Immunomodulatory cytokines as therapeutic agents for melanoma

Immunotherapy

Volumn 3, Issue 5, 2011, Pages 673-690

  Nicholas, Courtney ^a   Lesinski, Gregory B ^a  

^a OHIO STATE UNIVERSITY   (United States)

Author keywords

aldesleukin; cytokine; denenicokin; iboctadekin; IFN ; IL 12; IL 18; IL 2; IL 21; immunotherapy; melanoma

Indexed keywords

ALPHA INTERFERON; CYTOKINE; DENENICOKIN; GLYCOPROTEIN GP 100; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IBOCTADEKIN; INTERLEUKIN 15; IPILIMUMAB; RECOMBINANT INTERLEUKIN 12; RECOMBINANT INTERLEUKIN 2;

ANTINEOPLASTIC ACTIVITY; AUTOIMMUNITY; B LYMPHOCYTE; CANCER IMMUNOTHERAPY; CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; HUMAN; IMMUNOGENICITY; IMMUNOMODULATION; IMMUNOTHERAPY; MELANOMA; MEMORY T LYMPHOCYTE; NATURAL KILLER CELL; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; SOMATIC CELL; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT;

CLINICAL TRIALS, PHASE I AS TOPIC; CLINICAL TRIALS, PHASE II AS TOPIC; CYTOKINES; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOTHERAPY; MELANOMA; SKIN NEOPLASMS; TREATMENT OUTCOME;

EID: 79955909579     PISSN: 1750743X     EISSN: None     Source Type: Journal    
DOI: 10.2217/imt.11.45     Document Type: Review

References (176)

1. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J. Clin. 60(5), 277-300 (2010).
2. Balch CM: Biologic therapy. In:Cutaneous Melanoma (3rd Edition). Balch CM, Houghton A, Sober A, Soong S-J (Eds).Quality Medical Publishing, St Louis, MO, USA 419-436 (1998).
3. Atkins MB: Immunotherapy and experimental approaches for metastatic melanoma. Hematol. Oncol. Clin. North Am. 12(4), 877-902 (1998). (Pubitemid 28410381)
4. Saleh FH, Crotty KA, Hersey P, Menzies SW, Rahman W: Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens. J. Pathol. 200(3), 383-395 (2003). (Pubitemid 36827313)
5. Thor Straten P, Becker JC, Guldberg P, Zeuthen J: In situ T cells in melanoma. Cancer Immunol. Immunother. 48(7), 386-395 (1999). (Pubitemid 29461392)
6. Vajdic CM, Van Leeuwen MT, Webster AC et al.: Cutaneous melanoma is related to immune suppression in kidney transplant recipients. Cancer Epidemiol. Biomarkers Prev. 18(8), 2297-2303 (2009).
7. Kawakami Y, Eliyahu S, Delgado CH et al.: Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc. Natl Acad. Sci. USA 91(14), 6458-6462 (1994).
8. Gogas H, Ioannovich J, Dafni U et al.: Prognostic significance of toimmunity during treatment of melanoma with interferon. N. Engl. J. Med. 354(7), 709-718 (2006). (Pubitemid 43247141)
9. Bouwhuis MG, Ten Hagen TL, Suciu S, Eggermont AM: Autoimmunity and treatment outcome in melanoma. Curr. Opin. Oncol. (2010).
10. Gabrilovich DI, Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9(3), 162-174 (2009).
11. Kageshita T, Hirai S, Ono T, Hicklin DJ, Ferrone S: Down-regulation of HLA class I antigen-processing molecules in malignant melanoma: association with disease progression. Am. J. Pathol. 154(3), 745-754 (1999). (Pubitemid 29122593)
12. Parkinson DR, Talpaz M, Lee KH et al.: Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas MD Anderson Cancer Center. Cancer Treat. Rev. 16(Suppl. A), 39-48 (1989). (Pubitemid 19231451)
13. Zimmerer JM, Lehman AM, Ruppert AS et al.: IFN-α-2b-induced signal transduction and gene regulation in patient peripheral blood mononuclear cells is not enhanced by a dose increase from 5 to 10 megaunits/m2. Clin. Cancer Res. 14(5), 1438-1445 (2008). (Pubitemid 351413927)
14. Yoshimoto T, Morishima N, Okumura M, Chiba Y, Xu M, Mizuguchi J: Interleukins and cancer immunotherapy. Immunotherapy 1(5), 825-844 (2009).
