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Cytokines in the Treatment of Cancer

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Cancer Immunotherapy

Abstract

Cytokines are molecular mediators of intercellular signaling that function to regulate homeostasis of the immune system. There are five families of cytokines classified by their receptor usage. The effects of individual cytokines on immunity depend on several factors, including the local cytokine concentration, the pattern of cytokine receptor expression, and the integration of multiple signaling pathways in responding immune cells. Cytokines have shown therapeutic potential for the initiation and potentiation of antitumor immunity. Interferon-α and interleukin-2 (IL-2) have been approved as single agents for the treatment of metastatic melanoma and renal cell carcinoma, and several other cytokines have shown promise in preclinical tumor models. New strategies for improving the therapeutic benefit of cytokines are in development and include cytokine-antibody fusion molecules, delivery in recombinant viral vectors, expression by irradiated whole tumor cells, PEGylation, DNA vaccination, and ex vivo exposure to immune effector cells.

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References

  1. Kaplan D, Shankaran V, Dighe A et al (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 95:7556–7561

    Article  PubMed  CAS  Google Scholar 

  2. Picaud S, Bardot B, De Maeyer E et al (2002) Enhanced tumor development in mice lacking a functional type I interferon receptor. J Interferon Cytokine Res 22:457–462

    Article  PubMed  CAS  Google Scholar 

  3. Shankaran V, Ikeda H, Bruce AT et al (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111

    Article  PubMed  CAS  Google Scholar 

  4. Petrulio CA, Kim-Schulze S, Kaufman HL (2006) The tumour microenvironment and implications for cancer immunotherapy. Expert Opin Biol Ther 6:671–684

    Article  PubMed  CAS  Google Scholar 

  5. Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9:480–490

    Article  PubMed  CAS  Google Scholar 

  6. Yin T, Taga T, Tsang ML et al (1993) Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J Immunol 151:2555–2561

    PubMed  CAS  Google Scholar 

  7. Beekman J, Verhagen L, Geijsen N et al (2009) Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output. Blood 114:3917–3927

    Article  PubMed  CAS  Google Scholar 

  8. Nakashima K, Taga T (1998) gp130 and the IL-6 family of cytokines: signaling mechanisms and thrombopoietic activities. Semin Hematol 35:210–221

    PubMed  CAS  Google Scholar 

  9. Kishimoto T, Shizuo A, Narazaki M et al (1995) Interleukin-6 family of cytokines and gp130. Blood 86:1243–1253

    PubMed  CAS  Google Scholar 

  10. Hermanns HM, Radtke S, Haan C, Schmitz-Van de Leur H, Tavernier J, Heinrich PC, Behrmann I (1999) Contributions of leukemia inhibitory factor receptor and oncostatin M receptor to signal transduction in heterodimeric complexes with glycoprotein 130. J Immunol 163:6651–6658

    PubMed  CAS  Google Scholar 

  11. Sakamaki K, Miyajima I, Kitamura T et al (1992) Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J 11:3541–3549

    PubMed  CAS  Google Scholar 

  12. Kotenko SV, Pestka S (2000) Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 19:2557–2565

    Article  PubMed  CAS  Google Scholar 

  13. Hanlon AM, Jang S, Salgame P (2002) Signaling from cytokine receptors that affect Th1 responses. Front Biosci 7:d1247–d1254

    Article  PubMed  CAS  Google Scholar 

  14. Curiel TJ (2007) Tregs and rethinking cancer immunotherapy. J Clin Invest 117:1167–1174

    Article  PubMed  CAS  Google Scholar 

  15. Jonuleit H, Schmitt E, Stassen M et al (2001) Identification and functional characterization of human CD4 + CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285–1294

    Article  PubMed  CAS  Google Scholar 

  16. Asseman C, Mauze S, Leach MW et al (1999) An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190:995–1004

    Article  PubMed  CAS  Google Scholar 

  17. Setoguchi R, Hori S, Takahashi T et al (2005) Homeostatic maintenance of natural FOXP3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201:723–735

    Article  PubMed  CAS  Google Scholar 

  18. Pestka S, Krause CD, Walter MR (2004) Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202:8–32

    Article  PubMed  CAS  Google Scholar 

  19. Constantinescu SN, Croze E, Wang C et al (1994) Role of interferon alpha/beta receptor chain 1 in the structure and transmembrane signaling of the interferon alpha/beta receptor complex. Proc Natl Acad Sci USA 91:9602–9606

    Article  PubMed  CAS  Google Scholar 

  20. Muller U, Steinhoff U, Reis LF et al (1994) Functional role of type I and type II interferons in antiviral defense. Science 264:1918–1921

    Article  PubMed  CAS  Google Scholar 

  21. Muller M, Ibelgaufts H, Kerr IM (1994) Interferon response pathways—a paradigm for cytokine signalling? J Viral Hepat 1:87–103

    Article  PubMed  CAS  Google Scholar 

  22. Pestka S (2007) The interferons: 50 years after their discovery. There is much more to learn. J Biol Chem 282:20047–20051

    Article  PubMed  CAS  Google Scholar 

  23. Isaacs A, Lindenmann J (1987) Virus interference. I. The interferon. By A. Isaacs and J. Lindenmann. J Interferon Res 7:429–38

    Article  PubMed  CAS  Google Scholar 

  24. Basham TY, Bourgeade MF, Creasey AA et al (1982) Interferon increases HLA synthesis in melanoma cells: interferon-resistant and -sensitive cell lines. Proc Natl Acad Sci USA 79:3265–3269

