Program Genealogies: Bone Marrow Transplantation at Fred Hutch

Fred Hutchinson Cancer Research Center’s (Fred Hutch) Bone Marrow Transplantation Program, one of the largest in the world, had an inauspicious beginning. The program predates Fred Hutch itself—bone marrow transplantation as we know it has its roots in the vision and perseverance of one physician scientist, and my former mentor, the late Dr. E. Donnall "Don" Thomas. Dr. Thomas came to the University of Washington (UW) from the Mary Imogene Bassett Hospital in Cooperstown, New York, in late 1963. I came to Seattle as a research fellow in 1965, joining a small team of researchers led by Dr. Thomas: myself; another fellow, Dr. C. Dean Buckner; an Instructor in Medicine, Dr. Bob Epstein; an animal technician, former U.S. Marine Sergeant Ted Graham; a laboratory technician; and Dr. Thomas’ wife and long-term “right hand,” the late Dottie Thomas, who acted as a mother to us all.

In the early 1960s, the field of clinical bone marrow transplantation was nearly dead. Early reported human marrow transplantations had failed. All patients had died from complications, including immune reactions that were not predicted from studies on inbred rodents. Most investigators left the field, and prominent immunologists declared that the barriers between individuals could never be crossed, but Dr. Thomas did not give up. He began to study dogs, the only species to share an unusual phenotypic diversity and a well-mixed gene pool with humans. Most importantly, however, like humans, dogs develop spontaneous cancers including non-Hodgkin lymphoma, which represented a perfect preclinical disease model. When I came to Seattle, there wasn’t room for our team in the UW Medical School, so we occupied a tiny laboratory in a corner of the 10th floor of what used to be the United States Public Health Service Hospital, which later came to brief local fame as Amazon’s original headquarters. At that time, transplantation was not a widely known concept. In fact, when the university’s print shop produced stationery letterhead for us, it said, “Division of Hematology and Transportation.”

To save money, the opposing Cobalt-60 sources used for total body irradiation of lymphoma in dogs and later of human patients were located underground in an abandoned World War II bunker several miles away. Under Dr. Thomas’ guidance, Dr. Epstein and I spent the 1960s in the laboratory tackling the “insurmountable” problems encountered in early human marrow transplantation. We knew that many of these problems would need to be solved in a pre-clinical animal model, so we honed in on the dogs with naturally occurring lymphoma. This had dual benefits: We were able to answer many pressing clinical problems in a model system that had important similarities to humans, and we provided hope and, in some cases, cures to families with sick pets. We established a collaboration with veterinary offices throughout the Pacific Northwest; more than 1,500 family dogs with lymphoma were brought to us by their owners, sometimes even by plane. We developed high-intensity irradiation and chemotherapy regimens to kill the cancer cells and established the importance of in vitro tissue matching for transplantation outcome. To control and treat graft-versus-host disease (GVHD), we developed drug combinations capable of modifying immune reactions. For several years, we produced antibodies against human thymocytes, since such antibodies were as yet not commercially available. To that end, we immunized rabbits and horses housed at a farm several miles across Lake Washington. This effort once involved an hour-and-a-half chase, on foot, of an antibody-producing horse.

Don’s leadership always encouraged free, and often heated, exchanges of ideas. Many of the concepts in the early days that later led to improvements in marrow transplantation were put through the wringer in rigorous free-flowing discussions. Everyone on our team was treated as an equal: Nurses and technicians were highly respected and given just as much voice as medical doctors and investigators, and often their input led to important advances. Such a rigorous and open atmosphere was necessary to advance transplantation to the point of clinical translation. We received new National Institutes of Health (NIH) funding and began our program’s first patient transplants in 1969 after having addressed some of the most pressing issues, including establishing protocols for irradiation, tissue matching, and control of GVHD. At that time, we were joined by Dr. Paul Neiman, the late Dr. Alex Fefer, and an unusual research technician, the late Reg Clift, who became an integral part of the team. Another hallmark of Dr. Thomas’ team was the indelible partnership between laboratory and clinic. We continuously transferred knowledge from the bench to the bedside, and back again.

Our first transplantation did not work. The patient, who had chronic myeloid leukemia in blast crisis phase, developed a severe viral infection of a type that we couldn’t have anticipated from our animal work, but we pressed ahead. Today, there are patients still alive for whom we performed a transplantation in 1971 — 45 years ago. In 1972, a young patient with leukemia to whom all the members of our team had grown attached, developed severe acute GVHD after her transplantation. I had conducted research using antithymocyte serum to treat GVHD in animal models and made antihuman thymocyte globulin in rabbits. After another heated discussion, I convinced the research team and the young woman’s family to try this approach. The patient’s intense swelling at the injection site was frightening for us all, but the treatment worked to rid her of GVHD—she lived until a few years ago when she succumbed to metastatic breast cancer, but her leukemia never returned.

