The IL2/IL2R growth factor/receptor system, initially characterized for T-lymphocytes, is now known to regulate a variety of non-T-cells, including neoplastic hematopoietic lineage cells. Several recent studies report that neoplastic cells from several forms of leukemia/lymphoma have IL2 membrane binding properties. In addition, a variety of ex vivo stimuli hae been shown to modulate IL2R-negative leukemia to an IL2R-positive state. Our objectives are to generate additional data on constitutive and inducible IL2 membrane binding proteins on leukemia/lymphoma cells, and to determine if these binders -- whether constitutive or induced-- render these cells susceptible to killing by IL2-based hybrid toxins. In pursuing these studies we will: (i) define IL2 receptor status in a large series of fresh leukemia/lymphoma cell samples, together with the conditions for ex vivo induction of receptors in IL2R-negative cells, using as inducers biologically relevant agents; and (ii) quantitate IL2- hybrid toxin killing ex vivo of naturally IL2R-positive, and induced IL2R-positive cells. We will also (iii) establish an IL2R-positive lethal disease in nude mice, and define the efficacy of IL2-hybrid toxin as a therapeutic modality in this disease. Finally, using the biologically relevant ex vivo inducers of IL2R expression we identify, we will (iv) attempt to convert, in vivo, an IL2R- negative lethal disease in nude mice to IL2R-positive status, and characterize the efficacy of IL2R-hybrid toxin as a therapeutic modality in this situation. These studies relate to the overall objectives of this NCDDG by providing critically important pre- clinical information on the potential use of IL2-based toxins as novel therapy in IL2R-positive leukemia/lymphoma in humans.
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