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. Most recently, we developed a 3-step pretargeting approach that permits us to deliver ten-fold 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 were 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, 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 with anti-Tac (daclizumab), MEDI-507 and CAMPATH-I with the patients being studied on the Metabolism Branch NCI. 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. Furthermore, we demonstrated that the cytokines IL-2 and IL-15 that share two receptor subunits manifest distinct contributions to immune responses. IL-2 through its pivotal role in activation-induced cell death (AICD) and its inhibition of memory T-cell survival is involved in the T-cell suicide required for self tolerance. In contrast, IL-15 inhibits AICD and favors the survival of CD8 memory cells and is thereby dedicated to the persistence of immunological memory to invading pathogens. Abnormalities of IL-15 expression have been demonstrated in patients with an array of autoimmune diseases and T-cell leukemias. We are translating this observation by the introduction of humanized MiK-Beta-1 directed toward IL-2/IL-15R beta that blocks IL-15 action into clinical trials involving these disorders. Our observations on the role of IL-15 in immunological memory are critical for the rational use of this cytokine in the treatment of cancer and as a component of vaccines. Our group in collaboration with the Berzofsky group demonstrated that the co-administration of an HIV vaccinia virus vaccine expressing IL-15 induced long lasting CD8 cytotoxic T-lymphocyte mediated immunity. In contrast T-cell immunity mediated by IL-2 was short-lived. The IL-15 environment at the time of immunological priming had persistent effects on the character of the memory CD8 T-cells long afterwards. In further studies, it was demonstrated that a vaccinia vaccine vector expressing IL-15 induced high-avidity cytotoxic lymphocytes (CTL) that expressed high levels of IL-15R alpha, the private receptor for IL-15. On the basis of these studies, we have suggested that the incorporation of IL-15 as a component of molecular vaccines may represent a major advance in the generation of agents that yield long-lasting immune responses. To test this hypothesis molecular vaccines that include IL-15 in association with HIV, HER-2/neu, anthrax and tuberculosis have been generated to yield agents that will be evaluated in trials focusing on the prevention and treatment of chronic infectious diseases and cancer. We are also evaluating the introduction of IL-15 in the treatment of neoplasia. In preclinical studies we demonstrated that IL-15 transgenic mice in contrast to wild-type mice did not develop the colon carcinoma (MC38) following intravenous introduction of the cancer cells and that MC38 cells transfected with IL-15R alpha no longer formed metastases in wild-type mice. These findings provide the scientific basis for the use of IL-15 in lieu of IL-2 in the treatment of select malignancies and for the incorporation of IL-15 into molecular vaccines for cancer and AIDS.
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