There is abundant data documenting that patients with CML have residual normal hematopoietic stem cells able to repopulate the marrow and yield major cytogenetic remissions of the disease after cytotoxic or Interferon therapy. Up until now remissions following cytotoxic therapy or autologous transplants have unfortunately been relatively short lived. Recently we have demonstrated for the first time that CML derived, Ph1 positive dendritic cells may activate autologous lymphocytes to yield leukemia specific cytotoxic effector cells (DC/AL). We hypothesize that these DC/AL may be used for the generation for effective anti-CML therapy. Our objective in this project is thus to develop novel autologous cellular therapies which will produce long-term cytogenetic remissions of this disease. In order to do so we propose clinical studies of DC/AL infusion in late chronic phase CML. The novel information regarding the activity of DC/AL will also be pursued in the laboratory in order to better define the nature of the effector cell interaction with and cytolysis of the leukemic cells. Specifically we will: 1) Define the toxicity and anti-leukemic efficacy of CML-dendritic cell (DC) stimulated autologous lymphocytes in patients with late chronic phase CML. 2) Correlate in-vitro anti-leukemic cellular recognition and other characteristic and other characteristics of anti-CML effector cells generated by stimulation of autologous lymphocytes by CML-dendritic cells. Dr. Belmont's NOD-SCID mouse system of will be used to verify the activity of DC/AL for the CML stem cell. 4) Establish the mechanism of anti-CML activity of CML-dendritic cell stimulated lymphocytes. The relative roles of perforin, granzyme B and Fas mediated cell death will be explored. This program has the potential to yield curative therapies for patients with advanced CML lacking other treatment options.
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