    Article  PubMed  CAS  Google Scholar 

  25. Dolei A, Capobianchi MR, Ameglio F (1983) Human interferon-gamma enhances the expression of class I and class II major histocompatibility complex products in neoplastic cells more effectively than interferon-alpha and interferon-beta. Infect Immun 40:172–176

    PubMed  CAS  Google Scholar 

  26. Ameglio F, Capobianchi MR, Dolei A et al (1983) Differential effects of gamma interferon on expression of HLA class II molecules controlled by the DR and DC loci. Infect Immun 42:122–125

    PubMed  CAS  Google Scholar 

  27. Trepiakas R, Pedersen AE, Met O, Svane IM (2009) Addition of interferon-alpha to a standard maturation cocktail induces CD38 up-regulation and increases dendritic cell function. Vaccine 27:2213–2219

    Article  PubMed  CAS  Google Scholar 

  28. Siegal F, Kadowaki N, Shodell M et al (1999) The nature of the principal type 1 interferon-producing cells in human blood. Science 284:1835–1837

    Article  PubMed  CAS  Google Scholar 

  29. Jewett A, Bonavida B (1995) Interferon-alpha activates cytotoxic function but inhibits interleukin-2-mediated proliferation and tumor necrosis factor-alpha secretion by immature human natural killer cells. J Clin Immunol 15:35–44

    Article  PubMed  CAS  Google Scholar 

  30. Wagner TC, Velichko S, Chesney SK et al (2004) Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors. Int J Cancer 111:32–42

    Article  PubMed  CAS  Google Scholar 

  31. Tsuruoka N, Sugiyama M, Tawaragi Y et al (1988) Inhibition of in vitro angiogenesis by lymphotoxin and interferon-gamma. Biochem Biophys Res Commun 155:429–435

    Article  PubMed  CAS  Google Scholar 

  32. Dunn GP, Ikeda H, Bruce AT et al (2005) Interferon-gamma and cancer immunoediting. Immunol Res 32:231–245

    Article  PubMed  CAS  Google Scholar 

  33. Dunn GP, Bruce AT, Sheehan KC et al (2005) A critical function for type I interferons in cancer immunoediting. Nat Immunol 6:722–729

    Article  PubMed  CAS  Google Scholar 

  34. Aaronson D, Horwath C (2002) A road map for those who don’t know JAK-STAT. Science 296:1653–1655

    Article  PubMed  CAS  Google Scholar 

  35. Chawla-Sarkar M, Lindner D, Liu Y et al (2003) Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 8:237–249

    Article  PubMed  CAS  Google Scholar 

  36. Kerbel R, Kamen B (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  PubMed  CAS  Google Scholar 

  37. Carnaud C, Lee D, Donnars O et al (1999) Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol 163:4647–4650

    PubMed  CAS  Google Scholar 

  38. Lighvani AA, Frucht DM, Jankovic D et al (2001) T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA 98:15137–15142

    Article  PubMed  CAS  Google Scholar 

  39. Frucht DM, Fukao T, Bogdan C et al (2001) IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol 22:556–560

    Article  PubMed  CAS  Google Scholar 

  40. Boehm U, Klamp T, Groot M et al (1997) Cellular responses to interferon-gamma. Annu Rev Immunol 15:749–795

    Article  PubMed  CAS  Google Scholar 

  41. Freedman AS, Freeman GJ, Rhynhart K et al (1991) Selective induction of B7/BB-1 on interferon-gamma stimulated monocytes: a potential mechanism for amplification of T cell activation through the CD28 pathway. Cell Immunol 137:429–437

    Article  PubMed  CAS  Google Scholar 

  42. Yong VW, Moumdjian R, Yong FP et al (1991) Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo. Proc Natl Acad Sci USA 88:7016–7020

    Article  PubMed  CAS  Google Scholar 

  43. Groettrup M, van den Broek M, Schwarz K et al (2001) Structural plasticity of the proteasome and its function in antigen processing. Crit Rev Immunol 21:339–358

    Article  PubMed  CAS  Google Scholar 

  44. Groettrup M, Khan S, Schwarz K et al (2001) Interferon-gamma inducible exchanges of 20S proteasome active site subunits: why? Biochimie 83:367–372

    Article  PubMed  CAS  Google Scholar 

  45. Snapper CM, Paul WE (1987) Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236:944–947

    Article  PubMed  CAS  Google Scholar 

  46. Street S, Trapani J, MacGregor D et al (2002) Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J Exp Med 196:129–134

    Article  PubMed  CAS  Google Scholar 

  47. Coughlin CM, Salhany KE, Gee MS et al (1998) Tumor cell responses to IFNgamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Immunity 9:25–34

    Article  PubMed  CAS  Google Scholar 

  48. Coughlin CM, Salhany KE, Wysocka M et al (1998) Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest 101:1441–1452

    Article  PubMed  CAS  Google Scholar 

  49. Friesel R, Komoriya A, Maciag T (1987) Inhibition of endothelial cell proliferation by gamma-interferon. J Cell Biol 104:689–696

    Article  PubMed  CAS  Google Scholar 

  50. Elhilali MM, Gleave M, Fradet Y et al (2000) Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma. The Canadian Urologic Oncology Group BJU Int 86:613–618

    CAS  Google Scholar 

  51. Couglin C, Salhany K, Gee M et al (1998) Tumor cell responses to IFNγ affect tumorigenicity and response to IL-12 therapy and antiangiogenesis. Immunity 9:25–34

