Waldmann co-discovered the cytokine IL-15 and elucidated its role in the development of NK cells and CD8 memory phenotype T-cells. He demonstrated that IL-15 acts as a cell-membrane associated molecule, that IL-15R alpha on antigen-presenting cells (APCs) presents IL-15 in trans to NK and CD8 T-cells. Waldmann demonstrated IL-15 to be of value in 4 murine models of neoplasia. IL-15 administered by continuous intravenous infusion (CIV) at 20 mcg/kg for 10 days to rhesus macaques was associated with an 80-100-fold increase in the number of circulating CD8 effector memory T-cells. Waldmann and Kevin Conlon, using IL-15 produced at the NCI, performed the first-in-human trial of rhIL-15. Five of 18 patients manifested a decrease in marker lesions, with 2 having clearing of lung lesions. A collaborative trial with the Cancer Immunotherapy Network (CITN) of subcutaneous Escherichia coli rhIL-15 has been completed where the MTD was 3 mcg/kg/day. In a trial performed by Waldmann and Conlon a dose escalation of IL-15 by CIV was completed in patients with metastatic malignancy with the MTD of 2 mcg/kg/day. In this trial there was initially an efflux of NK cells from the circulation followed on termination of the CIV administration by a 30-fold increase in the number of circulating NK cells and an over 200-fold increase in the number of CD56bright NK cells. A particular challenge with rhIL-15 is that there is a low-level expression of IL-15R alpha on antigen-presenting cells including DCs. IL-15 and IL-15R alpha are always produced and expressed together. To address this issue, the IL-15 and IL-15R alpha combination is being evaluated in a clinical trial. An additional major scientific effort with IL-15 involves the evaluation of combination therapy with IL-15 and other agents in preclinical models and in clinical trials. Normally generation of antigen-specific CD8 T-cells utilizes an initial step involving antigen-bound CD4 cells with APCs, followed by interaction of CD8 T-cells with these APCs. An agonistic anti-CD40 antibody can substitute for the initial interaction of APCs with CD4 T- cells. Waldmann demonstrated that the combination of IL-15 with an agonistic anti-CD40 antibody showed additivity/synergy in 2 murine tumor models. The combination circumvented the problem of helpless CD8 T-cells wherein the CD8 T-cells produced are not tumor-antigen specific. Administration of the combination of IL-15 plus the agonistic anti-CD40 antibody but not the individual agents was associated with a marked increase in TRAMP C2 tumor specific tetramer positive CD8 T-cells. Ravetch and Waldmann are translating this observation into a clinical trial involving an optimized agonistic anti-CD40 antibody used in combination with rhIL-15 for patients with metastatic malignancy. Waldmann, Conlon and Alice Chan are initiating a trial translating preclinical studies of the Waldmann Laboratory that use IL-15 in combination with anti-CTLA-4, lymphocyte antigen-4 (CTLA-4) and anti-program death-1 (PD-L1). An additional group of studies involves combination therapy with IL-15 in association with anticancer monoclonal antibodies to augment antibody-dependent cell mediated cytotoxicity (ADCC). The predominant approach involving IL-15 is based on the hypothesis that the host is making an immune response albeit inadequate to tumor, and that this can be augmented by administration of IL-15. Given the capacity to increase the number of activated NK cells, a strategy is being evaluated wherein IL-15 is used in combination with antitumor monoclonal antibodies to augment their ADCC. In preclinical studies the Waldmann Group demonstrated markedly augmented ADCC and antitumor efficacy when IL-15 was added to antitumor monoclonal antibodies. A clinical trial has been initiated involving IL-15 with alemtuzumab in the treatment of patients with acute adult T-cell leukemia (ATL). Identify disorders of IL-15 in disease, and evaluate treatments using novel agents targeting the IL-15 receptor binding or IL-15 signaling. The studies we have just discussed focus on augmenting IL-15 action to increase patient immune responses to their tumor. The Waldmann Laboratory has also initiated a major program with the opposite goal of diminishing the action of IL-15 in situations where disorders of IL-15 play a role. Abnormalities of IL-15 expression have been described in refractory celiac disease, type 1 diabetes, cutaneous T-cell lymphoma, and in diseases associated with HTLV-1. The Waldmann Group has initiated collaborations to explore Mik-Beta-1, anti-IL-2/IL-15 directed monoclonal antibody produced at the NIH to block IL-15 binding in patients with refractory celiac disease and associated CD8 T-cell lymphoma (EATL). In addition, Waldmann has entered into collaborations evaluating AZ3, a pure JAK1 inhibitor, JAK3i, a pure JAK3 inhibitor, and H2-RETR and BMZ-1 small-molecule agents that bind respectively either to IL-2/IL-15R beta alone or yc alone to block both IL-15 and IL-2 actions. In summary, the Waldmann Laboratory has made major contributions to the evaluation of IL-15 in the treatment of patients with metastatic malignancy and into therapy-directed disorders of IL-15.

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Ratner, Lee; Waldmann, Thomas A; Janakiram, Murali et al. (2018) Rapid Progression of Adult T-Cell Leukemia-Lymphoma after PD-1 Inhibitor Therapy. N Engl J Med 378:1947-1948
Perera, Liyanage P; Zhang, Meili; Nakagawa, Masao et al. (2017) Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am J Hematol 92:892-901
Parra, Marcela; Liu, Xia; Derrick, Steven C et al. (2015) Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein. PLoS One 10:e0141141
Waldmann, Thomas A (2015) The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res 3:219-27
Yu, Huifeng; Sui, Yongjun; Wang, Yichuan et al. (2015) Interleukin-15 Constrains Mucosal T Helper 17 Cell Generation: Influence of Mononuclear Phagocytes. PLoS One 10:e0143001
Mitra, Suman; Ring, Aaron M; Amarnath, Shoba et al. (2015) Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 42:826-38
Pilipow, Karolina; Roberto, Alessandra; Roederer, Mario et al. (2015) IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy. Cancer Res 75:5187-5193
Conlon, Kevin C; Lugli, Enrico; Welles, Hugh C et al. (2015) 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 33:74-82
Zhang, Yi; Tian, Shenghe; Liu, Zuqiang et al. (2014) Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency. Oncoimmunology 3:e959321
Valkenburg, Sophie A; Li, Olive T W; Mak, Polly W Y et al. (2014) IL-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires CD4+ T cells for heterosubtypic protection. Proc Natl Acad Sci U S A 111:5676-81

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