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Thomas A. Waldmann

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Thomas Waldmann

Thomas A. Waldmann (21 September 1930 – 25 September 2021) was an American immunologist who has worked on therapeutic monoclonal antibodies to the IL-2 receptor, Interleukin 15 (IL-15), and Adult T-cell Leukemia (ATL). Until the week he died, he was an active distinguished investigator at the Lymphoid Malignancies Branch of the National Cancer Institute.[1]

Biography and career

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Thomas A. Waldmann was born in New York City as the only child of Elisabeth Sipos and Charles Waldmann. He received his M.D. from Harvard Medical School in 1955. He joined the National Cancer Institute in 1956 and became chief of the Lymphoid Malignancies Branch (formerly Metabolism Branch) in 1973. He married the late Katharine Waldmann in 1958 and has three children: Richard, Robert, and Carol Waldmann.[2]

Research

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Waldmann's research has focused on lymphokines, their receptors, and use of lymphokines and monoclonal antibodies to their receptors in the treatment of cancer and of autoimmune diseases. He studied the IL-2/IL-2 receptor system in the growth of normal and neoplastic cells. He co-discovered IL-15 and has initiated clinical trials employing IL-15 in the treatment of metastatic malignancy.

He studied the role played by the receptor for interleukin-2 (IL-2) on the growth, differentiation and regulation of normal and neoplastic T-cells. He defined the IL-2 receptor subunits IL-2R beta and IL-2R alpha using the first reported anticytokine monoclonal antibody (anti-Tac)[3] leading to the definition of the IL-2R alpha as a target for the therapy of leukemia and autoimmune diseases.

The scientific basis for this approach was the fact that normal resting cells do not express IL-2R alpha, but it is expressed by abnormal T-cells in patients with lymphoid malignancies. He introduced different forms of IL-2R-directed therapy, including unmodified murine antibodies to IL-2R alpha (anti-Tac, the first antibody to a cytokine receptor to receive FDA approval),[4] humanized anti-Tac (daclizumab, Zenapax) and the antibody armed with toxins or alpha and beta-emitting radionuclides.

He showed that daclizumab contributes to reducing renal transplant rejection and is of value in the treatment of T-cell-mediated autoimmune disorders including multiple sclerosis.[5]

He demonstrated that refractory and relapsed Hodgkin's lymphoma (HL) patients could be effectively treated with daclizumab armed with Yttrium-90, because most normal cells do not express CD25, but it is expressed by some Reed-Sternberg cells and by rosetting polyclonal T-cells in lymphomatous masses. Responses were seen among the patients whose Reed-Sternberg cells were CD25 negative, provided that the associated rosetting T-cells expressed CD25.[6][7]

Waldmann co-discovered the cytokine interleukin 15 (IL-15)[8][9] and elucidated its role in the development of NK and CD8-memory T cells and its inhibition of activation induced cell death. He demonstrated that it is bound to IL-15 R alpha on the surface of antigen presenting cells and presented in trans to T-cells in an immune synapse.[10] He demonstrated that IL-15 is useful in the treatment of cancer in mice and has completed a clinical trial using IL-15 in therapy of patients with metastatic malignant melanoma and renal cell cancer.[11]

Furthermore, Waldmann demonstrated that vaccines containing IL-15 induced long-lasting, high-avidity CD8-mediated CTL immunity.[12][13]

Waldmann studied adult T-cell leukemia that develops in individuals infected with the retrovirus human T-cell lymphotropic virus-1 (HTLV-1). Dr. Waldmann demonstrated that the HTLV-1 encoded protein Tax constitutively activates two autocrine (IL-2R/IL-2, IL-15R/IL-15) and one paracrine (IL-9) system. Waldmann demonstrated that daclizumab provides effective therapy for some patients with a previously invariably fatal leukemia, HTLV-I associated adult T-cell leukemia (ATL).[14]

In the early 80s Waldmann studied immunoglobulin gene rearrangement in and cell surface markers on acute lymphocyte leukemias.[15]

In 1961 Waldmann described Waldmann disease.