15. Cheever MA, Schlom J, Weiner LM et al.: Translational Research Working Group developmental pathway for immune response modifiers. Clin. Cancer Res. 14(18), 5692-5699 (2008).
16. Allen G, Diaz MO: Nomenclature of the human interferon proteins. J. Interferon Cytokine Res. 16(2), 181-184. (1996). (Pubitemid 26071111)
17. Lafleur Dw, Nardelli B, Tsareva T et al.: Interferon-k, a novel type I interferon expressed in human keratinocytes. J. Biol. Chem. 276(43), 39765-39771 (2001).
18. Isaacs A, Lindenmann J: Virus interference I: the interferon. Proc. R. Soc. Lond. Ser. B 147, 258-267 (1957).
19. Isaacs A, Lindenmann J, Valentine RC: Virus interference, II: some properties of interferon. Proc. R. Soc. Lond. 147B, 268-273 (1957).
20. Gresser I, Bourali C: Exogenous interferon and inducers of interferon in the treatment Balb-C mice inoculated with RC19 tumour cells. Nature 223(208), 844-845 (1969).
21. Paucker K, Cantell K, Henle W: Quantitative studies on viral interference in suspended L cells, III: effect of interfering viruses and interferon on the growth rate of cells. Virology 17, 324-334 (1962).
22. Rubinstein M, Rubinstein S, Familletti PC et al.: Human leukocyte interferon purified to homogeneity. Science 202(4374), 1289-1290 (1978). (Pubitemid 9116085)
23. Taniguchi T, Fujii-Kuriyama Y, Muramatsu M: Construction and identification of a bacterial plasmid containing the human fibroblast interferon gene sequences. Proc. Japan Acad. 55B, 464-469 (1979).
24. Carpi A, Nicolini A, Antonelli A, Ferrari P, Rossi G: Cytokines in the management of high risk or advanced breast cancer: an update and expectation. Curr. Cancer Drug Targets 9(8), 888-903 (2009).
25. Plosker G: Interferon-β-1b: a review of its use in multiple sclerosis. CNS Drugs 25(1), 67-88 (2011).
26. Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL: Prediction of sustained response to peginterferon α-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology 52(4), 1251-1257 (2010).
27. Kim Sh, Cohen B, Novick D, Rubinstein M: Mammalian type I interferon receptors consists of two subunits: IFNaR1 and IFNaR2. Gene 196(1-2), 279-286 (1997). (Pubitemid 27380121)
28. Darnell JE Jr, Kerr IM, Stark GR: Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164), 1415-1421 (1994). (Pubitemid 24217131)
29. Haque SJ, Williams BR: Signal transduction in the interferon system. Semin. Oncol. 25(1 Suppl. 1), 14-22 (1998). (Pubitemid 28093151)
30. Ransohoff RM: Cellular responses to interferons and other cytokines: the JAK-STAT paradigm. N. Engl. J. Med. 338(9), 616-618 (1998). (Pubitemid 28114653)
31. Levy DE, Kessler DS, Pine R, Reich N, Darnell JE Jr: Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 2(4), 383-393 (1988).
32. Bibeau-Poirier A, Servant MJ: Roles of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling. Cytokine 43(3), 359-367 (2008).
33. Kramer OH, Knauer SK, Greiner G et al.: A phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev. 23(2), 223-235 (2009).
34. Uddin S, Lekmine F, Sharma N et al.: The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon a-dependent transcriptional activation but not serine phosphorylation of Stat proteins. J. Biol. Chem. 275(36), 27634-27640 (2000).
35. Uddin S, Majchrzak B, Woodson J et al.: Activation of the p38 mitogen-activated protein kinase by type I interferons. J. Biol. Chem. 274(42), 30127-30131 (1999).
36. Bos JL, De Rooij J, Reedquist KA: Rap1 signalling: adhering to new models. Nat. Rev. Mol. Cell Biol. 2(5), 369-377 (2001). (Pubitemid 33674049)
37. Fish EN, Uddin S, Korkmaz M, Majchrzak B, Druker BJ, Platanias LC: Activation of a CrkL-stat5 signaling complex by type I interferons. J. Biol. Chem. 274(2), 571-573 (1999).
