We propose an integrated, multi-disciplinary program of basic and clinical research aimed at elucidating those genetically defined characteristics of normal or malignant hematopoietic cells, dendritic cells and effector T and NK cells, distinguishing a leukemic host from a normal allogeneic marrow transplant donor which can provoke or modify cellular interactions contributing to limited engraftment or graft failure, Graft versus Host Disease, leukemia resistance and full or impaired reconstitution of immunity. Project II proposes to identify and characterize genetic polymorphisms of killer inhibitory receptors (KIR) expressed on NK cells and to assess whether donor/host disparities for KIRs are correlated with imparied engraftment or altered leukemia resistance. Project III will compare phenotypic and functional characteristics of dendritic cells and their precursors and their ability to present alloantigens, microbial antigens or leukemia fusion gene-induced antigens at different stages of life, define states of dendritic cell chimerism post- transplant and assess the effects of dendritic cell chimerism on the development of donor alloreactive and neo-antigen-specific responses. Project IV proposes to develop and assess in pre- clinical models, strategies for adoptive cell therapy of EBV lymphomas and relapsed leukemias using donor T-cells, transvected early after sensitization, with novel dicistronic vectors encoding a cell surface expressed mutant nerve growth factor receptor for immunoselective and either HSV-TK or cytosine deaminase to render the cells sensitive to granciclovir or 5- fluorocytosine. Project V proposes to identify immunogenic leukamia-specific fusion gene encoded peptides, the generate peptide-specific T-cells and assess their activity in vitro and in vivo in pre-clinical models against fresh human leukemias bearing these fusion genes. Integrated with and complementing this program of basic research, Project VI proposes randomized trails comparing HLA compatible related T-cell depleted versus unmodified BMT and single armed phase VII studies to evaluate approaches for transplantation of HLA matched or haplotype disparate leukemic hosts using improved cytoreduction regimens and the combined use of T-cell depleted marrow and peripheral blood stem cells, as well as trials evaluating adoptive transfer of escalating doses of unselected or virus-specific T-cells for the treatment of relapsed leukemia or EBV lumphoma. By intergrating studies of donor/recipient pairs conducted in Projects II-V with results of ongoing trials proposed in Project VI, new insights into the biology ofmarrow grafts and improved approaches to their application should be achieved.
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