Allogeneic hematopoietic stem cell transplantation, often referred to as """"""""bone marrow transplantation"""""""", represents a curative therapy for many individuals with leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. However, the broadened application of transplantation therapy of these cancers is limited by two immune reactions that are mediated primarily by T cells, namely graft-versus-host disease (GVHD; T cell attack of donor cells against the patient) and graft rejection (or the host-versus-graft response; HVGR). GVHD is the main cause of lethality after transplantation. The HVGR results in the need to administer toxic doses of chemotherapy prior to transplanation, and results in the current limitation of transplantation to individuals having a closely matched donor either from within the family or through the National Marrow Donor Program. Our laboratory focuses on new T cell graft engineering strategies designed to prevent GVHD and graft rejection. In murine models, we have shown that donor Th2 cells, which are generated ex vivo in the presence of the immune modulation drug rapamycin, can potently inhibit GVHD while preserving a component of the beneficial graft-versus-tumor (GVT) effect; furthermore, such Th2 cells effectively prevent the rejection of fully genetically mis-matched hematopoietic stem cells. We have made significant progress in translating these findings to the clinic. We have developed a method for generating human Th2 cells in rapamycin, and we have initiated a clinical trial investigating these cells in patients with refractory hematologic malignancy. Current data are consistent with our murine data, as recipients of Th2 cells grown in rapamycin have a low rate of acute GVHD; furthermore, administration of Th2 cells has allowed for a significant reduction in the amount of preparative chemotherapy required to achieve engraftment of the allograft.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010288-11
Application #
7735405
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2008
Total Cost
$1,256,076
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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