38. Feller SM: Crk family adaptors-signalling complex formation and biological roles. Oncogene 20(44), 6348-6371 (2001). (Pubitemid 32977844)
39. Stork PJ: Does Rap1 deserve a bad Rap? Trends Biochem. Sci. 28(5), 267-275 (2003). (Pubitemid 36588669)
40. Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY: Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol. Cell Biol. 17(9), 5328-5337 (1997). (Pubitemid 27357631)
41. Huang S, Bucana CD, Van Arsdall M, Fidler IJ: Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene 21(16), 2504-2512 (2002). (Pubitemid 34438103)
42. Selleri C, Sato T, Del Vecchio L et al.: Involvement of Fas-mediated apoptosis in the inhibitory effects of Interferon-α in chronic myelogenous leukemia. Blood 89(3), 957-964 (1997). (Pubitemid 27121289)
43. Baker PK, Pettitt AR, Slupsky JR et al.: Response of hairy cells to IFN-a involves induction of apoptosis through autocrine TNF-α and protection by adhesion. Blood 100(2), 647-653 (2002). (Pubitemid 34761131)
44. Brassard DL, Grace MJ, Bordens RW: Interferon-α as an immunotherapeutic protein. J. Leukoc. Biol. 71(4), 565-581 (2002).
45. Lesinski GB, Anghelina M, Zimmerer J et al.: The anti-tumor effects of Interferon-α are abrogated in a STAT1-deficient mouse. J. Clin. Invest. 112(2), 170-180 (2003). (Pubitemid 38056353)
46. Biron CA: Interferons a and b as immune regulators - a new look. Imunity 14(6), 661-664 (2001). (Pubitemid 32592413)
47. + cells from patients with chronic myeloid leukemia and Interferon-α up-regulates this expression. Haematologica 85(2), 139-146 (2000). (Pubitemid 30366656)
48. Von Stamm U, Brocker EB, Von Depka Prondzinski M et al.: Effects of systemic Interferon-α (IFN-a) on the antigenic phenotype of melanoma metastases. EORTC melanoma group cooperative study No. 18852. Mel. Res. 3(3), 173-180 (1993). (Pubitemid 23228961)
49. Dengel LT, Norrod AG, Gregory BL et al.: Interferons induce CXCR3-cognate chemokine production by human metastatic melanoma. J. Immunother. 33(9), 965-974 (2010).
50. Kirkwood JM, Ernstoff MS, Davis CA, Reiss M, Ferraresi R, Rudnick SA: Comparison of intramuscular and intravenous recombinant a-2 interferon in melanoma and other cancers. Ann. Intern. Med. 103(1), 32-36 (1985). (Pubitemid 15068495)
51. Balch CM: Cutaneous Melanoma. (3rd Edition).Balch CM, Houghton AN, Sober AT, Soong SJ (Eds).Quality Medical Publishing, St Louis, MO, USA (1998).
52. Agarwala S: Improving survival in patients with high-risk and metastatic melanoma: immunotherapy leads the way. Am. J. Clin. Dermatol. 4(5), 333-346 (2003). (Pubitemid 36560719)
53. Eggermont A: Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: Analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients. J. Clin. Oncol. 27(Suppl. 15), Abstract 9007 (2009).
54. Hauschild A, Weichenthal M, Rass K et al.: Efficacy of low-dose interferon α2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized Phase III DeCOG trial. J. Clin. Oncol. 28(5), 841-846 (2010).
55. Janku F, Kurzrock R: Adjuvant interferon in high-risk melanoma: end of the era? J. Clin. Oncol. 28(2), E15-E16; author reply E17-E18 (2010).
56. Bottomley A, Coens C, Suciu S et al.: Adjuvant therapy with pegylated interferon α-2b versus observation in resected stage III melanoma: a Phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. J. Clin. Oncol. 27(18), 2916-2923 (2009).