References

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  1. ^ "Thomas A. Waldmann, M.D. | Center for Cancer Research – National Cancer Institute". Ccr.cancer.gov. Retrieved 2021-02-22.
  2. ^ Waldmann, Thomas A. (April 2003). "Bio". Annual Review of Immunology. 21 (1): 1–27. doi:10.1146/annurev.immunol.21.120601.140933. PMID 12359737. Retrieved 2021-02-22.
  3. ^ Uchiyama T, Broder S, Waldmann TA. "A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells". J Immunol 1981, 126(4):1393–1397. PMID 6970774
  4. ^ Waldmann TA, Goldman CK, Bongiovanni KF, Sharrow SO, Davey MP, Cease KB, Greenberg SJ, Longo DL. "Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2". Blood 1988, 72(5): 1805–1816. PMID 2846094
  5. ^ Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, McCartin J, Frank JA, Würfe J, Ohayon J, Waldmann TA, McFarland HF, Martin R. "Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon-beta". Proc Natl Acad Sci USA 2004, 101(23):8705–8708. PMID 15161974
  6. ^ Conlon KC, Sportes C, Brechbiel MW, Fowler DH, Gress R, Miljkovic MD, Chen CC, Whatley MA, Bryant BR, Corcoran EM, Kurdziel KA, Pittaluga S, Paik CH, Lee JH, Fleisher TA, Carrasquillo JA, Waldmann TA. "90Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma". Cancer Biother Radiopharm. 2020
  7. ^ Janik JE, Morris JC, O'Mahony D, Pittaluga S, Jaffe ES, Redon CE, Bonner WM, Brechbiel MW, Paik CH, Whatley M, Chen C, Lee-J-H, Fleisher TA, Brown M, White JD, Stewart DM, Fioravanti S, Lee CC, Goldman CK, Bryant BR, Junghans RP, Carrasquillo JA, Worthy TY, Corcoran E, Conlon KC, Waldmann TA. "90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's lymphoma". Proc Natl Acad Sci USA, 2015, 112(42):13045–13050. PMID 26438866
  8. ^ Burton JD, Bamford RN, Peters C, Grant AJ, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. "A lymphokine, provisionally designated interleukin-T, produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells". Proc Natl Acad Sci USA 1994, 91(11):4935–4939. PMID 8197160
  9. ^ Bamford RN, Grant AJ, Burton JD, Peters C, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA. "The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells". Proc Natl Acad Sci USA 1994, 91(11):4940–4944. PMID 8197161
  10. ^ Dubois S, Mariner J, Waldmann TA Tagaya Y. "IL-15R alpha recycles and presents IL-15 in trans to neighboring cells". Immunity 2002, 17(5):537–547. PMID 12433361
  11. ^ Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM, Goldman CK, Bryant BR, Decker JM, Chen J, Worthy TYA, Figg WD, Sr, Peer CJ, Sneller MC, Lane HC, Yovandich JL, Creekmore SP, Roederer M, Waldmann TA. "Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer". J Clin Oncol. 2015, 33(1):74–82. PMID 25403209
  12. ^ Perera LP, Waldmann TA, Mosca JD, Baldwin N, Berzofsky JA, Oh SK. "Development of smallpox vaccine candidates with integrated interleukin-15 that demonstrate superior immunogenicity, efficacy, and safety in mice". J Virol. 2007, 81(16):8774–8783. PMID 17553867
  13. ^ Poon LLM, Leung YHC, Nicholls JM, Perera P-Y, Lichy JH, Yamamoto M, Waldmann TA, Peiris JSM, Perera LP. "Vaccinia virus-based multivalent H5N1 avian influenza vaccines adjuvanted with IL-15 confer sterile cross-clade protection in mice." J Immunol. 2009, 182(5):3063–3071. PMID 19234203
  14. ^ Berkowitz JL, Janik JE, Stewart DM, Jaffe ES, Stetler-Stevenson M, Shih JH, Fleisher TA, Turner M, Urquhart NE, Wharfe GH, Figg WD, Peer CJ, Goldman CK, Waldmann TA, Morris JC. "Safety, efficacy and pharmacokinetics/pharmacodynamics, of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma". Clin Immunol. 2014, 155(2):176–187. PMID 25267440
  15. ^ Korsmeyer SJ, Arnold A, Bakhshi A, Ravetch JV, Siebenlist U, Hieter PA, Sharrow SO, LeBien TW, Kersey JH, Poplack DG, Leder P, Waldmann TA. "Immunoglobulin gene rearrangement and cell surface antigen expression of acute lymphocyte leukemias of T-cell and B-cell precursor origins". J Clin Invest 1983, 71(2):301–313. PMID 6401769
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