by Kathleen O’Neil
City of Hope researchers are developing a treatment that could give leukemia patients improved chances of fighting their cancer while eliminating a common side effect of bone marrow transplantation.
Patients undergoing transplants of donated bone marrow often face graft-versus-host disease, in which donated immune T-cells attack patients’ own tissues.
A new approach developed by Defu Zeng, Ph.D., assistant professor in the divisions of Hematology & Hematopoietic Cell Transplantation and Diabetes, Endocrinology & Metabolism, uses an antibody to prepare the recipient’s system for transplanted stem cells and T-cells. The antibody almost eliminates the risk of graft-versus-host disease, Zeng said.
It is the first such therapy to do away with radiation or chemotherapy during bone marrow transplant conditioning, making the process potentially less toxic for patients. Results of a preclinical trial of the treatment appeared in the Jan. 15 issue of the Journal of Immunology.
“Depending on how closely matched a donor is, 30 to 60 percent of all leukemia patients treated with classic hematopoietic cell transplants develop graft-versus-host disease, which significantly reduces patients’ immune function and their chances of survival,” Zeng said. “This new therapy offers the best of both worlds — we can keep the donor T-cells active to fight leukemia while greatly lowering the chances that the cells will attack the patient.”
Allogeneic bone marrow transplantion — infusions of hematopoeitic stem cells from a healthy donor with compatible transplantation antigens — is a common treatment for advanced leukemia, but physicians currently lack a completely effective way to prevent the transplanted T-cells from attacking patients’ organs.
For donated immune T-cells to grow and react against a patient’s cancer, the patient’s own T-cells must first be destroyed or inactivated. Traditionally, physicians use radiation to kill the cells, but that also damages other organs and tissues, which respond by releasing chemicals to signal other cells — including donor T-cells — to come to their defense. The donor T-cells attack the host’s organs because they identify the tissues as foreign.
Immunosuppresive drugs can sometimes prevent acute attacks of graft-versus-host disease, but the medications may cause side effects, patients sometimes have to take the drugs for years, and graft-versus-host disease may still occur.
City of Hope’s experimental treatment, which has shown success in preclinical tests, uses the antibody anti-CD3 to inactivate the host’s immune T-cells. The donor T-cells can then fully take over immune duties to fight off leukemia without causing graft-versus-host disease.
“This treatment could allow more widespread use of hematopoietic cell transplantation to fight autoimmune diseases for which total-body radiation is too damaging to justify the benefits, such as systemic lupus, multiple sclerosis and type I diabetes,” Zeng said. He plans to work with Stephen Forman, M.D., the Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation and chair of the Division of Hematology & Hematopoietic Cell Transplantation, to conduct a phase I clinical trial of the therapy.
The research was supported by grants from the National Institutes of Health and a pilot grant from City of Hope’s Lymphoma Special Program Grant of Research Excellence, which is led by Forman. Zeng’s postdoctoral researchers Chunyan Zhang, Ph.D., Jingwei Lou, Ph.D., and Nainong Li, Ph.D., contributed to the research, and they were aided by Forman, Ivan Todorov, Ph.D., associate research scientist in the Department of Diabetes, Endocrinology & Metabolism, and Fouad R. Kandeel, M.D., Ph.D., director of the Department of Diabetes, Endocrinology & Metabolism.