57. Baker PE, Gillis S, Smith KA: Monoclonal cytolytic T-cell lines. J. Exp. Med. 149(1), 273-278 (1979). (Pubitemid 9081285)
58. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA: Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J. Exp. Med. 155(6), 1823-1841 (1982). (Pubitemid 12074218)
59. Lotze MT, Grimm EA, Mazumder A, Strausser JL, Rosenberg SA: Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res. 41(11 Pt 1), 4420-4425 (1981). (Pubitemid 12201351)
60. Gesbert F, Delespine-Carmagnat M, Bertoglio J: Recent advances in the understanding of interleukin-2 signal transduction. J. Clin. Immunol. 18(5), 307-320 (1998). (Pubitemid 28467548)
61. Lin JX, Leonard WJ: The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19(21), 2566-2576 (2000). (Pubitemid 30339212)
62. Theze J, Alzari PM, Bertoglio J: Interleukin 2 and its receptors: recent advances and new immunological functions. Immunol. Today 17(10), 481-486 (1996).
63. Kondadasula SV, Varker KA, Lesinski GB et al.: Activation of extracellular signaling regulated kinase in natural killer cells and monocytes following IL-2 stimulation in vitro and in patients undergoing IL-2 immunotherapy: analysis via dual parameter flow-cytometric assay. Cancer Immunol. Immunother. 57(8), 1137-1149 (2008).
64. Behbod F, Nagy ZS, Stepkowski SM et al.: Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells. J. Immunol. 171(8), 3919-3927 (2003). (Pubitemid 37238663)
65. Fung MM, Rohwer F, Mcguire KL: IL-2 activation of a PI3K-dependent STAT3 serine phosphorylation pathway in primary human T cells. Cell Signal 15(6), 625-636 (2003). (Pubitemid 36385168)
66. Yu TK, Caudell EG, Smid C, Grimm EA: IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway. J. Immunol. 164(12), 6244-6251 (2000). (Pubitemid 30408804)
67. Imada K, Bloom ET, Nakajima H et al.: Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188(11), 2067-2074 (1998). (Pubitemid 28562523)
68. Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN: Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity 11(2), 225-230 (1999). (Pubitemid 29428815)
69. Moriggl R, Topham DJ, Teglund S et al.: Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10(2), 249-259 (1999). (Pubitemid 29115630)
70. Kagami S, Nakajima H, Kumano K et al.: Both STAT5a and STAT5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue. Blood 95(4), 1370-1377 (2000). (Pubitemid 30099849)
71. Battle TE, Frank DA: The role of STATs in apoptosis. Curr. Mol. Med. 2(4), 381-392 (2002). (Pubitemid 35452886)
72. Zamorano J, Wang HY, Wang R, Shi Y, Longmore GD, Keegan AD: Regulation of cell growth by IL-2: role of STAT5 in protection from apoptosis but not in cell cycle progression. J. Immunol. 160(7), 3502-3512 (1998). (Pubitemid 28164745)
73. Yang JC, Sherry RM, Steinberg SM et al.: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J. Clin. Oncol. 21(16), 3127-3132 (2003). (Pubitemid 46606294)
74. Ilkovitch D, Lopez DM: Immune modulation by melanoma-derived factors. Exp. Dermatol. 17(12), 977-985 (2008).
75. + subsets. Cell Immunol. 182(2), 152-160 (1997). (Pubitemid 28134002)
76. Atkins MB: Interleukin-2 in metastatic melanoma: what is the current role? Cancer J. Sci. Am. 6(Suppl. 1), S8-S10 (2000).
77. Malek TR: The biology of interleukin-2. Annu. Rev. Immunol. 26, 453-479 (2008). (Pubitemid 351600382)
78. Moschos SJ, Mandic M, Kirkwood JM, Storkus WJ, Lotze MT: Focus on FOCIS: interleukin 2 treatment associated autoimmunity. Clin. Immunol. 127(2), 123-129 (2008). (Pubitemid 351474602)
79. Waithman J, Gebhardt T, Davey GM, Heath WR, Carbone FR: Cutting edge: enhanced IL-2 signaling can convert self-specific T cell response from tolerance to autoimmunity. J. Immunol. 180(9), 5789-5793 (2008).
