Our clinical research in transplantation is focused on both autologous transplant (in which the patient’s own stem cells are reinfused into the bloodstream) and allogeneic transplant (in which stem cells from the marrow or peripheral blood of another person — either a related or unrelated donor — are given to the patient). With both types of transplants, patients first undergo a preparative or cytoreductive regimen, which is a course of high-dose chemotherapy or radiation therapy, or a combination of both.
Since 1973, when our physicians performed the first successful transplant of bone marrow from an unrelated donor, our investigators have been at the forefront of bone marrow and stem cell transplantation. Current research is focused on several areas to make transplantation available to many more patients, including a program to evaluate transplants from matched unrelated donors; the use of T cell-depleted allogeneic transplants and donor lymphocyte infusions, which permit HLA-mismatched relatives to serve as donors; and other transplant-preparative regimens that have resulted in one of the lowest rates of graft-versus-host disease in the nation.
Among our recent research accomplishments:
- We showed that the class and quantity of inhibitory killer Ig-like receptors (KIRs) for the self-MHC class I ligands HLA-B and HLA-C by human natural killer cells have important implications for NK cell responses to malignancy and for donor selection in allogeneic hematopoietic stem cell transplantation. J Immunol. 2007 Nov 1;179(9):5977-89. [PubMed Abstract].
- We showed that allogeneic T cell precursors can be transferred to irradiated individuals irrespective of MHC disparities and give rise to host-MHC-restricted and host-tolerant functional allogeneic T cells, which improve antitumor responses and survival in irradiated recipients. This finding demonstrated the feasibility of an “off-the-shelf” immunotherapy. Nat Biotechnol. 2008 Apr;26(4):453-61. [PubMed Abstract]
- We found that gut-derived dendritic cells induced alloreactive donor T cells with a gut-homing phenotype caused increased mortality and morbidity from graft-versus-host disease (GVHD) compared with T cells stimulated with dendritic cells from spleen, liver, and peripheral lymph nodes in an MHC-mismatched murine bone marrow transplant model. This underlined the importance of the gut in the pathophysiology of GVHD. Blood. 2008 Mar 1;111(5):2929-40. [PubMed Abstract]
- We demonstrated that patients who had refractory myeloid leukemia and advanced myelodysplastic syndrome (MDS), but who had 20 percent or fewer bone marrow blasts, attained an estimated three-year probability of overall survival of 40 percent and disease-free survival of 39 percent. These patients had a relatively low cumulative incidence of GVHD after cytoreduction with busulfan and melphalan and unmodified allografts with tacrolimus and methotrexate GVHD prophylaxis. Biol Blood Marrow Transplant. 2007 Feb;13(2):235-44. [PubMed Abstract]
- We showed that cytoreduction with hyperfractionated total body irradiation, thiotepa, and fludarabine provided sustained engraftment of T cell-depleted allogeneic hematopoietic stem cell grafts and resulted in a low incidence of GVHD, despite the lack of antithymocyte globulin. Blood. 2007 Dec 15;110(13):4552-9. [PubMed Abstract]
- We described an immune benefit of allogeneic, or donor-provided, blood stem cell transplants in patients being treated for leukemia, underscoring the promise of harnessing natural killer (NK) cells for treatment of cancer. In studies of NK cells that had formed from HLA-matched transplants in leukemia patients, we found that such cells can defend against cancer for a certain period of time, due to a previously unknown ability of NK cells to break their tolerance to self. We are now examining if patients with other cancer types, such as neuroblastoma, also benefit from NK cell activity after receiving HLA-matched transplants. Blood. 2009 Apr 16;113(16):3875-84. [PubMed Abstract]
- We have described a noninvasive imaging system for monitoring human antigen-specific T cells that have been transferred into mice. The system employs T cells engineered to produce a protein marker that can be imaged using a radiolabeled probe, and could be further developed for monitoring transduced T cells in human patients. Cancer Res. 2007 Dec 15;67(24):11959-69. [PubMed Abstract]
- Our researchers are exploring new ways to enhance the efficacy of T cell-based therapies. We have shown that genetically engineered T cells that overexpress the proteins CD80 and 4-1BBL can provoke tumor rejection in immunodeficient mice, indicating that they could be applied to enhance antitumor responses in targeted adoptive transfer therapies. Nat Med. 2007 Dec;13(12):1440-9. [PubMed Abstract]