    Article  Google Scholar 

  52. Krieg C, Létourneau S, Pantaleo G et al (2010) Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci USA 2107:11906–11911

    Article  Google Scholar 

  53. Waldmann TA (1987) The interleukin-2 receptor on normal and malignant lymphocytes. Adv Exp Med Biol 213:129–137

    PubMed  CAS  Google Scholar 

  54. Begley CG, Burton JD, Tsudo M et al (1990) Human B lymphocytes express the p75 component of the interleukin 2 receptor. Leuk Res 14:263–271

    Article  PubMed  CAS  Google Scholar 

  55. Voss SD, Hank JA, Nobis CA, Fisch P, Sosman JA, Sondel PM (1989) Serum levels of the low-affinity interleukin-2 receptor molecule (TAC) during IL-2 therapy reflect systemic lymphoid mass activation. Cancer Immunol Immunother 29:261–269

    Article  PubMed  CAS  Google Scholar 

  56. Thornton AM, Donovan EE, Piccirillo CA et al (2004) Cutting edge: IL-2 is critically required for the in vitro activation of CD4 + CD25+ T cell suppressor function. J Immunol 172:6519–6523

    PubMed  CAS  Google Scholar 

  57. Shevach EM, Piccirillo CA, Thornton AM, et al.: Control of T cell activation by CD4 + CD25+ suppressor T cells. Novartis Found Symp 252:24–36; discussion 36–44, 106–14, 2003

    Google Scholar 

  58. Golgher D, Jones E, Powrie F et al (2002) Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 32:3267–3275

    Article  PubMed  CAS  Google Scholar 

  59. McHugh RS, Shevach EM, Thornton AM (2001) Control of organ-specific autoimmunity by immunoregulatory CD4(+)CD25(+) T cells. Microbes Infect 3:919–927

    Article  PubMed  CAS  Google Scholar 

  60. Trincheri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Ann Rev Immunol 13:251–276

    Article  Google Scholar 

  61. Perussia B, Chan SH, D'Andrea A et al (1992) Natural killer (NK) cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-alpha beta+, TCR-gamma delta + T lymphocytes, and NK cells. J Immunol 149:3495–3502

    PubMed  CAS  Google Scholar 

  62. Chehimi J, Starr SE, Frank I et al (1992) Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients. J Exp Med 175:789–796

    Article  PubMed  CAS  Google Scholar 

  63. Chan SH, Kobayashi M, Santoli D et al (1992) Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J Immunol 148:92–98

    PubMed  CAS  Google Scholar 

  64. Rao JB, Chamberlain RS, Bronte V et al (1996) IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression. J Immunol 156:3357–3365

    PubMed  CAS  Google Scholar 

  65. Li Q, Carr AL, Donald EJ et al (2005) Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. Cancer Res 65:1063–1070

    PubMed  Google Scholar 

  66. Kaufman HL, Flanagan K, Lee CS et al (2002) Insertion of interleukin-2 (IL-2) and interleukin-12 (IL-12) genes into vaccinia virus results in effective antitumor responses without toxicity. Vaccine 20:1862–1869

    Article  PubMed  CAS  Google Scholar 

  67. Yoshimoto T, Takeda K, Tanaka T et al (1998) IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 161:3400–3407

    PubMed  CAS  Google Scholar 

  68. Yoshimoto T, Nagai N, Ohkusu K et al (1998) LPS-stimulated SJL macrophages produce IL-12 and IL-18 that inhibit IgE production in vitro by induction of IFN-gamma production from CD3intIL-2R beta + T cells. J Immunol 161:1483–1492

    PubMed  CAS  Google Scholar 

  69. Smyth MJ, Swann J, Kelly JM et al (2004) NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 200:1325–1335

    Article  PubMed  CAS  Google Scholar 

  70. Kawamura T, Takeda K, Mendiratta SK et al (1998) Critical role of NK1+ T cells in IL-12-induced immune responses in vivo. J Immunol 160:16–19

    PubMed  CAS  Google Scholar 

  71. Luster A, Greenberg S, Leder P (1995) The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J Exp Med 182(1):219–31

    Article  PubMed  CAS  Google Scholar 

  72. Boggio K, Nicoletti G, Di Carlo E et al (1998) Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med 188:589–596

    Article  PubMed  CAS  Google Scholar 

  73. Kurzrock R (2000) Hematopoietic growth factors. In: Bast RC, Kufe DW, Pollock RE et al (eds) Cancer medicine, 5th edn. BC Decker, Hanover

    Google Scholar 

  74. Martinez-Moczygemba M, Huston DP (2003) Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol 112:653–665

    Article  PubMed  CAS  Google Scholar 

  75. Dranoff G, Jaffee E, Lazenby A et al (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci 90:3539–3543

    Article  PubMed  CAS  Google Scholar 

  76. Fong L, Kwek SS, O’Brien S et al (2009) Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69:609–615

    Article  PubMed  CAS  Google Scholar 

  77. Hodi FS, Butler M, Oble DA et al (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A 105:3005–3010

    Article  PubMed  CAS  Google Scholar 

  78. Grabstein KH, Urdal DL, Tushinski RJ et al (1986) Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factor. Science 232:506–508

    Article  PubMed  CAS  Google Scholar 

  79. Grabstein K, Mochizuki D, Kronheim S et al (1986) Regulation of antibody production in vitro by granulocyte-macrophage colony stimulating factor. J Mol Cell Immunol 2:199–207

