“This combined approach could be the ‘holy grail’ of transplantation,” says investigator Judith Shizuru, MD, PhD (associate professor, Blood and Marrow Transplantation), who was awarded a $20 million grant from the California Institute for Regenerative Medicine (CIRM) to develop this antibody-based therapy. The discovery could lead to safe, long-term treatment for a multitude of inherited blood disorders and cancers, and expand treatment options for autoimmune diseases like multiple sclerosis, lupus, and childhood diabetes.

Making bone marrow transplantation safer so that patients benefit from the procedure without toxicity, and expanding the procedure to treat a range of autoimmune diseases have been the goals of Shizuru’s research for more than a decade.

Bone marrow transplantation is so dangerous and so toxic that it is reserved for people with life-threatening diseases. Despite the dangers of a transplant, including rejection of the new, disease-free cells in the transplanted tissue, more than 50,000 patients get bone marrow transplants each year because it is the only curative treatment possible for patients with inherited disorders of blood formation; for immunodeficiencies such as severe combined immunodeficiency disease (SCID); and for many types of cancer.

The need to deliver DNA-damaging treatments, and the possibility of graft-vs-host disease remain the biggest hurdles in bone marrow transplants, as an average of 10 to 20 percent of bone marrow transplant patients die from complications. Prior to the transplant, patients will receive chemotherapy or radiation to make space in the bone marrow for the healthy donor cells. Patients also receive medications to suppress donor lymphocytes from attacking the transplant recipient’s body, which can cause life-threatening graft-vs-host disease.

At Stanford, researchers are developing a safer bone marrow transplantation approach, which will begin clinical trials next spring. Instead of chemotherapy and radiation, the trial will use the first biologic agent to eradicate the disease-producing stem cells to treat children with SCID; patients will then receive grafts of pure blood-forming stem cells from a donor. The mixed cell grafts will be processed so that only pure stem cells will be infused, devoid of contaminating donor lymphocytes that cause graft-vs-host disease.

“This combined approach could be the ‘holy grail’ of transplantation,” says investigator Judith Shizuru, MD, PhD (associate professor, Blood and Marrow Transplantation), who was awarded a $20 million grant from the California Institute for Regenerative Medicine (CIRM) to develop this antibody-based therapy. The discovery could lead to safe, long-term treatment for a multitude of inherited blood disorders and cancers, and expand treatment options for autoimmune diseases like multiple sclerosis, lupus, and childhood diabetes.

Making bone marrow transplantation safer so that patients benefit from the procedure without toxicity, and expanding the procedure to treat a range of autoimmune diseases have been the goals of Shizuru’s research for more than a decade.

This is an exemplary story of the promise of translational medicine, starting with studies of the basic biology of blood-forming cells at Stanford; then the laboratory discovery of the antibodies to target stem cells; and then adapting the development of those antibodies by off-campus biotech companies, with the empowering support from CIRM that allows Shizuru’s team to deliver these new treatment options to patients.

This research builds on groundbreaking discoveries in mice by Irving Weissman, MD, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and a consultant to the Shizuru team. In the late 1980s his laboratory developed methods to isolate mouse stem cells by sorting them, using the fluorescence-activated cell sorter technology developed at Stanford. His team subsequently founded a company that applied these methods to isolate human stem cells.

Next, a Stanford medical student working in the Weissman lab, Agnieszka Czechowicz, identified the target antibody that the researchers will soon test in a clinical trial. Czechowicz’s project was to test different antibodies to see if any of them could remove the blood-forming stem cells as well as or better than chemotherapy would do in humans (or radiation would do in mice). She discovered that an antibody that recognizes the CD117 molecule, which is present on blood-forming stem and progenitor cells, could accomplish this goal. “We have always envisioned that antibodies could replace toxic treatments, and targeting CD117 seemed ideal,” Shizuru explains, “and we began to investigate if a similar antibody that targets human stem cells could be tested in a clinical trial.”

The next lucky discovery was that a local biotech company had already developed and safety-tested a human antibody to target human CD117, but for treatment of inflammatory disease and not for bone marrow transplantation. Scientists at the company agreed to collaborate in Shizuru’s investigations, and openly shared their biologic and safety tests with the antibody. This vital assistance from the company has accelerated the ability of the Stanford team to move to clinical trials, and CIRM funding has supported the many steps needed to obtain FDA approval for the study, including testing to validate use of the human anti-CD117 antibody in patients.

“This is the most exciting thing I have done in my life,” Shizuru says. “One important reason why I became a bone marrow transplanter was so I could help to cure autoimmune disease, and diabetes was my PhD topic.” Shizuru began her career as a technician in a Stanford lab, where her mentors encouraged her to pursue a PhD. She then completed her studies to become an MD at Stanford and became a physician-scientist after receiving advice and support from the founding members of the Juvenile Diabetes Foundation. “If we can make bone marrow transplants safer, that offers a potential way to cure autoimmune disease, including diabetes,” says Shizuru.

Shizuru has set out to change the field of bone marrow transplantation, and she is confident this work will create the pathway. “I want to make the transplantation procedure an order of magnitude safer, and to achieve this end-goal we have to evolve from the current toxic, DNA-damaging approach and infusion of undefined cell populations to a more targeted and nuanced one.”