Our studies in basic, preclinical and clinical immunology focus on the regulation of the human immune response and how its disregulation can lead to autoimmune, immune deficiency and malignant disorders. We apply insights gained in our fundamental research to the development of new approaches to the treatment of patients with leukemia and lymphoma. A major focus of our efforts is on the roles played by the IL-2/IL-2R and IL-15/IL-15R systems in the life and death of normal and abnormal T cells and the use of these insights to develop IL-2R and IL-15R directed therapies for leukemia and autoimmune diseases. Previously, we defined the IL-2 receptor subunits, IL-2/IL-15R beta and IL-2R alpha, using the first ever reported anti-cytokine receptor monoclonal antibody (anti-Tac, daclizumab) that was developed in our laboratory. These seminal studies on the IL-2 receptor have culminated in the definition of the IL-2R as an exceptionally valuable target for the therapy of leukemia and for autoimmune diseases. The scientific basis for this approach was our demonstration that virtually all normal resting cells do not express IL-2R alpha whereas it is expressed by abnormal T cells in patients with lymphoid malignancies, autoimmune disorders and those involved in organ allograft rejection. We introduced different forms of IL-2 receptor directed therapy including unmodified murine antibodies to IL-2R alpha anti-Tac), humanized anti-Tac (daclizumab), the first antibody directed toward a cytokine receptor to receive FDA approval and this antibody armed with toxins or beta and alpha-emitting radionuclides. We developed a 3-step pretargeting approach that permits us to deliver tenfold greater quantities of radionuclide to the tumor than does a conventional radionuclide armed monoclonal antibody. In clinical trials we demonstrated that anti-Tac (daclizumab) provides effective therapy for a subset of patients with HTLV-I associated adult T-cell leukemia (ATL). The leukemic cells are of the CD4+ CD25+ phenotype, that profoundly suppress immune responses. We suggested in 1984 that they represent the leukemic counterpart of modern T-regs, the normal negative immunoregulatory T-cell. Furthermore, in a clinical trial that included ATL patients and that involved anti-Tac armed with 90Y we observed remissions in over 50% of trial patients who had this previously universally fatal leukemia/lymphoma. In parallel studies with our collaborators, we have shown that humanized anti-Tac is of value in the therapy of T-cell mediated autoimmune noninfectious uveitis. Furthermore, we and our collaborators demonstrated that there was a 78% reduction in gadolinium-enhanced MRI lesions in patients with multiple sclerosis who are failing beta interferon therapy when they were treated with humanized anti-Tac. On the basis of these studies, Phase II-III trials are being initiated to evaluate daclizumab in the treatment of these autoimmune disorders. In other studies, in preclinical efforts using a model of human adult T-cell leukemia in SCID/NOD mice we demonstrated that effective therapy can be achieved with daclizumab in combination with Flavopiridol or Velcade. Furthermore, we demonstrated effective therapy in this murine model of ATL with the anti-CD2 monoclonal antibody MEDI-507 as well as with the anti-CD52 monoclonal antibody CAMPATH-I. On the basis of these encouraging preclinical results, clinical trials have been initiated by the Metabolism Branch Clinical Trials Team with anti-Tac (daclizumab), MEDI-507 and CAMPATH-I. Remissions have been observed with each of these monoclonal antibodies. In a most critical development, as part of our studies of IL-2 receptor directed therapy for HTLV-I associated ATL, we co-discovered a novel lymphokine, IL-15, that is required for the development and maintenance of NK-cells as well as CD8 memory T-cells.
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