    PubMed  CAS  Google Scholar 

  80. Spada FM, Borriello F, Sugita M et al (2000) Low expression level but potent antigen presenting function of CD1d on monocyte lineage cells. Eur J Immunol 30:3468–3477

    Article  PubMed  CAS  Google Scholar 

  81. Gillessen S, Naumov YN, Nieuwenhuis EE et al (2003) CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion. Proc Natl Acad Sci 100:8874–8879

    Article  PubMed  CAS  Google Scholar 

  82. Jinushi M, Nakazaki Y, Dougan M et al (2007) MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J Clin Invest 117:1902–1913

    Article  PubMed  CAS  Google Scholar 

  83. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  PubMed  CAS  Google Scholar 

  84. Becker JC, Czerny C, Brocker EB (1994) Maintenance of clonal anergy by endogenously produced IL-10. Int Immunol 6:1605–1612

    Article  PubMed  CAS  Google Scholar 

  85. Buchwald UK, Geerdes-Fenge HF, Vockler J et al (1999) The functional characterization of interleukin-10 receptor expression of granulocytes and monocytes in comparison with prednisolone. Eur J Med Res 4:85–64

    PubMed  CAS  Google Scholar 

  86. de Waal Malefyt R, Yssel H, de Vries JE (1993) Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 150:4754–4765

    PubMed  Google Scholar 

  87. Carson WE, Lindemann MJ, Baiocchi R et al (1995) The functional characterization of interleukin-10 receptor expression on human natural killer cells. Blood 85:3577–3585

    PubMed  CAS  Google Scholar 

  88. Beatty PR, Krams SM, Martinez OM (1997) Involvement of IL-10 in the autonomous growth of EBV-transformed B cell lines. J Immunol 158:4045–4051

    PubMed  CAS  Google Scholar 

  89. Jovasevic VM, Gorelik L, Bluestone JA, Mokyr MB (2004) Importance of IL-10 for CTLA-4-mediated inhibition of tumor-eradicating immunity. J Immunol 2004(5):1134–1142

    Google Scholar 

  90. Smith DR, Kunkel SL, Burdick MD et al (1994) Production of interleukin-10 by human bronchogenic carcinoma. Am J Pathol 145:18–25

    PubMed  CAS  Google Scholar 

  91. Sato T, McCue P, Masuoka K et al (1996) Interleukin 10 production by human melanoma. Clin Cancer Res 2:1383–1390

    PubMed  CAS  Google Scholar 

  92. Huettner C, Czub S, Kerkau S et al (1994) Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res 17:3217–3224

    Google Scholar 

  93. Mori N, Prager D (1998) Interleukin-10 gene expression and adult T-cell leukemia. Leuk Lymphoma 29:239–248

    Article  PubMed  CAS  Google Scholar 

  94. Voorzanger N, Touitou R, Garcia E et al (1996) Interleukin-10 and IL-6 are produced in vivo by non-Hodgkin’s lymphoma cell lines and act as cooperative growth factors. Cancer Res 56:5499–5505

    PubMed  CAS  Google Scholar 

  95. Ortegel JW, Staren ED, Faber LP et al (2000) Cytokine biosynthesis by tumor-infiltrating T lymphocytes from human non-small-cell lung carcinoma. Cancer Immunol Immunother 48:627–634

    Article  PubMed  CAS  Google Scholar 

  96. Santin AD, Bellone S, Ravaggi A et al (2001) Increased levels of interleukin-10 and transforming growth factor-beta in the plasma and ascitic fluid of patients with advanced ovarian cancer. BJOG 108:804–808

    PubMed  CAS  Google Scholar 

  97. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB et al (2003) Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124:1193–1201

    Article  PubMed  CAS  Google Scholar 

  98. Nikolova PN, Pawelec GP, Mihailova SM, Ivanova MI, Myhailova AP, Baltadjieva DN et al (2007) Association of cytokine gene polymorphisms with malignant melanoma in Caucasian population. Cancer Immunol Immunother 56:371–379

    Article  PubMed  CAS  Google Scholar 

  99. Havranek E, Howell WM, Fussell HM et al (2005) An interlukin-10 promoter polymorphism may influence tumor development in renal cell carcinoma. J Urol 173:709–712

    Article  PubMed  CAS  Google Scholar 

  100. Golomb HM, Jacobs A, Fefer A et al (1986) Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients. J Clin Oncol 4:900–905

    PubMed  CAS  Google Scholar 

  101. Quesada JR, Gutterman JU (1986) Alpha interferons in B-cell neoplasms. Br J Haematol 64:639–646

    Article  PubMed  CAS  Google Scholar 

  102. Goodman GR, Burian C, Koziol JA et al (2003) Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol 21:891–896

    Article  PubMed  Google Scholar 

  103. Kirkwood JM, Strawderman MH, Ernstoff MS et al (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14:7–17

    PubMed  CAS  Google Scholar 

  104. Kirkwood JM, Ibrahim JG, Sondak VK et al (2000) High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444–2458

    PubMed  CAS  Google Scholar 

  105. Kirkwood JM, Ibrahim JG, Sosman JA et al (2001) High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19:2370–2380

