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. These seminal studies on the IL-2 receptor have culminated in the definition of the IL-2R as an exceptionally valuable target for the therapy of leukemia and for autoimmune diseases. 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), 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 clinical trials we demonstrated that anti-Tac (daclizumab) provides effective therapy for a subset of patients with HTLV-I associated adult T-cell leukemia (ATL). In a clinical trial that included ATL patients and that involved anti-Tac armed with 90Y we observed remissions in over 65% of trial patients. Furthermore, refractory or relapsed Hodgkins lymphoma (HL) patients were treated with up to seven intravenous infusions of the anti-CD25 antibody, 90Y-daclizumab. The study's scientific basis is that most normal cells do not express CD25 whereas it is expressed by some Reed-Sternberg cells and 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. Responses were seen in patients whose Reed-Sternberg cells expressed CD25 and among the 25 patients whose neoplastic cells were CD25- provided that associated rosetting-T cells expressed CD25. Toxicities were limited to myelodysplastic syndrome in 3 cases and transient bone-marrow suppression. In conclusion repeated 90Y-daclizumab infusions predominantly directed toward non-malignant T cells rosetting around Reed-Sternberg cells provided effective therapy for select HL patients. In a most critical development, as part of our studies of IL-2 receptor directed therapy for HTLV-I associated ATL, we co-discovered a lymphokine, IL-15, that is required for the development and maintenance of NK-cells as well as CD8 memory phenotype T-cells. Furthermore, we demonstrated that the cytokines IL-2 and IL-15 that share two receptor subunits manifest distinct contributions to immune responses. IL-2 through its pivotal role in the generation and survival of CD4+ CD25+ Tregs (suppressor cells) and activation-induced cell death (AICD) is involved in the T-cell suicide required for self tolerance. In contrast, IL-15 inhibits AICD and favors the survival of CD8 memory cells and is thereby dedicated to the persistence of immunological memory to invading pathogens. IL-15 expression have been demonstrated in patients with an array of autoimmune diseases and T-cell leukemias. We are translating this observation by the introduction of humanized Mik-Beta-1 directed toward IL-2/IL-15R beta that blocks IL-15 action into clinical trials involving these disorders. We are also evaluating the introduction of IL-15 in the treatment of neoplasia. In preclinical studies we demonstrated that IL-15 transgenic mice in contrast to wild-type mice did not develop the colon carcinoma (MC38) following intravenous introduction of the cancer cells and that MC38 cells transfected with IL-15R alpha no longer formed metastases in wild-type mice. In addition we demonstrated that IL-15 provided effective therapy in the MC38 and CT26 colon carcinoma, B16 melanoma and TRAMP-C2 prostatic carcinoma models. These findings provide the scientific basis for the use of IL-15 in lieu of IL-2 in the treatment of select malignancies and for the incorporation of IL-15 into molecular vaccines for cancer and AIDS. In a seminal observation we demonstrated that IL-15 bound to IL-15R alpha on antigen presenting cells is presented in trans to target NK and CD8 cells that express the other IL-15 receptor subunits beta and gamma. In translation of this observation we have demonstrated that addition of an agonist antibody to CD40 increases IL-15R alpha expression and augments IL-15 efficacy in these murine syngeneic tumor models. Abnormalities of IL-15 expression have been described in inflammatory autoimmune disorders and CD8 T-cell leukemia/lymphoma. We have introduced antibodies to the IL-2/IL-15R beta subunit to prevent the transpresentation of IL-15 and thereby inhibit IL-15 action. We have used an antibody TMbeta-1 (anti-IL2/IL-15Rbeta) to inhibit such IL-15 transpresentation in mice. We are utilizing this antibody in preclinical therapeutic trials in a series of autoimmune disorders of mice. One major focus of these efforts is in a murine model of celiac disease. Disorders of IL-15 and its private receptor for IL-15R alpha have been invoked as causative in this disease. This provides a rationale for selective targeting of IL-15 and its receptor in patients with refractory celiac disease who have a high incidence of CD8 lymphoma. We evaluated blockade of IL-15 action in IL-15 transgenic mice that express human IL-15 in intestinal cells using the enterocyte-specific T3b promoter to derive the transgene. These mice developed florid inflammation in the duodenojejunal region with extensive villous atrophy and massive accumulation of NK like CD8+ T-cells. TMbeta-1 antibody that blocks IL-15 transpresentation was administered to such IL-15 transgenic mice at 6 months of age when they had already developed the intestinal inflammatory disorder. The TMbeta-1 administration was associated with a reversal of all of the macroscopic and microscopic pathological changes in the intestine of T3b hIL-15 Tg mice. On the basis of these studies, in press in the Proceedings of the National Academy of Sciences USA, we proposed a collaborative clinical trial with Dr. Bana Jabri of the University of Chicago, Dr. Peter H. R. Green of Columbia University, New York and Dr. Joseph A. Murray of the Mayo Clinic, to explore if IL-2/IL-15R beta directed blockade of IL-15 action with Hu-Mik-beta-1, the human counterpart of TMbeta-1, would be a valuable therapeutic modality for refractory celiac disease. This proposed clinical trial would provide a test of the hypothesis that disordered IL-15/IL-15R alpha plays a critical role in the pathogenesis of refractory celiac disease. We have produced humanized Mik-beta-1 that is directed to human IL-2/IL15R beta (CD122) to block IL-15 action and have shown that it prolongs cardiac allograft survival in Cynomolgus monkeys. Clinical trials are underway using Hu-Mik-Beta-1 in the study of CD8 positive T-cell large granular lymphocytic leukemia and to evaluate this monoclonal antibody in patients with adult T-cell leukemia and with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Trials are being planned with this agent in patients with rheumatoid arthritis, multiple sclerosis and refractory celiac syndrome associated with premalignant and malignant CD8 T-cell lymphoma. In studies with Craig Thomas we showed that the addition of the Jak 3 inhibitor CP690, 550 suppressed the [summary truncated at 7800 characters]

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC004002-40
Application #
7969733
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
40
Fiscal Year
2009
Total Cost
$1,786,679
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
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
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
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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