In 1954 Harvard Medical School gave Sherman Weissman and me a $50 grant to study erythropoietin thereby initiating my 64-year odyssey in biomedical research. My fascination with immunology emerged during my internal medicine residency at the Massachusetts General Hospital when I was assigned to the Massachusetts General Hospital polio ward during the last polio epidemic when over 300 patients were admitted to Massachusetts General Hospital, 70 of whom were encased in giant mechanical respirators called iron lungs. In the next year Jonas Salk developed the polio vaccine. I was truly impressed that a vaccine could be effective in preventing a very serious acute infectious disease. Following my internship, I joined the NIH in a research position in lieu of serving 2 years in the military between the Korean and Vietnam Wars when the general medical draft and the doctors’ draft were in effect.
The dominant area of my research, clinical immunology, has undergone a revolution changing from a largely phenomenal endeavor into a deeply analytical and technical field. Movement in this field like the growth of our children may not appear impressive when viewed from one day to the next, however its progress has been dramatic when viewed using the portfolio of images taken over 6 to 7 decades. Questions that could not even be asked 60 years ago have been definitely answered. To give a sense of the dramatic progress in the field of Immunology I quote from the textbook Clinical Hematology by Maxwell Wintrobe that appeared in 1956, the year I joined the NIH. “The function of the lymphocyte is still obscure. Because of their strategic position in lymph nodes and because they are rich in adenosinase which splits adenosine it has been suggested that the lymphocyte is instrumental in the destruction of toxic products of protein metabolism. A role of transference of fat from the intestinal epithelium to the lactates has been denied.” This reflects the primitive understanding we had concerning the immune system, especially cellular immunology at the time. The role of the thymus and T cells in immunity had not been defined. One could not even consider the nature of the T-cell receptor for antigen or meaningfully discuss how antibody and T-cell diversity were generated when neither the T-cell antigen receptor nor the multichain structure of immunoglobulin had been demonstrated. By 1951 none of the primary immunodeficiency diseases had been shown to involve a defined molecular defect of an element of the immune system. Moreover, we did not have anything approaching our present understanding of a disease such as AIDS caused by a retrovirus, a form of pathogen that had not been defined that infects CD4 expressing target T-cells that had not been discovered.
My own entry into the field of Immunology was through the back door by the study of serum protein metabolism, especially that of the immunoglobulins. We defined the metabolism of the 5 classes of immunoglobulins and demonstrated their different rates of synthesis, patterns of distribution, and rates of catabolism in normal individuals. Furthermore, we demonstrated diseases of immunoglobulin catabolism and loss. We showed that hypogammaglobulinemia may be the result of hypercatabolism of a single protein as in patients with myotonic dystrophy where we defined a selective decrease in IgG survival. Alternatively, we showed endogenous hypercatabolism affecting many immunoglobulin classes and albumin in a disease we called familial hypercatabolic hypoproteinemia, a disorder subsequently shown to represent a mutation in the signal peptide of beta-2 microglobulin. In a major discovery, our group in collaboration with Robert Gordon defined yet another form of short protein survival, excess bulk loss of serum proteins into the gastrointestinal tract, a disorder that we called protein-losing gastroenteropathy. We demonstrated a number of new diseases with this disorder including the syndrome intestinal lymphangiectasia (termed Waldmann’s disease by the National Organization for Rare Disorders). Most recently this was shown in part to be associated with a mutation of CD55, a complement-decay accelerating factor.
Another focus of our research was on the primary human immunodeficiency diseases. Despite their great heuristic value, our understanding of the immune system was hindered by the fact that unseparated lymphocytes represent mixtures of complex populations of cells with different and at times opposing functions. To circumvent this problem Samuel Broder and I took advantage of the fact that in a given patient human T-lymphoid leukemic cells represent homogenous populations of T cells that could theoretically retain a single function. We demonstrated that the leukemic cells of patients with the Sézary syndrome could act as helper T cells. In contrast, the T cells of patients with human T-cell lymphotropic virus 1 (HTLV-1) associated adult T-cell leukemia (ATL) profoundly inhibited immune responses by functioning as immune suppressors.
In the mid 1970’s, the cardinal question regarding the immune system remained unanswered: How does our body with its limited amount of genetic material generate a diversity of antibodies and T cells that can recognize a myriad of foreign configurations in our environment? The solution to this paradox emerged from the brilliant studies of Tonegawa, Leder and Hood who used recombinant DNA technology to show that the genes encoding antibodies and those for T-cell receptors used discontinuous bits of genetic material in different combinations. Our studies applying immunoglobulin and T-cell receptor gene rearrangement were used to define the lineage (T or B cells) of leukemic cells lacking conventional markers, to determine the state of maturation of leukemic B and T-cell precursors, and to broaden the scientific basis for monitoring the therapy of lymphoid neoplasms.