    PubMed  CAS  Google Scholar 

  106. Kirkwood JM, Manola J, Ibrahim J et al (2004) A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670–1677

    Article  PubMed  CAS  Google Scholar 

  107. Mocellin S, Pasquali S, Rossi CR, Nitti D (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102(7):493–501

    Article  PubMed  CAS  Google Scholar 

  108. Eggermont AM, Suciu S, Santinami M et al (2008) Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372:117–126

    Article  PubMed  CAS  Google Scholar 

  109. Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718

    Article  PubMed  CAS  Google Scholar 

  110. Bouwhuis MG, Suciu S, Collette S et al (2009) Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. J Natl Cancer Inst 16:869–877

    Article  CAS  Google Scholar 

  111. Jonasch E, Kumar UN, Linette GP et al (2000) Adjuvant high-dose interferon alfa-2b in patients with high-risk melanoma. Cancer J 6:139–145

    PubMed  CAS  Google Scholar 

  112. Jonasch E, Haluska FG (2001) Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 6:34–55

    Article  PubMed  CAS  Google Scholar 

  113. Greenberg DB, Jonasch E, Gadd MA et al (2000) Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes. Cancer 89:356–362

    Article  PubMed  CAS  Google Scholar 

  114. Jones TH, Wadler S, Hupart KH (1998) Endocrine-mediated mechanisms of fatigue during treatment with interferon-alpha. Semin Oncol 25:54–63

    PubMed  CAS  Google Scholar 

  115. Brenard R (1997) Practical management of patients treated with alpha interferon. Acta Gastroenterol Belg 60:211–213

    PubMed  CAS  Google Scholar 

  116. Dalekos GN, Christodoulou D, Kistis KG et al (1998) A prospective evaluation of dermatological side-effects during alpha-interferon therapy for chronic viral hepatitis. Eur J Gastroenterol Hepatol 10:933–939

    Article  PubMed  CAS  Google Scholar 

  117. Gogas H, Kirkwood JM, Falk CS et al (2010) Correlation of molecular human leukocyte antigen typing and outcome in high-risk melanoma patients receiving adjuvant interferon. Cancer 116:4326–4333

    Article  PubMed  Google Scholar 

  118. Gogas H, Dafni U, Koon H et al (2010) Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial. J Transl Med 8:108

    Article  PubMed  CAS  Google Scholar 

  119. Barnetson RS, Halliday GM (1997) Regression in skin tumours: a common phenomenon. Australas J Dermatol 38(Suppl 1):S63–65

    PubMed  Google Scholar 

  120. Panagopoulos E, Murray D (1983) Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol 23:8–10

    Article  PubMed  CAS  Google Scholar 

  121. Gromet MA, Epstein WL, Blois MS (1978) The regressing thin malignant melanoma: a distinctive lesion with metastatic potential. Cancer 42:2282–2292

    Article  PubMed  CAS  Google Scholar 

  122. Dudley ME, Wunderlich J, Nishimura MI et al (2001) Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 24:363–373

    Article  PubMed  CAS  Google Scholar 

  123. Atkins MB, Regan M, McDermott D (2004) Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin Cancer Res 10:6342S–6346S

    Article  PubMed  CAS  Google Scholar 

  124. Atkins MB (2002) Interleukin-2: clinical applications. Semin Oncol 29:12–17

    Article  PubMed  CAS  Google Scholar 

  125. McDermott DF, Regan MM, Clark JI et al (2005) Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 23:133–141

    Article  PubMed  CAS  Google Scholar 

  126. Yang JC, Sherry RM, Steinberg SM et al (2003) Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127–3132

    Article  PubMed  CAS  Google Scholar 

  127. Fisher RI, Rosenberg SA, Fyfe G (2000) Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6(Suppl 1):S55–57

    PubMed  Google Scholar 

  128. Schwartzentruber DJ (2001) Guidelines for the safe administration of high-dose interleukin-2. J Immunother 24:287–293

    Article  PubMed  CAS  Google Scholar 

  129. Atkins MB, Lotze MT, Dutcher JP et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1998. J Clin Oncol 17:2105–2116

    PubMed  CAS  Google Scholar 

  130. Pockaj BA, Topalian SL, Steinberg SM, White DE, Rosenberg SA (1993) Infectious complications associated with interleukin-2 administration: a retrospective review of 935 treatment courses. J Clin Oncol 11:136–147

    PubMed  CAS  Google Scholar 

  131. Kirkwood JM, Harris JE, Vera R et al (1985) A randomized study of low and high doses of leukocyte alpha-interferon in metastatic renal cell carcinoma: the American Cancer Society collaborative trial. Cancer Res 45:863–871

    PubMed  CAS  Google Scholar 

  132. Amato R (1999) Modest effect of interferon alfa on metastatic renal-cell carcinoma. Lancet 353:6–7

    Article  PubMed  CAS  Google Scholar 

  133. Flanigan RC, Salmon SE, Blumenstein BA et al (2001) Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655–1659

    Article  PubMed  CAS  Google Scholar 

  134. Hamm C, Verma S, Petrella T, Bak K, Charette M (2008) Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review. Cancer Treat Rev 34:145–156

    Article  PubMed  CAS  Google Scholar 

  135. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM (2008) Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 26:5748–5754

    Article  PubMed  CAS  Google Scholar 

  136. O'Day SJ, Atkins MB, Boasberg P, Wang HJ, Thompson JA, Anderson CM, Gonzalez R, Lutzky J, Amatruda T, Hersh EM, Weber JS (2009) Phase II multicenter trial of maintenance biotherapy after induction concurrent biochemotherapy for patients with metastatic melanoma. J Clin Oncol 27:6207–6212

