The overall objective of this grant application concerns the development of new biologic therapies for Ph/1 chronic myelogenous leukemia (CML). Interferon (IFN) as a prototype biologic treatment showed that biologic therapy possesses clinical activity in CML, that this activity is extremely heterogenous, and that striking survival benefits are observed only in patients who achieved complete cytogenetic responses. The therapeutic targets of biologic therapies focus on the improvement in the incidence of the complete cytogenetic response and also the consolidation of responses achieved with either interferon, autologous bone marrow transplantation or chemotherapies. Within the framework of biologic therapies, we intend to incorporate three novel therapeutic concepts: (1) natural growth inhibitors with specific emphasis on growth factor inhibitors; (2) therapies leading to facilitated differentiation of the malignant clone and/or accompanied facilitated cell death; (3) therapies intent on generating an augmented autologous immune response to the residual leukemic disease; and (4) biological selection of the Ph- cells for transplant. Preliminary data suggest that the selective effects of MIP-1alpha on normal and chronic phase CML cells should be further studied to evaluate if the effects of this cytokine could be of value in therapy. For example, MIP-1alpha may protect early normal hematopoietic progenitors, while CML primitive precursors are eradicated by cell cycle-specific chemotherapy, or conversely, MIP-1alpha may suppress residual leukemic progenitors if administered following conventional chemotherapy to patients with blast crisis CML. Using several tissue culture assays including the delta suspension culture assay that selects proliferating primitive progenitors, cell fractionation techniques to select and study cellular population of marrow progenitors, the thymidine suicide technique to study the cell-cycle status of normal and CML progenitors, and polymerase chain reaction (PCR) and the hybridization protection assay to obtain the ratio of normal/leukemic progenitors in our culture, we intend to investigate mechanisms of action of MIP-1alpha and its possible clinical benefits in CML. Specifically, we will: a) investigate the effects of MIP-1alpha on primitive and mature CML progenitors from patients in chronic phase, accelerated phase and in blastic transformation; and b) identify conditions under which this cytokine will be used for purging CML marrow prior to autologous bone marrow transplantation and in therapy for CML.
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