- John Barrett, M.D. Research
The Barrett group has carried out clinical trials in stem cell transplantation (SCT) as a treatment for leukemia for over 23 years at NIH. His current research in SCT focuses on improving transplant outcome through immune manipulations using cell therapy and lymphocyte growth factors. Stem cell transplantation offers the chance of cure for leukemia patients through a unique graft-versus-leukemia GVL effect conferred by an immune reaction of the donor graft against the patient’s leukemia. Unfortunately the GVL reaction often develops alongside an unwanted and potentially fatal graft-versus host disease (GVHD). GVHD can be controlled through reducing the immunity of the graft and while transplants for leukemia can now be performed with considerable safety, fatal viral infections and disease relapse still reduce the success of SCT as a treatment for leukemia.
Dr Barrett’s approach to improve SCT outcome is to generate in the laboratory immune cells from the donor that are capable of fighting viruses and leukemia without causing GVHD. This can be done at the time of transplant by taking lymphocytes from the donor and stimulating them with viral or leukemia antigens. Antigen specific lymphocytes can be expanded over a two week culture period and infused into the patient after transplant to boost their immunity against viruses and reduce the risk of leukemia relapse. A clinical trial demonstrating the safety of infusions of virus specific lymphocyte infusions to prevent multiple virus infections has been completed and a trial of leukemia specific T cell infusions is now being developed. Fully matched transplant donors cannot be found for every patient who needs a transplant. In this case a relative who is partially matched may serve as a donor. However harmful GVH reactions are a particular problem for such partial matched transplants. Dr. Barrett’s group is therefore exploring ways to prevent GVHD in mismatched SCT. Grafts can be made more tolerant by treatment with low doses of a lymphocyte growth factor called interleukin-2 (IL-2), and Dr. Barrett’s group has used IL-2 to mitigate otherwise dangerous GVH reactions in a transplant protocol where the donor is a half-matched family member. He is also investigating the ability of a cell therapy approach to treating GVHD with mesenchymal stromal cell (MSC) infusions, which can both suppress the harmful immune reaction and help repair tissues damaged by GVHD.
As a physician-scientist, Dr. Barrett also leads a basic science program to better understand the nature of the interaction of acute leukemias with the patient’s immune system. An emerging concept from this work is that leukemia cells develop multiple ways to switch off the immune response that might otherwise successfully eradicate the leukemia. Understanding these mechanisms of “immune editing” should lead to ways to re-establish immune control of the leukemia by combining standard chemotherapy with immunotherapy to boost the patients’ own anti-leukemia defenses and preventing relapse of the leukemia. Furthermore the group plans to develop a comprehensive knowledge of the antigens on leukemia cells that render them targets for immune attack. This is the basis for generating powerful leukemia-specific killer cells that could enhance the GVL response after transplant and eventually extend to the treatment of patients in remission from leukemia to prevent relapse of their disease.
Through this combined translational and clinical strategy, Dr. Barrett’s group is working toward optimizing the tremendous potential that stem cell transplantation holds in curing leukemia and other serious blood and bone marrow disorders.