    Article  PubMed  Google Scholar 

  137. Atkins MB, Gollob JA, Sosman JA et al (2002) A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma. Clin Cancer Res 8:3075–3081

    PubMed  CAS  Google Scholar 

  138. Rosenberg SA, Yang JC, Schwartzentruber DJ et al (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327

    Article  PubMed  CAS  Google Scholar 

  139. Schwartzentruber D, Lawson D, Richards J et al (2009) A phase III multi-institutional randomized study of immunization with the gp, 100:209–217 (210 M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol 27:18s (abstract CRA 9011)

    Article  Google Scholar 

  140. Sosman JA, Carillo C, Urba WJ et al (2008) Three phase II cytokine working group trials of gp100 (210 M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. J Clin Oncol 26:2292–2298

    Article  PubMed  CAS  Google Scholar 

  141. Ugurel S, Schrama D, Keller G et al (2008) Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol Immunother 57:685–691

    Article  PubMed  CAS  Google Scholar 

  142. Sabatino M, Kim-Schulze S, Panelli MC et al (2009) Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 27:2645–2652

    Article  PubMed  CAS  Google Scholar 

  143. McDermott DF, Atkins MB (2006) Interleukin-2 therapy of metastatic renal cell carcinoma—predictors of response. Semin Oncol 33:583–587

    Article  PubMed  CAS  Google Scholar 

  144. Atkins MB, Regan M, McDermott D et al (2005) Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11:3714–3721

    Article  PubMed  CAS  Google Scholar 

  145. Cesana GC, DeRaffele G, Cohen S et al (2006) Characterization of CD4 + CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 24:1169–1177

    Article  PubMed  CAS  Google Scholar 

  146. Lorenzen I, Dingley A, Jacques Y et al (2006) The structure of the interleukin-15 receptor and its implications for ligand binding. J Biol Chem 281:6642–6647

    Article  PubMed  CAS  Google Scholar 

  147. Waldmann TA, Tagaya Y (1999) The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Ann Rev Immunol 17:19–49

    Article  CAS  Google Scholar 

  148. Marks-Konczalik J, Dubois S, Losi JM et al (2000) IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci USA 97:11445–11450

    Article  PubMed  CAS  Google Scholar 

  149. Ku CC, Murakami M, Sakamoto A et al (2000) Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288:675–678

    Article  PubMed  CAS  Google Scholar 

  150. Waldmann TA (2003) IL-15 in the life and death of lymphocytes: immunotherapeutic implications. Trends Mol Med 9:517–521

    Article  PubMed  CAS  Google Scholar 

  151. Meresse B, Chen Z, Ciszewski C et al (2004) Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21:357–366

    Article  PubMed  CAS  Google Scholar 

  152. Zaft T, Sapozhnikov A, Krauthgamer R et al (2005) CD11chigh dendritic cell ablation impairs lymphopenia-driven proliferation of naive and memory CD8+ T cells. J Immunol 175:6428–6435

    PubMed  CAS  Google Scholar 

  153. Di Carlo E, Comes A, Basso S et al (2000) The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement. J Immunol 165:3111–3118

    PubMed  Google Scholar 

  154. Sato N, Patel HJ, Walmann TA, Tagaya Y (2007) The IL-15/IL15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl Acad Sci USA 104:588–593

    Article  PubMed  CAS  Google Scholar 

  155. Okamura H, Tsutsi H, Komatsu T et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91

    Article  PubMed  CAS  Google Scholar 

  156. Tsutsui H, Matsui K, Kawada N et al (1997) IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice. J Immunol 159:3961–3967

    PubMed  CAS  Google Scholar 

  157. Tomura M, Zhou XY, Maruo S et al (1998) A critical role for IL-18 in the proliferation and activation of NK1.1+ CD3- cells. J Immunol 160:4738–4746

    PubMed  CAS  Google Scholar 

  158. Tomura M, Maruo S, Mu J et al (1998) Differential capacities of CD4+, CD8+, and CD4-CD8- T cell subsets to express IL-18 receptor and produce IFN-gamma in response to IL-18. J Immunol 160:3759–3765

    PubMed  CAS  Google Scholar 

  159. Takeda K, Tsutsui H, Yoshimoto T et al (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8:383–390

    Article  PubMed  CAS  Google Scholar 

  160. Okamura H, Tsutsui H, Kashiwamura S et al (1998) Interleukin-18: a novel cytokine that augments both innate and acquired immunity. Adv Immunol 70:281–312

    Article  PubMed  CAS  Google Scholar 

  161. Okamura H, Kashiwamura S, Tsutsui H et al (1998) Regulation of interferon-gamma production by IL-12 and IL-18. Curr Opin Immunol 10:259–264

    Article  PubMed  CAS  Google Scholar 

  162. Park CC, Morel JC, Amin MA et al (2001) Evidence of IL-18 as a novel angiogenic mediator. J Immunol 167:1644–1653

    PubMed  CAS  Google Scholar 

  163. Robertson MJ, Kirkwood JM, Logan TF et al (2008) A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin Cancer Res 14:3462–3469

    Article  PubMed  CAS  Google Scholar 

  164. Robertson MJ, Mier JW, Logan T et al (2006) Clinical and biological effects of recombination human interlukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res 12:4265–4273

    Article  PubMed  CAS  Google Scholar 

  165. Parrish-Novak J, Dillon SR, Nelson A et al (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63

    Article  PubMed  CAS  Google Scholar 

  166. Habib T, Nelson A, Kaushansky K (2003) IL-21: a novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses. J Allergy Clin Immunol 112:1033–1045

