prevented worsening of metastatic renal-cell carcinoma in approximately one-third of terminally ill patients enrolled in the study. Researchers are optimistic that with further refinement, the procedure could offer new hope for patients with the disease, for which no effective chemotherapy exists.
Q. If mini stem-cell transplants are so much easier on the patient, why are traditional, or myeloablative, transplants still being done?
A. Unfortunately, mini or non-myeloablative transplants can’t be used in every situation. This type of treatment works best for treatment of certain diseases and is not effective for other diseases, depending on whether immune cells of the donor can eliminate malignant cells in the recipient. Immune cells of the donor are most effective when the patient has a low number of malignant cells. In order to have a successful outcome, the patient’s disease might have to be in remission before a non-myeloablative transplant. Clinical trials are in progress to find out whether mini or non-myeloablative transplants can be successful for patients who do not have a fully HLA-matched donor. Further research is needed to determine whether mini-transplant is a safe and effective treatment for all types of disease that are treated by stem-cell transplant.
Q. Are the long-term effects of a mini (nonmyeloablative) transplant different from a standard (myeloablative) transplant?
A.Because the first mini-transplants were performed less than 10 years ago, it’s difficult to say whether the long-term effects will be similar to those that occur after a myeloablative transplant. The number of patients with long-term effects due to radiation will likely be lower after a non-myeloablative transplant. For example, the risk of skin cancer will likely be lower after a non-myeloablative transplant, since higher levels of radiation have been associated with an increased risk of skin cancer. Long-term effects related to immunosuppressive medications would depend on the dose and duration of treatment. Analysis of data on long-term survivors of non-myeloablative transplants will be needed to determine whether there are any differences between the two types of transplant.
Q. How is rejection prevented and controlled when the patient’s own immune system is still functioning in a mini (non-myeloablative) stem-cell transplant?
A. First, cells from a fully HLA-matched donor are used whenever possible to reduce the risk of rejection. Low-dose radiation, with or without chemotherapy, is used before the transplant to suppress, rather than to destroy the patient’s immune system. Immunosuppressant drugs are then used to maintain the immune suppression at the proper level. Carefully controlling the level of immunosuppression allows the donor stem cells to take hold and begin producing a full range of blood and immune system cells in the patient.