We propose an integrated multi-disciplinary program of basic and clinical research to distinguish those interactions of an allogenic donor?s hematopoietic cells, dendritic cells and T-lymphocytes with a transplanted leukemic host which contribute to reconstitution of hematopoiesis and immunity, the development of tolerance or graft versus Host disease (GVHD) and the acquisition of leukemic resistance in the post transplant period. Our goal is to develop and evaluate improved strategies for 1) enhancing leukemia resistance and 2)promoting reconstitution of immunity in transplanted hosts. Project 1 will explore strategies incorporating retroviral vector constructs encoding co-stimulatory molecules, HLA alleles and host leukemia-associated immunogenic peptides to create more effective, accessible antigen presenting cells for the generation of donor leukemia-reactive T-cells. Sensitized T- cells, transduced to express a suicide vector, will then be tested for their allospecific, leukemia-targeted activity and drug sensitivity in SCID xenograft models and ultimately in phase I trials. Project 2 proposes to develop and evaluate synthetic analogues of leukemic fusion gene peptides and specific donor T-cell responses in the transplanted host. Project 3 will test lymphoid and myeloid dendritic cells for their capacity to stimulate or tolerize T-cell responses against LAA, and minor alloantigens and correlate their development post transplant with GVHD, immunity and leukemic resistance. Project 5 will examine EBV and CMV specific T-cell repertoires in post transplant using viral peptide HLA tetramers to quantitate virus specific T-cell populations and to isolate these cells for evaluation of their function and clonal diversity. Project 4 will test in murine allogeneic HSC transplants the capacity of IL-7, IGF-1, KGF and thymic stromal lymphopoietin to foster immune reconstitution and to limit or augment leukemia resistance and/or GVHD. Project 6 proposes novel phase II trials of transplants and cell therapies for leukemic patients with leukemia, including studies of a) T-cell depleted - HLA matched and disparate, related and unrelated HSC transplants administered after new, less toxic myeloablative regimens, b)non-myeloablative cytoreduction regimens combined with leukemia-targeted monoclonal antibodies and unmodified HLA matched PBSC transplants, c) adjuvant use of bcr/abl fusion gene peptide vaccination with donor leukocyte infusions for relapsing CML and d) use of donor T-cells transduced with a suicide vector early after sensitization to EBV antigens for treatment of EBV lymphomas as well as e) a trial of growth hormone to support the immunobiology of HSC transplants and improved clinical outcomes.
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