    Article  PubMed  CAS  Google Scholar 

  167. Brandt K, Bulfone-Paus S, Jenckel A et al (2003) Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo. J Invest Dermatol 121:1379–1382

    Article  PubMed  CAS  Google Scholar 

  168. Brandt K, Bulfone-Paus S, Foster DC et al (2003) Interleukin-21 inhibits dendritic cell activation and maturation. Blood 102:4090–4098

    Article  PubMed  CAS  Google Scholar 

  169. Sivakumar P, Foster D, Clegg C (2004) Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses. Immunology 112(2):177–182

    Article  PubMed  CAS  Google Scholar 

  170. Curti BD (2006) Immunomodulatory and antitumor effects of interleukin-21 in patients with renal cell carcinoma. Expert Rev Anticancer Ther 6:905–909

    Article  PubMed  CAS  Google Scholar 

  171. Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, Sievers EL, Hughes SD, DeVries TA, Hausman DF (2008) Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 26:2034–2039

    Article  PubMed  CAS  Google Scholar 

  172. Petrella TM, Tozer R, Belanger K et al (2012) Interlukin-21 Has Activity in Patients With Metastatic Melanoma: A Phase II Study. J Clin Oncol [Epub ahead of print] Aug 20 2012

    Google Scholar 

  173. Gollob JA, Veenstra KG, Parker RA et al (2003) Phase I trial of concurrent twice-weekly recombinant human interlukin-21 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma. J Clin Oncol 21:2564–2573

    Article  PubMed  CAS  Google Scholar 

  174. Atkins MB, Robertson MJ, Gordon M et al (1997). Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3:409–417

    PubMed  CAS  Google Scholar 

  175. Gollob JA, Mier JW, Veenstra K et al (2000) Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 6:1678–1692

    PubMed  CAS  Google Scholar 

  176. Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, Munster PN, Sullivan DM, Ugen KE, Messina JL, Heller R (2008) Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 26:5896–5903

    Article  PubMed  CAS  Google Scholar 

  177. Dranoff G (2003) GM-CSF-secreting melanoma vaccines. Oncogene 22:3188–3192

    Article  PubMed  CAS  Google Scholar 

  178. Ridolfi L, Ridolfi R, Ascari-Raccagni A et al (2001) Intralesional granulocyte-monocyte colony-stimulating factor followed by subcutaneous interleukin-2 in metastatic melanoma: a pilot study in elderly patients. J Eur Acad Dermatol Venereol 15:218–223

    Article  PubMed  CAS  Google Scholar 

  179. Si Z, Hersey P, Coates AS (1996) Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF. Melanoma Res 6:247–255

    Article  PubMed  CAS  Google Scholar 

  180. Spitler LE, Grossbard ML, Ernstoff MS et al (2000) Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 18:1614–1621

    PubMed  CAS  Google Scholar 

  181. Lawson DH, Lee SJ, Tarhini AA et al (2010) E4697: phase III cooperative group study of yeast-derived granulocyte macrophage colony-stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patients with completely resected stage III-IV melanoma. J Clin Oncol 28:15s (suppl; abstr 8504)

    Google Scholar 

  182. Kaufman HL, Bines SD (2010) OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol 6:941–949

    Article  PubMed  CAS  Google Scholar 

  183. Satomi H, Wang B, Fujusawa H et al (2002) Interferon beta from melanoma cells suppresses the proliferations of melanoma cells in an autocrine manner. Cytokine 18:108–115

    Article  PubMed  CAS  Google Scholar 

  184. Borden EC, Hogan TF, Voelkel JG (1982) Comparative antiproliferative activity in vitro of natural interferons alpha and beta for diploid and transformed human cells. Cancer Res 42:4948–4953

    PubMed  CAS  Google Scholar 

  185. Johns TG, Mackay IR, Callister KA et al (1992) Antiproliferative potencies of interferons on melanoma cell lines and xenografts: higher efficacy of interferon beta. J Natl Cancer Inst 84:1185–1190

    Article  PubMed  CAS  Google Scholar 

  186. Chawla-Sarkar M, Leaman DW, Borden EC (2001) Preferential induction of apoptosis by interferon (IFN)-beta compared with IFN-alpha2: correlation with TRAIL/Apo2L induction in melanoma cell lines. Clin Cancer Res 7:1821–1831

    PubMed  CAS  Google Scholar 

  187. Sabzevari H, Gillies SD, Mueller BM et al (1994) A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. Proc Natl Acad Science USA 91:9626–9630

    Article  CAS  Google Scholar 

  188. Christ O, Seiter S, Matzku S et al (2001) Efficacy of local versus systemic application of antibody-cytokine fusion proteins in tumor therapy. Clin Cancer Res April 7:985–998

    CAS  Google Scholar 

  189. Johnson EE, Lum HD, Rakhmilevich AL, Schmidt BE, Furlong M, Buhtoiarov IN, Hank JA, Raubitschek A, Colcher D, Reisfeld RA, Gillies SD, Sondel PM (2008) Intratumoral immunocytokine treatment results in enhanced antitumor effects. Cancer Immunol Immunother 57:1891–1902

    Article  PubMed  CAS  Google Scholar 

  190. Hank JA, Gan J, Ryu H, Ostendorf A, Stauder MC, Sternberg A, Albertini M, Lo KM, Gillies SD, Eickhoff J, Sondel PM (2009) Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. Clin Cancer Res 15:5923–5930

