Eight projects and eight cores are proposed forming a translational research program with the goal of advancing the treatment of chronic myelogenous leukemia. Projects 1-3 involve 1) clinical investigation of novel chemo- and biologic therapies, 2) allogeneic blood and marrow transplantation focusing on enhancement of graft-versus-leukemia and improving the therapeutic index of preparative regimen, and 3) Use of """"""""leukemic"""""""" dendritic cells to generate autologous anti-leukemic T-cells for adoptive immunotherapy. Projects 4 and 5 are designed to improve the safety and effectiveness of allogeneic transplants for CML. The allogeneic graft-versus-leukemia effect can independently produce prolonged remissions in CML patients,b ut its efficacy is limited by the development of graft-versus-host disease. Project 4 studies the induction of GVL using lymphocytes transduced with Herpes virus thymidine kinase which renders them sensitive to the antiviral drug ganciclovir; if GVHD occurs the effectors cells can be ablated by ganciclovir treatment. In a preclinical murine model, the hypothesis that this strategy can abrogate GVHD while retaining GVL will be tested and strategies for optimally employing TK transduced donor lymphocyte infusions will be developed. Project 5 focuses on development of less toxic preparative regimens to achieve engraftment of allogeneic stem cell grafts and strategies to induce GVL without GVHD in histoincompatible recipients. Projects 6 and 7 examine the function of the bcr-abl tyrosine kinase and molecular strategies to block its transforming effects. Project 8 examines abnormalities in DNA methylation which occur in the course of CML and their significance for therapeutic intervention. Core A is for administration. Core B provides biostatistical support for the program. Core C is for minimal disease detection using fluorescence in situ hybridization (C1) or quantitative polymerase chain reaction (C2). Core D is for cell culture assays, in vitro (D1) and in a NOD-SCID murine model (D2). Core E provides flow cytometry support and Core F is the sample collection, processing and distribution core.
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