Around this same time, the Public Health Service hospital was shut down by the federal government, and we were faced with an uncertain future. After a few years in a temporary space at Providence Hospital and the UW’s Harborview Medical Center, our team moved to the Fred Hutchinson Cancer Research Center, established in 1975, in part thanks to Dr. Thomas’ relationship with Dr. Bill Hutchinson, who founded the center in his late brother’s name. We abandoned the World War II bunker. The adjacent Swedish Hospital Medical Center provided the ever-increasing clinical space for our transplantation patients.

In those days, everything was new. Dr. Thomas recognized the importance of recruiting different specialists to improve transplantation on multiple fronts. Dr. Dean Buckner led efforts with supportive care. Since the blood center did not provide platelet transfusions, we developed our own transfusion program, which was supervised by Dr. Meera Benaji, with patient families, staff, and investigators donating platelets until we convinced the Puget Sound Blood Center to take over. Dr. John Hansen set up our tissue typing (human leukocyte antigen [HLA] typing) laboratories that continue to this day at the Seattle Cancer Care Alliance, now Fred Hutch’s treatment arm. Dr. Effie Petersdorf conducts molecular research of the HLA region and its relation to transplantation outcome. Dr. Thomas recruited the late Dr. Joel Myers, an infectious disease expert from the Centers for Disease Control and Prevention, who laid the groundwork for what is now the largest group of infectious disease researchers of any cancer center. In 1972, Dr. George McDonald joined the team to address gastrointestinal complications of transplantation. A pulmonary group was also established, now led by Dr. David Madtes. Drs. Kenneth Lerner and George Sale established the pathology group which continues at the Seattle Cancer Care Alliance. Pediatrician Dr. Jean Sanders joined our team from Stanford University in 1975 and was instrumental in broadening the application of transplantation to pediatric patients. In the early 1980s, Drs. Thomas and Hansen, together with the fathers of two of our patients, laid the foundations for the National Marrow Donor Program. As we ourselves grew older, we recognized the need for developing so-called “mini-transplants” — transplant procedures using less toxic conditioning regimens for use in elderly patients who were not previously eligible for traditional high-intensity transplantations. These rely largely on powerful allogeneic graft-versus-tumor effects for eradicating cancer and are done in an outpatient setting.

More than 160 trainees from all parts of the globe went through my laboratory. The first European trainee, Dr. Hans-Jochem Kolb, pioneered using donor lymphocyte infusions for patients relapsing after transplantation upon his return to Munich. My second European trainee, Dr. Eliane Gluckman, pioneered umbilical cord blood transplantation after returning to her native France. Dr. Paul Weiden published two pivotal papers in the late 1970s/early 1980s in The New England Journal of Medicine, describing allogeneic graft-versus-tumor effects that were instrumental in eradicating the last leukemic cells after transplantation. Dr. Brenda Sandmaier plays a leading role in the mini-transplant effort. Dr. Keith Sullivan, before leaving for Duke University, developed both Fred Hutch’s long-term follow-up group and transplantation for autoimmune diseases — two research areas that he passed on to Drs. Paul Martin and Mary Flowers, more recently joined by Dr. Stephanie Lee, and to Drs. Richard Nash and George Georges, respectively. Dr. Mark Walters, now at Oakland Children’s Hospital, pioneered transplantation for sickle cell disease. Pediatricians Drs. Ann Woolfrey and Lauri Burroughs are broadening efforts of transplantation for nonmalignant diseases. Dr. Fred Appelbaum rose to the administrative challenges of succeeding Dr. Thomas as Director of the Clinical Research Division. Drs. Joachim Deeg and Bart Scott specialize in transplantation and conventional treatment for myeloproliferative neoplasms and myelodysplastic syndromes, while Dr. Hans-Peter Kiem has established gene therapy at Fred Hutch. My early colleague and friend, Dr. Epstein left Seattle to lead the Division of Oncology at the University of Oklahoma School of Medicine.

It is a testament to the strength of the program Dr. Thomas built that many of the fellows who passed through the program stayed on at Fred Hutch or UW as I did. Many of us, too many to name, continue to work on improving transplantation outcomes, broadening its reach to more patient populations for more diseases other than leukemia and lymphoma, and reducing transplantation adverse effects. In addition to the fellows, hundreds of visiting physicians trained at Fred Hutch. As one of them said: “Virtually every major transplant center in the world got its start by sending someone to train under Don Thomas.” The observations describing the power of the immune system to eliminate cancer by graft-versus-tumor effects are now bearing fruit in the modern field of cancer immunotherapy. Many of today’s leading immunotherapy researchers trained here, including Fred Hutch’s Drs. Phil Greenberg, Stanley Riddell, Cameron Turtle, and David Maloney, and the University of Pennsylvania’s Dr. Carl June. In the end, transplantation’s success and its ripples into other spheres of medicine are due largely to Dr. Thomas’ willingness to take on an adventure as long as it ultimately helped the patient. In recognition of his vision and leadership, Dr. Thomas shared the Nobel Prize in in Physiology or Medicine with Joseph E. Murray in 1990. Importantly, transplantation has become a mainstay in medicine. Since 1969, more than 1,000,000 transplants have been performed around the world.