    Article  PubMed  CAS  Google Scholar 

  191. Yamane B, Hank J, Albertini M et al (2009) The development of antibody-based immunotherapy with (EMD-273063) Hu14.18-IL2 in melanoma and neuroblastoma. Expert Opin Investig Drugs 18:991–1000

    Article  PubMed  CAS  Google Scholar 

  192. Hu JC, Coffin RS, Davis CJ et al (2006) A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res 12:6737–6747

    Article  PubMed  CAS  Google Scholar 

  193. Senzer NN, Kaufman HL, Amatruda T et al (2009) Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol 27:5763–5771

    Article  PubMed  CAS  Google Scholar 

  194. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S (2010) Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol 17:718–730

    Article  PubMed  Google Scholar 

  195. Jackaman C, Nelson DJ (2010) Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution. Cancer Gene Ther 17:429–440

    Article  PubMed  CAS  Google Scholar 

  196. Mahvi DM, Henry MB, Albertini MR et al (2007) Intratumoral injection of IL-12 plasmid DNA—results of a phase I//IB clinical trial. Cancer Gene Ther 14:717–723

    Article  PubMed  CAS  Google Scholar 

  197. Eder JP, Kantoff PW, Roper K et al (2000) A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res 6:1632

    PubMed  CAS  Google Scholar 

  198. Mastrangelo MJ, Maguire HC, Eisenlohr LC et al (1999) Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 6:409–422

    Article  PubMed  CAS  Google Scholar 

  199. Le DT, Pardoll DM, Jaffee EM (2010) Cellular vaccine approaches. Cancer J 16:304–310

    Article  PubMed  CAS  Google Scholar 

  200. Jinushi M, Hodi FS, Dranoff G (2008) Enhancing the clinical activity of granulocyte-macrophage colony-stimulating factor-secreting tumor cell vaccines. Immunol Rev 222:287–298

    Article  PubMed  CAS  Google Scholar 

  201. Soiffer R, Hodi FS, Haluska F et al (2003) Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol 21:3343–3350

    Article  PubMed  CAS  Google Scholar 

  202. Bergman P, Camps-Palau M, McKnight J et al (2006) Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center. Vaccine 24:4582–4585

    Article  PubMed  CAS  Google Scholar 

  203. Kim JJ, Ayyayoo V, Badarazzi ML et al (1997) In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol 158:816–826

    PubMed  CAS  Google Scholar 

  204. Heller L, Pottinger C, Jaroszeski MJ (2000) In vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunity. Melanoma Res 10(6):577–583

    Article  PubMed  CAS  Google Scholar 

  205. Eliason J (2001) Pegylated cytokines: potential application in immunotherapy of cancer. BioDrugs 15:705–711

    Article  PubMed  CAS  Google Scholar 

  206. Brassard DL, Delorenzo MM, Cox S et al (2004) Regulation of gene expression by pegylated IFN-alpha2b and IFN-alpha2b in human peripheral blood mononuclear cells. J Interferon Cytokine Res 24:455–469

    Article  PubMed  CAS  Google Scholar 

  207. Fried MW, Shiffman ML, Reddy KR et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347(13):975–982

    Article  PubMed  CAS  Google Scholar 

  208. Ridgway D (2003) The first 1000 dendritic cell vaccines. Cancer Invest 21:873–886

    Article  PubMed  Google Scholar 

  209. Schadendorf D, Ugurel S, Schuler-Thurner B et al (2006) Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 17:563–570

    Article  PubMed  CAS  Google Scholar 

  210. Kirkwood J, Tarhini A, Panelli M et al (2008) Next generation of immunotherapy for melanoma. J Clin Oncol 26:3445–3455

    Article  PubMed  CAS  Google Scholar 

  211. Slingluff C, Petroni G, Yamsshchikov G et al (2003) Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026

    Article  PubMed  CAS  Google Scholar 

  212. Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Engl J Med 363:411–422

    Article  PubMed  CAS  Google Scholar 

  213. Drake C (2010) Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol 10:580–593

    Article  PubMed  CAS  Google Scholar 

  214. Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21:233–240

    Article  PubMed  CAS  Google Scholar 

  215. Rosenberg SA, Yanelli JR, Yang JC et al (1994) Treatment of patients with metastatic melanoma using autologous tumor-infiltrating lymphocytes and interleukin-2. J Natl Cancer Inst 86:1159–1166

    Article  PubMed  CAS  Google Scholar 

  216. Dudley ME, Wunderlich JR, Robbins PF et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854

    Article  PubMed  CAS  Google Scholar 

  217. Dudley ME, Wunderlich JR, Yang JC et al (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346–2357

    Article  PubMed  CAS  Google Scholar 

  218. Dudley ME, Yang JC, Sherry R et al (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26:5233–5239

    Article  PubMed  CAS  Google Scholar 

  219. Chapuis AG, Thompson JA, Margolin KA et al (2012) Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci U S A 109:4592–4597

    Article  PubMed  CAS  Google Scholar 

  220. Berger C, Berger M, Hackman RC et al (2009) Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood 114:2417–2426

    Article  PubMed  CAS  Google Scholar 

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Margolin, K., Lazarus, M., Kaufman, H.L. (2013). Cytokines in the Treatment of Cancer. In: Curiel, T. (eds) Cancer Immunotherapy. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4732-0_7

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