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.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC004002-36
Application #
7292002
Study Section
(MB)
Project Start
Project End
Budget Start
Budget End
Support Year
36
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Yu, P; Petrus, M N; Ju, W et al. (2015) Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model. Leukemia 29:556-66
Chen, Jing; Zhang, Meili; Ju, Wei et al. (2009) Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25. Blood 113:1287-93
O'Mahony, Deirdre; Morris, John C; Stetler-Stevenson, Maryalice et al. (2009) EBV-related lymphoproliferative disease complicating therapy with the anti-CD2 monoclonal antibody, siplizumab, in patients with T-cell malignancies. Clin Cancer Res 15:2514-22
Pise-Masison, Cynthia A; Radonovich, Michael; Dohoney, Kathleen et al. (2009) Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability. Blood 113:4016-26
O'Mahony, Deirdre; Morris, John C; Quinn, Cate et al. (2007) A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res 13:958-64
Bene, Laszlo; Kanyari, Zsolt; Bodnar, Andrea et al. (2007) Colorectal carcinoma rearranges cell surface protein topology and density in CD4+ T cells. Biochem Biophys Res Commun 361:202-7
Waldmann, T A (2007) Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma. Oncogene 26:3699-703
Sato, Noriko; Patel, Hiral J; Waldmann, Thomas A et al. (2007) The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl Acad Sci U S A 104:588-93
Waldmann, Thomas A (2007) Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J Clin Immunol 27:1-18
Perera, Liyanage P; Waldmann, Thomas A; Mosca, Joseph D et al. (2007) Development of smallpox vaccine candidates with integrated interleukin-15 that demonstrate superior immunogenicity, efficacy, and safety in mice. J Virol 81:8774-83

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