80. Mcdermott DF, Regan MM, Clark JI et al.: 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(1), 133-141 (2005). (Pubitemid 41702632)
81. Lissoni P, Bordin V, Vaghi M et al.: Ten-year survival results in metastatic renal cell cancer patients treated with monoimmunotherapy with subcutaneous low-dose interleukin-2. Anticancer Res. 22(2B), 1061-1064 (2002). (Pubitemid 34836151)
82. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J. Sci. Am. 6(Suppl. 1), S55-S57 (2000).
83. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol. 13(3), 688-696 (1995).
84. Mcdermott DF, Atkins MB: Application of IL-2 and other cytokines in renal cancer. Expert Opin. Biol. Ther. 4(4), 455-468 (2004). (Pubitemid 38480546)
85. Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS: Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J. Clin. Oncol. 25(25), 3802-3807 (2007). (Pubitemid 47477253)
86. Dutcher JP, Atkins M, Fisher R et al.: Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J. Sci. Am. 3(Suppl. 1), S73-S78 (1997).
87. Dutcher JP, Fisher RI, Weiss G et al.: Outpatient subcutaneous interleukin-2 and Interferon-α for metastatic renal cell cancer: five-year follow-up of the Cytokine Working Group Study. Cancer J. Sci. Am. 3(3), 157-162 (1997).
88. Dutcher JP, Logan T, Gordon M et al.: Phase II trial of interleukin 2, interferon a, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study. Clin. Cancer Res. 6(9), 3442-3450 (2000).
89. Rosenberg SA, Dudley ME: Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr. Opin. Immunol. 21(2), 233-240 (2009).
90. Bakker AB, Schreurs MW, De Boer AJ et al.: Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J. Exp. Med. 179(3), 1005-1009 (1994).
91. Sosman JA, Carrillo C, Urba WJ et al.: Three Phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. J. Clin. Oncol. 26(14), 2292-2298 (2008).
92. Gunturu KS, Meehan KR, Mackenzie TA et al.: Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. J. Clin. Oncol. 28(7), 1196-1202 (2010).
93. Atkins MB, Hsu J, Lee S et al.: Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon α-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(35), 5748-5754 (2008).
94. Schwartzentruber DJ: A Phase III multi-institutional randomized study of immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J. Clin. Oncol. 27(Suppl. 18) Abstract CRA9011 (2009).
95. Prieto PA: Cytotoxic T lymphocyte-associated antigen 4 blockade with ipilimumab: Long-term follow-up of 179 patients with metastatic melanoma. J. Clin. Oncol. 28(Suppl. 15), Abstract 8544 (2010).
96. Sabatino M, Kim-Schulze S, Panelli MC et al.: Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J. Clin. Oncol. 27(16), 2645-2652 (2009).
97. Kobayashi M, Fitz L, Ryan M et al.: Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170(3), 827-845 (1989). (Pubitemid 19226667)
98. Stern AS, Podlaski FJ, Hulmes JD et al.: Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc. Natl Acad. Sci. USA 87(17), 6808-6812 (1990).
99. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'shea JJ: Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202, 139-156 (2004). (Pubitemid 39576910)
100. Thierfelder WE, Van Deursen JM, Yamamoto K et al.: Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382(6587), 171-174 (1996). (Pubitemid 26242884)
101. Trinchieri G: Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3(2), 133-146 (2003). (Pubitemid 37328691)
102. Brunda MJ, Luistro L, Warrier RR et al.: Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J. Exp. Med. 178(4), 1223-1230 (1993). (Pubitemid 23277355)
103. Trinchieri G: Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251-276 (1995).
104. Nagai H, Oniki S, Fujiwara S, Yoshimoto T, Nishigori C: Antimelanoma immunotherapy: clinical and preclinical applications of IL-12 family members. Immunotherapy 2(5), 697-709 (2010).
105. Voest EE, Kenyon BM, O'reilly MS, Truitt G, D'amato RJ, Folkman J: Inhibition of angiogenesis in vivo by interleukin 12. J. Natl Cancer Inst. 87(8), 581-586 (1995).
