Our Science – Waldmann Website

Thomas A. Waldmann, M.D.

Metabolism Branch Head, Cytokine Immunology and Immunotherapy Section Branch Chief Building 10, Room 4N115 NCI-Bethesda Bethesda, MD 20892-1374 Phone:   301-496-6656 Fax:   301-496-9956 E-Mail:   tawald@helix.nih.gov

Biography

Dr. Waldmann received his M.D. from Harvard Medical School. He joined the NCI in 1956 and has been chief of the Metabolism Branch since 1973. He studies the IL-2/IL-2 receptor system in growth of normal and neoplastic cells. He codiscovered IL-15 and introduced various forms of IL-2/IL-15R-directed therapy for leukemia, and autoimmune diseases. His honors include the Ehrlich medal, Stratton, Lila Gruber, Simon Shubitz, Milken, Artois-Baillet Latour, Bristol-Myers Squibb prizes, and election to the National Academy of Sciences, American Academy of Arts and Sciences, and Institute of Medicine, NAS.

Research

The IL-2/IL-15 Receptor System in the Life and Death of Lymphocytes: A Target for Cancer Therapy and Vaccine Design

Our work on basic and clinical immunology focuses on the regulation of the human immune response and how its dysregulation can lead to autoimmune, immunodeficiency and malignant disorders. We apply insights gained in our fundamental research to the development of new approaches to the treatment of patients. A major area of our efforts focuses on the critical role played by the receptor for interleukin-2 (IL-2) on the growth, differentiation and regulation of normal and neoplastic T-cells. We defined the IL-2 receptor subunits IL-2R beta and IL-2R alpha using the first reported anti-cytokine monoclonal antibody (anti-Tac) that we developed. This was followed by molecular cloning and expression of this receptor. These studies have culminated in the definition of the IL-2R as an exceptionally valuable target for the therapy of leukemia and autoimmune diseases. The scientific basis for this approach was our demonstration that normal resting cells do not express IL-2R alpha whereas it is expressed by normal T-cells in patients with lymphoid malignancies. We introduced different forms of IL-2R directed therapy including unmodified antibodies to IL-2R alpha (anti-Tac, the first antibody to a cytokine receptor to receive FDA approval), humanized anti-Tac (daclizumab, Zenapax) and the antibody armed with toxins or alpha and beta-emitting radionuclides. We showed that humanized anti-Tac contributes to reducing renal transplant rejection. The FDA then approved daclizumab for use in humans to prevent acute kidney transplant rejection. In addition, we showed that humanized anti-Tac is of value in the treatment of such T-cell mediated autoimmune disorders as noninfectious uveitis and multiple sclerosis. Furthermore, we demonstrated that anti-Tac provides effective therapy for a subset of patients with a previously fatal leukemia, HTLV-I associated adult T-cell leukemia (ATL). In addition, in a clinical trial for ATL patients using anti-Tac armed with 90Y for therapy we observed remissions in over 50% of trial patients.

In a most critical development, as part of our studies of IL-2 receptor directed therapy for human T-cell lymphotropic virus I (HTLV-I) associated adult T-cell leukemia (ATL), our group co-discovered a novel lymphokine IL-15 that stimulates T-cell proliferation and is required for the development and maintenance of NK cells as well as CD8 memory T-cells. We demonstrated that in T and NK cells the IL-15 receptor includes a cytokine specific IL-15R alpha chain defined by Giri as well as the IL-2R/IL-15R beta chain that is shared with IL-2 and the common gamma chain (c) also used by IL-2, IL-4, IL-7, IL-9 and IL-21. Our group and others demonstrated that IL-2 and IL-15 manifest distinct contributions to adaptive immune responses. IL-2 through its pivotal role in activation-induced cell death (AICD) and its inhibition of memory CD8 T-cell survival as well as its role in the induction of negative regulatory T-cells is involved in the negative control of T cells that is required for self tolerance. In contrast, IL-15 inhibits AICD and favors the survival of CD8 memory cells and is thus dedicated to the persistence of immunological memory to invading pathogens. These findings provided the scientific basis for our studies that use IL-15 in lieu of IL-2 in the treatment of cancer and that involve the incorporation of IL-15 into molecular vaccines. We demonstrated that the co-administration of an HIV vaccine with a vaccinia virus expressing IL-15 induced long-lasting CD8 mediated CTL immunity. In contrast, T-cell immunity mediated by IL-2 was short-lived. Thus, on the basis of these insights we are suggesting the incorporation of IL-15 as a component of molecular vaccines that represent a major advance in the generation of agents that yield a long-lasting immune response.

Recently our group demonstrated that IL-15R alpha provides novel contributions to IL-15 functions. IL-15 and IL-15R alpha form stable complexes on the cell surface of activated antigen presenting cells. The formation of IL-15/IL-15R alpha complexes induces a transendosomal cycling of IL-15 leading to the persistence of cell surface IL-15 due to the constant reappearance of IL-15 on plasma membranes. These complexes on activated monocyctes present IL-15 in trans to target cells such as resting NK and CD8+ T-cells that express only IL-2R/IL-15R beta and c upon cell-cell interaction. Abnormalities of IL-15 have been described in patients with rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease and in diseases associated with the retrovirus HTLV-I. We demonstrated a role for IL-15 and its receptor in HTLV-I associated ATL in the neurological disease HAM/TSP. In our efforts to inhibit the actions of IL-15 for therapy of autoimmune disease and HTLV-I associated disorders we focus on the cytokine receptor subunit IL-2R/IL-15R beta that we co-discovered. We demonstrated that a monoclonal antibody humanized MiK-Beta-1 directed toward this IL-2R/IL-15R beta receptor subunit prevents the trans and cis presentation of IL-15 to NK and CD8 T-cells and thereby inhibits IL-15 actions. We are translating these observations concerning IL-15 blockade from animal models to clinical trials involving the humanized version of Hu-MiK-Beta-1 in patients with rheumatoid arthritis, multiple sclerosis, LGL leukemia as well as those with disorders caused by the retrovirus HTLV-I.

Thus, in summary the clinical application of new therapeutic agents we have developed including monoclonal antibodies that target IL-2, IL-15 and their receptors has provided a new perspective for the treatment of select leukemias and autoimmune disorders as well as for the prevention of allograft rejection.

RECENT PUBLICATIONS:

Dubois S. et al. Immunity 2002;17:537-547
Oh S. et al. PNAS 2003;100 3392-3397
Waldmann TA, Nature Med 2003;9 269-277
Waldmann TA, Ann Rev Immunol 2003;21 1-17

This page was last updated on 6/12/2008.