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 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. We introduced different forms of IL-2 receptor directed therapy using agents we developed including unmodified murine antibodies to IL-2R alpha (anti-Tac), humanized anti-Tac (daclizumab), Zenapex the first antibody directed toward a cytokine receptor to receive FDA approval and this antibody armed with toxins or beta and alpha-emitting radionuclides. In a separate clinical trial that included patients with refractory Hodgkins Lymphoma daclizumab armed with 90Y we observed remissions in 63% of trial patients. The study's scientific basis was that most normal cells do not express CD25 whereas it is expressed by some Reed-Sternberg cells and specially by rosetting-polyclonal T cells in lymphomatous masses. Yttrium-90 provides strong beta emissions that kill tumor cells at a distance by crossfire. In the 30 HL patients treated with 90Y-daclizumab there were 6 with progressive disease, 5 with stable disease, 7 with partial responses and 12 with complete responses. A major effort to take advantage of the role of IL-15 in the development of memory CD8 T-cells is its use as a molecular adjuvant in vaccines against infectious diseases, bioterrorism agents, and cancer. Central to this vaccine development effort is the use of the live virus vector MVA vaccinia delivery platform in addition to LC16M8 and Wyeth vector platforms with integrated IL-15 cytokines. These vaccines are capable of delivering the vaccine cargo directly into antigen presenting dendritic cells by efficient infection. Using this technology we have demonstrated the enhancement of both CD8 T-cellmediated immune responses as well as antibody-mediated humoral immune responses to several candidate vaccine antigens that are currently being evaluated. These vaccinia-based vaccine candidates, that are in various stages of preclinical development, include pentavalent HCV vaccine that expresses E1, E2, NS3, NS4 and NS5B in tandem, a multivalent HIV vaccine candidate that co-expresses env, gag, pol, nef and tat;dual and single-agent Biodefense vaccines against smallpox and anthrax;multi-valent tuberculosis vaccine (ESAT6, Ag85A, Ag85B, HSP65 and Mtb39A);multi-valent malarial vaccines (CSP, AMA-1, MSP-1 and SSP-2);multivalent pandemic influenza vaccines (H5, NA, M1, M2 and NP);hexavalent human papillomavirus (HPV) vaccine (L1, E6 and E7 of HPV16, and L1, E6 and E7 of HPV18);breast cancer vaccine targeting the HER2 oncogene and a trivalent prostate cancer vaccine that expresses full-length prostate specific antigen (PSA), prostate specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP) polypeptides in tandem with IL-15 as a molecular adjuvant. It is becoming increasingly clear that IL-15 may play a central pathogenic role in select inflammatory autoimmune diseases. Recent evidence suggests that in a number of inflammatory autoimmune diseases including refractory celiac disease, autoimmune diabetes, and rheumatoid arthritis activated T cells destroy parenchymal cells predominantly via a mechanism that is independent of TCR engagement but is very much dependent upon the NKG2D-MIC pathway. IL-15 not only upregulates the expression of MIC-A in parenchymal tissues but also induces the expression of the activating NKG2D receptor as well. Furthermore, IL-15 upregulates DAP10 expression and the phosphorylation of ERK involved in NKG2D-mediated signaling cascade in T cells thereby perpetuating a vicious cycle of continuous tissue destruction and chronic inflammation. These observations suggest that blockade of IL-15 activity may be an effective therapeutic modality in the management and treatment of inflammatory autoimmune disorders. Recently in a landmark study we reported in the PNAS the utility of IL-15 blockade as a therapeutic modality in the treatment of a murine model of celiac disease, especially in the RIT form of celiac disease refractory to dietary gluten withdrawal with a high propensity (40-50%) for the development of enteropathy associated T-cell lymphoma (EATL). In two murine models of refractory celiac disease we have demonstrated that an antibody, TM-Beta-1 that blocks the transpresentation and function of IL-15 reverses all pathological aspects in these two models. These observations provide the scientific basis for the selective targeting of IL-2/IL-15R beta in patients with autoimmune diseases and CD8 T-cell