106. Alatrash G, Hutson TE, Molto L et al.: Clinical and immunologic effects of subcutaneously administered interleukin-12 and interferon α-2b: Phase I trial of patients with metastatic renal cell carcinoma or malignant melanoma. J. Clin. Oncol. 22(14), 2891-2900 (2004). (Pubitemid 41079909)
107. Eisenbeis CF, Lesinski GB, Anghelina M et al.: Phase I study of the sequential combination of interleukin-12 and interferon α-2b in advanced cancer: evidence for modulation of interferon signaling pathways by interleukin-12. J. Clin. Oncol. 23(34), 8835-8844 (2005). (Pubitemid 46211530)
108. Del Vecchio M, Bajetta E, Canova S et al.: Interleukin-12: biological properties and clinical application. Clin. Cancer Res. 13(16), 4677-4685 (2007). (Pubitemid 47294773)
109. Cebon J, Jager E, Shackleton MJ et al.: Two Phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma. Cancer Immun. 3, 7 (2003).
110. Peterson AC, Harlin H, Gajewski TF: Immunization with Melan-A peptide-pulsed peripheral blood mononuclear cells plus recombinant human interleukin-12 induces clinical activity and T-cell responses in advanced melanoma. J. Clin. Oncol. 21(12), 2342-2348 (2003). (Pubitemid 46628465)
111. Atkins MB, Robertson MJ, Gordon M et al.: Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin. Cancer Res. 3(3), 409-417 (1997). (Pubitemid 27158065)
112. Leonard JP, Sherman ML, Fisher GL et al.: Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-g production. Blood 90(7), 2541-2548 (1997). (Pubitemid 27413462)
113. Heinzerling L, Burg G, Dummer R et al.: Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum. Gene Ther. 16(1), 35-48 (2005). (Pubitemid 40250330)
114. Fewkes NM, Mackall CL: Novel g-chain cytokines as candidate immune modulators in immune therapies for cancer. Cancer J. 16(4), 392-398 (2010).
115. + T cells. J. Exp. Med. 196(7), 935-946 (2002).
116. Waldmann TA, Tagaya Y: The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu. Rev. Immunol. 17, 19-49 (1999). (Pubitemid 29241118)
117. Lewko WM, Smith TL, Bowman DJ, Good RW, Oldham RK: Interleukin-15 and the growth of tumor derived activated T-cells. Cancer Biother. 10(1), 13-20 (1995).
118. Gu Y, Kuida K, Tsutsui H et al.: Activation of interferon-g inducing factor mediated by interleukin-1b converting enzyme. Science 275(5297), 206-209 (1997). (Pubitemid 27034760)
119. Sims JE, Smith DE: The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10(2), 89-102 (2010).
120. Park S, Cheon S, Cho D: The dual effects of interleukin-18 in tumor progression. Cell Mol. Immunol. 4(5), 329-335 (2007).
121. Srivastava S, Salim N, Robertson MJ: Interleukin-18: biology and role in the immunotherapy of cancer. Curr. Med. Chem. 17(29), 3353-3357 (2010).
122. + T lymphocytes. J. Immunol. 160(8), 3642-3647 (1998). (Pubitemid 28176063)
123. Gracie JA, Robertson SE, McInnes IB: Interleukin-18. J. Leukoc. Biol. 73(2), 213-224 (2003). (Pubitemid 36158296)
124. Kim YM, Im JY, Han SH, Kang HS, Choi I: IFN-γ up-regulates IL-18 gene expression via IFN consensus sequence-binding protein and activator protein-1 elements in macrophages. J. Immunol. 165(6), 3198-3205 (2000).
125. Moller B, Paulukat J, Nold M et al.: Interferon-g induces expression of interleukin-18 binding protein in fibroblast-like synoviocytes. Rheumatology (Oxford) 42(3), 442-445 (2003). (Pubitemid 36367535)
126. Okamura H, Tsutsi H, Komatsu T et al.: Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 378(6552), 88-91 (1995).
127. Tominaga K, Yoshimoto T, Torigoe K et al.: IL-12 synergizes with IL-18 or IL-1beta; for IFN-γ production from human T cells. Int. Immunol. 12(2), 151-160 (2000). (Pubitemid 30088307)
128. Ahn HJ, Maruo S, Tomura M et al.: A mechanism underlying synergy between IL-12 and IFN-γ-inducing factor in enhanced production of IFN-γ. J. Immunol. 159(5), 2125-2131 (1997). (Pubitemid 127681000)
129. Vidal-Vanaclocha F, Mendoza L, Telleria N et al.: Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression. Cancer Metastasis Rev. 25(3), 417-434 (2006). (Pubitemid 44922359)
130. Carroll RG, Carpenito C, Shan X et al.: Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells. PLoS One 3(9), E3289 (2008).
131. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H: Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 19, 423-474 (2001). (Pubitemid 32368042)
132. Guo L, Wei G, Zhu J et al.: IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc. Natl Acad. Sci. USA 106(32), 13463-13468 (2009).
133. Hata H, Yoshimoto T, Hayashi N, Hada T, Nakanishi K: IL-18 together with anti-CD3 antibody induces human Th1 cells to produce Th1-and Th2-cytokines and IL-8. Int. Immunol. 16(12), 1733-1739 (2004). (Pubitemid 40003861)
134. Chaix J, Tessmer MS, Hoebe K et al.: Cutting edge: Priming of NK cells by IL-18. J. Immunol. 181(3), 1627-1631 (2008).
135. Lissoni P, Brivio F, Rovelli F et al.: Serum concentrations of interleukin-18 in early and advanced cancer patients: enhanced secretion in metastatic disease. J. Biol. Regul. Homeost. Agents 14(4), 275-277 (2000). (Pubitemid 32124116)
136. Tsuboi K, Miyazaki T, Nakajima M et al.: Serum interleukin-12 and interleukin-18 levels as a tumor marker in patients with esophageal carcinoma. Cancer Lett. 205(2), 207-214 (2004). (Pubitemid 38230128)
137. Akahiro J, Konno R, Ito K, Okamura K, Yaegashi N: Impact of serum interleukin-18 level as a prognostic indicator in patients with epithelial ovarian carcinoma. Int. J. Clin. Oncol. 9(1), 42-46 (2004). (Pubitemid 38470662)
138. Cho D, Song H, Kim YM et al.: Endogenous interleukin-18 modulates immune escape of murine melanoma cells by regulating the expression of Fas ligand and reactive oxygen intermediates. Cancer Res. 60(10), 2703-2709 (2000). (Pubitemid 30318247)
139. Robertson MJ, Mier JW, Logan T et al.: Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin. Cancer Res. 12(14 Pt 1), 4265-4273 (2006).
140. Robertson MJ, Kirkwood JM, Logan TF et al.: A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin. Cancer Res. 14(11), 3462-3469 (2008).
141. Golab J, Stoklosa T: Technology evaluation: SB-485232, GlaxoSmithKline. Curr. Opin. Mol. Ther. 7(1), 85-93 (2005).
142. Tarhini AA, Millward M, Mainwaring P et al.: A Phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Cancer 115(4), 859-868 (2009).
143. Davis ID, Skak K, Smyth MJ, Kristjansen PE, Miller DM, Sivakumar PV: Interleukin-21 signaling: functions in cancer and autoimmunity. Clin. Cancer Res. 13(23), 6926-6932 (2007). (Pubitemid 350276871)
144. Parrish-Novak J, Dillon SR, Nelson A et al.: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408(6808), 57-63 (2000).
145. Coquet JM, Kyparissoudis K, Pellicci DG et al.: IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol. 178(5), 2827-2834 (2007). (Pubitemid 46333160)
146. Andorsky DJ, Timmerman JM: Interleukin-21: biology and application to cancer therapy. Expert Opin. Biol. Ther. 8(9), 1295-1307 (2008).
147. Skak K, Kragh M, Hausman D, Smyth MJ, Sivakumar PV: Interleukin 21: combination strategies for cancer therapy. Nat. Rev. Drug Discov. 7(3), 231-240 (2008).
148. Nurieva R, Yang XO, Martinez G et al.: Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152), 480-483 (2007). (Pubitemid 47123514)
149. Petersen CC, Diernaes JE, Skovbo A, Hvid M, Deleuran B, Hokland M: Interleukin-21 restrains tumor growth and induces a substantial increase in the number of circulating tumor-specific T cells in a murine model of malignant melanoma. Cytokine 49(1), 80-88 (2010).
