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.
Rainer Storb, MDRainer Storb is a native of Germany where he attended the University of Freiburg Medical School. After his clinical training, he spent three years doing research in Paris on a NATO Science Fellowship, working with Drs. Najean, Bernard and Bessis. In 1965 he traveled to Seattle on a Fulbright Fellowship and began work in the Division of Hematology at the University of Washington with Dr. E. Donnall Thomas. It was here that he participated in the birth of the Seattle marrow transplantation program. He participated in the foundation of the Fred Hutchinson Cancer Research Center in 1975, is Head of its Transplantation Biology Program, and a Professor of Medicine at the University of Washington. He has worked for the past 40 plus years to develop new concepts in allogeneic hematopoietic cell transplantation.
Stacy ZellmerProject Manager I Stacy joined the Storb Lab in 1998 then moved to Comparative Medicine in 2004 – all while sitting in the same chair. She is involved with coordination and data support related to experiments in a large animal model for Researchers in the Transplantation Biology Program as well as any number of different tasks for the Comparative Medicine Department. firstname.lastname@example.org 206.667.2767
Mohamed Sorror, MD, MScAssistant Member, Clinical Research Division Assistant Professor of Medicine, University of Washington Mohamed Sorror joined the Storb Lab in 2002. His research is focused on studying the impacts of medical comorbidities on outcomes of hematopoietic cell transplantation (HCT) for hematologic malignancies in order to improve decision-making and lessen the HCT morbidity and mortality. For more information, visit his web page. email@example.com 206.667.2765
Carol LoretzResearch Technician Carol joined the Storb lab in 2002 and originally worked primarily on murine models of solid organ transplantation. She now focuses mainly on the development and testing of costimulatory antibodies and fusion proteins and has assisted on the DMD project. She is also the go-to person for questions about marine life and carnivorous plants. 206.667.1310
Diane StoneResearch Technician IV Clinical Research Division Diane joined the Storb Lab in 2005 after 20 years in Biotechnology. Her primary focus has been the cloning, mammalian expression, purification and characterization of costimulatory fusion proteins and antibodies. She is also known as the ELISA Queen. firstname.lastname@example.org 206.667.6496
Zejing Wang, MD, PhDAssociate in Clinical Research Zejing joined the Storb lab in 2003 as a post -doctoral fellow. From 2004 to 2007, she left temporarily to pursue her graduate work with Dr. Stephen Tapscott in the Molecular and Cellular Biology Program at the University of Washington. Zejing returned to the lab after receiving her Ph.D. in 2007. Zejing is also a Research Assistant Professor in the Department of Medicine at the University of Washington. Her research interests have been focusing on establishing gene therapy as a therapeutical intervention for muscular dystrophy using Duchenne muscular dystrophy as a model system, from understanding vector immunity, host immune responses to therapeutical vectors, to developing strategies for monitoring and overcoming immune responses for sustained transgene expression. Current research also includes developing gene and cell therapy strategies for treating heart disease in muscular dystrophies. email@example.com 206.667.5558
Maura Parker, PhDAssociate in Clinical Research Maura joined the lab in October of 2004 as a post-doctoral fellow following graduate work with Dr. Michael Rudnicki in Ottawa, Canada. Her projects focus on establishing cell transplantation as a viable therapeutic option for muscular dystrophy. Specifically, she uses mixed hematopoietic chimerism as a platform for inducing tolerance, followed by intramuscular transplantation of donor cells. Currently, she is quantitatively comparing engraftment of various cell populations and testing the ability of modulating factors to enhance engraftment. Additional interests include determining the best conditions for ex vivo expansion of donor cells, and ways of modifying the recipient muscle environment to encourage donor cell engraftment. firstname.lastname@example.org 206.667.1623
Scott S. Graves, PhDStaff Scientist Clinical Research Division Scott joined the Storb Laboratory in 2003 as a visiting investigator after over 18 years working in the Seattle biotech industry with focus on development of therapeutic monoclonal antibodies for the treatment of cancer. He became the laboratory manager and staff scientist in 2004, directing the program of engineering and development of monoclonal antibodies and fusion proteins against costimulatory molecules. In addition, he has conducted several large animal model studies focusing on the understanding of immune tolerance as applied to solid organ transplantation. Additional research interests are aimed at augmenting the graft versus tumor effects and minimizing graft versus host disease associated with hematopoietic cell transplantation. In 2008, Scott obtained positions of Research Associate Professor in the Department of Medicine at the University of Washington and Member, Fred Hutchinson/University of Washington Cancer Consortium. email@example.com 206.667.5267
Steven Rosinski, MD, PhDActing Instructor/Research Associate Clinical Research Division Steve joined the Storb Laboratory in 2010 at the completion of his clinical training in Hematology/Oncology. His research goal is to translate the knowledge of minor histocompatibility antigens into a therapeutic vaccine to treat or prevent relapse following an allogeneic hematopoietic cell transplantation. He won the 2011 ASH fellows award for this project. firstname.lastname@example.org 206.667.1460
Bruce Swearingen, MDPost-Doctoral Research Fellow Clinical Research Division Bruce trained in general surgery in New York, NY. Following residency, he went to Louisville, KY to complete a two year research and clinical fellowship in hand and microsurgery. His research there consisted of immunomodulation of Vascularized Composite tissue Allograft (VCA) recipients in the rodent model. In July 2012, he joined David Mathes in the Division of Plastic Surgery at UW as a research fellow. His research with David and Rainer Storb encompasses inducing and maintaining tolerance to vascularized composite allograft (VCA) transplantations. Specifically focusing on utilizing stem cell transplantation to create a tolerant state in which the survival of the transplanted graft is no longer dependent on chronic immunosuppression. email@example.com; firstname.lastname@example.org 206.667.5101