leukemia/lymphoma associated with disorders of IL-15/IL-15R. To this end, the humanized Mik-Beta-1 monoclonal antibody directed to the IL-2/IL-15 beta receptor (CD122) produced by the BDP NCI that blocks transpresentation of IL-15 and all IL-15 action has been used in clinical trials involving patients with T-cell large granular lymphocytic leukemia (T-LGL) and hematocytopenia as well as in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), a demyelinating neurological disease. We have received NExT NCI funding for the use of Hu-Mik-Beta-1 in a multicenter trial of patients with refractory celiac disease In certain diseases not only IL-15 but also IL-9 and IL-2 are involved in the pathogenesis. In these cases it is difficult to achieve therapeutic efficacy with an antibody directed toward an individual cytokine or cytokine receptor (e.g., IL-2R). IL-2, IL-9 and IL-15 all utilize the JAK3 signaling molecule, suggesting a therapeutic strategy that involves targeting JAK3. We evaluated the action of the JAK3 inhibitor, CP-690,550 (Tasocitinib)produced by Craig Thomas at the NIH on the cytokine dependent ex vivo proliferation that is characteristic of the peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL or those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15 and their receptors. CP-690,550 inhibited the ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by means of 67% and 86% respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL cells ex vivo. Finally an in vivo test of biological activity CP-690,550 treatment of mice with a form of CD8 T-cell IL-15 transgenic leukemia that manifests an autocrine IL-15/IL-15R alpha pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the JAK3 inhibitor, CP-690,550 in the treatment of select patients with HTLV-1 associated ATL and HAM/TSP, in those with refractory celiac disease as well as those developing type 1 diabetes where a disorder of the IL-15/IL-15R JAK3 signaling system has been demonstrated. In conclusion the emerging understanding of the IL-2/IL-2R and IL-15/IL15-R systems and their signalling pathway provided by the work of Dr. Waldmann has yielded the scientific basis for the development of more rational immune interventions for small molecule,cytokine and monoclonal antibody mediated receptor directed therapy, that are of value in the prevention of organ allograft rejection, in the treatment of T-cell mediated autoimmune disorders and in a broad range of leukemia/lymphomas including Hodgkins lymphoma. Furthermore, the co-discovery of IL-15 and its production under cGMP may lead to the development of new IL-15 mediated approaches for the treatment of cancer and as a component of molecular vaccines directed toward cancer or AIDS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC004002-42
Application #
8350042
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
42
Fiscal Year
2011
Total Cost
$1,751,169
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Waldmann, Thomas A; Chen, Jing (2017) Disorders of the JAK/STAT Pathway in T Cell Lymphoma Pathogenesis: Implications for Immunotherapy. Annu Rev Immunol 35:533-550
Waldmann, Thomas A (2017) JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics. Mol Cell Endocrinol 451:66-70
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
Sharma, Kamal; Janik, John E; O'Mahony, Deirdre et al. (2017) Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-cell Leukemia/lymphoma. Clin Cancer Res 23:35-42
Mocsár, Gábor; Volkó, Julianna; Rönnlund, Daniel et al. (2016) MHC I Expression Regulates Co-clustering and Mobility of Interleukin-2 and -15 Receptors in T Cells. Biophys J 111:100-12
Yeh, Chien-Hung; Bai, Xue Tao; Moles, Ramona et al. (2016) Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia. Mol Cancer 15:15
Ju, Wei; Zhang, Meili; Wilson, Kelli M et al. (2016) Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma. Proc Natl Acad Sci U S A 113:1624-9
Yeh, Chien-Hung; Bai, Xue Tao; Moles, Ramona et al. (2016) Erratum to: 'Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia'. Mol Cancer 15:20
Yokoyama, Seiji; Perera, Pin-Yu; Terawaki, Seigo et al. (2015) Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS). J Clin Immunol 35:661-7
Zhang, Meili; Mathews Griner, Lesley A; Ju, Wei et al. (2015) Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2-dependent adult T-cell leukemia. Proc Natl Acad Sci U S A 112:12480-5

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