The latest adventures in my immunological odyssey involved the critical roles played by the cytokines IL-2 and IL-15 and their receptors in the growth and differentiation of normal and neoplastic T cells. These basic insights concerning IL-2 and IL −15 systems are being translated into receptor-directed monoclonal antibody mediated treatment of patients with leukemias/lymphomas and autoimmune diseases and the use of the cytokine IL-15 in combination therapy for patients with malignancy. We discovered the IL-2R beta and IL-2R alpha receptor subunits using the first reported anticytokine receptor antibodies (anti-Tac, daclizumab, Zenapax, Zinbryta) that we developed. Our recognition that the IL-2 receptor was not expressed by most normal cells but was expressed by malignant T cells provided the scientific basis for the use of this antibody to treat these disorders. We showed that daclizumab contributed to reducing renal transplant rejection episodes leading to its FDA approval in 1997. Furthermore, we found that daclizumab therapy is useful in autoimmune diseases including uveitis and multiple sclerosis where with daclizumab we and our coworkers achieved a 78% reduction in new brain lesions. Subsequently daclizumab was approved by the FDA for use in multiple sclerosis in 2016. My insights and discoveries made me a world leader in the rational development and the use of monoclonal antibodies.
In 1994, we co-discovered the cytokine IL-15 and elucidated its role in the development and persistence of NK cells and CD8 memory T-cells. IL-15 binds to a cytokine specific IL-15R alpha chain as well as beta and gamma chains that are shared with the IL-2 receptor system. Despite this sharing of receptor subunits, we showed that IL-2 and IL-15 provide distinct contributions to adaptive immune responses. IL-2 through its induction of regulatory T cells and activation-induced cell death (ACID) is involved the T-cell suicide required for self-tolerance. In contrast, IL-15 inhibits AICD and favors the survival of CD8 memory T-cells and is thus dedicated to supporting persistence of an immune response to invading pathogens. In a landmark observation we showed that IL-15 acts as a cell membrane associated molecule as part of an immunological synapse. We demonstrated that IL-15R alpha presents IL-15 in trans to neighboring NK and memory and effector CD8 T-cells. IL-15 was shown to be of therapeutic value in a number of murine xenograft models of malignancy. In a tour de force of drug development we oversaw the production of IL-15 under cGMP conditions, evaluated IL-15 in mouse tumor models and introduced it into three first in-human trials of IL-15 by bolus, subcutaneous and continuous intravenous infusions in patients with metastatic malignancy with clearing of lung lesions in select patients. IL-15 at 2 mcg/kg per day by continuous intravenous infusion was associated with the activation of CD8 T-cells, a 38-fold increase in the number of circulating NK cells and a 358-fold increase in the number of CD56bright NK cells. We translated these efforts of IL-15 on CD8 and NK-cells by introducing combination preclinical and clinical trials that involve IL-15 with established anticancer agents. We demonstrated that the combination of an agonistic anti-CD40 antibody with IL-15 substituted for ineffective helper T-cells and provided synergy in two mouse tumor models and was associated with a marked increase in tumor tetramer specific CD8 T-cells. Furthermore, in translation of the observation of the effect of IL-15 on circulating NK-cell numbers and receptor expression, we demonstrated that IL-15 increased the antibody dependent cellular cytotoxicity (ADCC) and antitumor efficacy of cancer directed monoclonal antibodies in syngeneic and xenograft murine tumor models. Culminating these studies, we have initiated five clinical trials involving IL-15 and antitumor monoclonal antibodies to augment their ADCC and antitumor efficacy.
In summary, for over six decades I have been a major figure in translational immunology who has guided the vertical integration and research from basic discovery of new cytokines, cytokine receptors, defined disorders of these elements in disease, produced novel therapeutic agents (anticytokine receptor antibodies, IL-15), demonstrated efficacy in preclinical models and clinical trials that involve his own patients. These accomplishments have been acknowledged by my election to the National Academy of Sciences, USA, the National Academy of Medicine, and the American Academy of Arts and Sciences.
Biography
About Thomas A. Waldmann. Dr. Waldmann received his M.D. degree from Harvard Medical School. He joined the National Cancer Institute in 1956, and has been Chief of the Metabolism Branch since 1973. Over his 56-year career he defined the IL-2 receptor subunits, IL-2Rβ and IL-2Rα using the first reported anti-cytokine receptor monoclonal antibody (MAb, anti-Tac, daclizumab, Zenapax). These studies culminated in the definition of the IL-2 receptor as an exceptionally valuable target for MAb-mediated therapy of leukemia, lymphoma, and multiple sclerosis. He co-discovered IL-15, elucidated its role in the persistence of NK and CD8 memory T-cells, and completed a first-in-man trial of IL-15 in patients with metastatic malignancy. He introduced the concept of blockade of the IL-15/IL-15 receptor and its Jak/STAT signaling pathway for leukemias and autoimmune diseases where γ-c cytokines including IL-15 play a pathogenic role. His honors include the Ehrlich Medal, Abbott Laboratories Prize, Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research, Milken Family Medical Foundation Distinguished Basic Scientist Award, Artois-Baillet Latour Health Prize, AAI-Dana Foundation Award in Human Immunology Research, and elections to the National Academy of Sciences, American Academy of Arts and Sciences, Institute of Medicine of the National Academy of Sciences and Royal Society of the Medical Sciences (UK).