• Claxton, David (PI)
  • Kornblau, Steven (PI)
  • Arlinghaus, Ralph Bernard (PI)
  • Reisner, Yair (PI)
  • Austin, David (PI)
  • Champlin, Richard (PI)
  • Kantarjian, Hagop (PI)
  • Champlin, Richard (PI)
  • Feinberg, Andrew (PI)
  • Deisseroth, Albert (PI)

Project: Research project

Project Details


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.
Effective start/end date9/30/981/31/99


  • National Cancer Institute

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