150. 3 by human B cells. J. Immunol. 172(9), 5154-5157 (2004). (Pubitemid 38542010)
151. Mehta DS, Wurster AL, Whitters MJ, Young DA, Collins M, Grusby MJ: IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol. 170(8), 4111-4118 (2003). (Pubitemid 36428174)
152. Ozaki K, Spolski R, Ettinger R et al.: Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173(9), 5361-5371 (2004). (Pubitemid 39392119)
153. + cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol. 33(12), 3439-3447 (2003). (Pubitemid 37541122)
154. Strengell M, Matikainen S, Siren J et al.: IL-21 in synergy with IL-15 or IL-18 enhances IFN-γ production in human NK and T cells. J. Immunol. 170(11), 5464-5469 (2003). (Pubitemid 36617833)
155. + T lymphocytes. J. Immunol. 178(2), 732-739 (2007). (Pubitemid 46095145)
156. + T cells for adoptive immunotherapy. Blood 111(11), 5326-5333 (2008).
157. + cytotoxic T lymphocytes. Blood 111(1), 229-235 (2008).
158. Korn T, Bettelli E, Gao W et al.: IL-21 initiates an alternative pathway to induce proinflammatory T(h)17 cells. Nature 448(7152), 484-487 (2007). (Pubitemid 47123515)
159. Davis ID, Skrumsager BK, Cebon J et al.: An open-label, two-arm, Phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin. Cancer Res. 13(12), 3630-3636 (2007). (Pubitemid 46955126)
160. Thompson JA, Curti BD, Redman BG et al.: Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J. Clin. Oncol. 26(12), 2034-2039 (2008).
161. Schmidt H, Brown J, Mouritzen U et al.: Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a Phase I trial. Clin. Cancer Res. 16(21), 5312-5319 (2010).
162. Hashmi MH, Van Veldhuizen PJ: Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma. Expert Opin. Biol. Ther. 10(5), 807-817 (2010).
163. Petrella TM: Phase II study of interleukin in patients with recurrent or metastatic melanoma. Presented at: The 7th World Congress on Melanoma. Vienna, Austria 12-16 May 2009.
164. Davis I: Activity of recombinant human interleukin-21 (rIL-21) in patients (pts) with stage IV malignant melanoma (MM) without prior treatment: clinical data from a Phase IIa study. J. Clin. Oncol. 26(Suppl. 20) Abstract 3042 (2008).
165. Huarte E, Fisher J, Turk MJ et al.: Ex vivo expansion of tumor specific lymphocytes with IL-15 and IL-21 for adotive immunotherapy in melanoma. Cancer Lett. 285(1), 80-88 (2009).
166. Jaime-Ramirez AC, Mundy-Bosse BL, Kondadasula SV et al.: Interleukin-12 enhances the anti-tumor actions of trastuzumab via NK cell IFN-γ production. J. Immunol. DOI: 10.4049/ jimmunol.1000328 (2011) (Epub ahead of print).
167. Cote AL, Usherwood EJ, Turk MJ: Tumor-specific T-cell memory: clearing the regulatory T-cell hurdle. Cancer Res. 68(6), 1614-1617 (2008). (Pubitemid 351416543)
168. Filipazzi P, Valenti R, Huber V et al.: Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J. Clin. Oncol. 25(18), 2546-2553 (2007). (Pubitemid 47041228)
169. Brody JR, Costantino CL, Berger AC et al.: Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8(12), 1930-1934 (2009).
170. +HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res. 70(11), 4335-4345 (2010).
171. Lechner MG, Liebertz DJ, Epstein AL: Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J. Immunol. 185(4), 2273-2284 (2010).
172. Toomey D, Conroy H, Jarnicki AG, Higgins SC, Sutton C, Mills KH: Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma. Vaccine 26(27-28), 3540-3549 (2008).
173. Gabrilovich DI, Chen HL, Girgis KR et al.: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2(10), 1096-1103 (1996). (Pubitemid 26338628)
174. Finke JH, Rini B, Ireland J et al.: Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin. Cancer Res. 14(20), 6674-6682 (2008).
175. + T cells in melanoma patients receiving interleukin 12. Cancer Res. 60(13), 3559-3568 (2000). (Pubitemid 30482177)
176. Bajetta E, Del Vecchio M, Mortarini R et al.: Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. Clin. Cancer Res. 4(1), 75-85 (1998). (Pubitemid 28062880)