Abstract
Cytokines represent a diverse group of small, soluble polypeptides that are involved in regulating a wide range of physiologic processes, including inflammation, tissue repair, and immunity. The expanding role of cytokines in these processes and the identification of over 100 putative cytokine family members have made it difficult to easily classify cytokines based on structure or function. In addition, many cytokines exhibit a variety of biologic activities and these effects may be dependent on the concentration, timing, and duration of target cell exposure to a given cytokine, as well as the influence of other cytokine and growth factors in the local microenvironment. In fact, much of the early characterization of cytokines was based on simple in vitro experiments, which have failed to accurately predict the activity of cytokines in vivo. More recent investigation using targeted knockout mice and analysis of cytokine signaling pathways is leading to new insights into the biology of many cytokines. This is perhaps best exemplified by interleukin-2 (IL-2), originally described as a T-cell growth factor and defined by its ability to induce T-cell proliferation in vitro. Such ex vivo studies predicted that IL-2 would function to promote cellular immunity through expansion of naive T-cell populations in vivo. The availability of IL-2 and IL-2 receptor knockout mice, however, demonstrated that in the absence of IL-2 signaling T-cell proliferation was increased, significant lymphadenopathy occurred, and animals succumb to aggressive autoimmune disease. This unexpected result suggests that IL-2 may actually function in vivo, not as a T-cell stimulant, but rather as a regulatory cytokine maintaining peripheral tolerance through balancing effector and regulatory T-cell pools (1).
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References
Malek T, Bayer A. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004;4(9): 665–674.
Fleischman W, Georgiades J, Osborne L. Potentiation of interferon activity by mixed preparations of fibroblast and immune interferon. Infect Immun 1979;26:248–153.
Feinman R, Henriksen-DeStefano D, Tsujimoto M, Vilcek J. Tumor Necrosis Factor is an important mediator of tumor cell killing by human monocytes. Journal of Immunology 1987; 138:635–640.
Kloke O, Wandl U, Moritz T, et al. A prospective randomized comparison of single-agent interferon (IFN)-alpha with the combination of IFN-alpha and low-dose IFN-gamma in chronic myelogenous leukemia. Eur J Haematol 1992;48:93–98.
Talpaz M, Kurzrock R, Kantarjian H, et al. A Phase II Study Alternating Alpha-2a-Interferon and Gamma-Interferon Therapy in Patients with Chronic Myelogenous Leukemia. Cancer 1991; 68:2125–2130.
Janson E, Kauppinen H-L, Oberg K. Combined Alpha-and Gamma-Interferon Therapy for Malignant Midgut Carcinoid Tumors. Acta Oncologica 1993;32(2):231–233.
Ozzello L, Habif D, De Rosa C, Cantell K. Cellular Events Accompanying Regression of Skin Recurrences of Breast Carcinomas Treated with Intralesional Injections of Natural Interferons alpha and gamma. Cancer Res 1992;52:4571–4581.
Grem J, McAtee N, Murphy R, et al. A Pilot Study of gamma-Interferon in Combination with Fluorouracil, Leucovorin, and alpha-2a-Interferon. Clin Cancer Res 1997;3:1125–1134.
Foon K, Doroshow J, Bonnem E, et al. A prospective randomized trial of alpha-2B-interferon/ gamma-interferon or the combination in advanced metastatic renal cell cancer. J Biolog Res Modifiers 1988;7(540-545).
DeMulder P, Oosteroff G, Bouffioux C, van OOsterom A, Vermeylen K, Sylvester R. EORTC (30885) randomised phase III study with recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. British Journal of Cancer 1995;71:371–375.
De Mulder P, Debruyne FMJ, Franssen M, et al. Phase I/II study of recombinant interferon alpha and gamma in advanced progressive renal cell carcinoma. Cancer Immunol Immunother 1990;31: 321–324.
Dutcher J, Fine J, Krigel R, et al. Stratification by Risk Factors Predicts Survival on the Active Treatment Arm in a Randomized Phase II Study of Interferon-gamma Plus/Minus Interferon-alpha in Advanced Renal Cell Carcinoma (E6890). Medical Oncology 2003;20(3):271–281.
Kramer G, Steiner GE, Sokol P, et al. Local Intratumoral Tumor Necrosis Factor-alpha and Systemic IFN-alpha 2b in Patients with Locally Advanced Prostate Cancer. Journal of Interferon and Cytokine Research 2001;21:475–484.
Van Mooreselaar RJ, Hendriks BT, Van Stratum P, Van Der Melde PH, Debruyne FMJ, Schalken JA. Synergistic antitumor effects of rat gamma interferon and human tumor necrosis factor alpha against androgen dependent and indeprendent rat prostatic tumors. Cancer Res 1991;51:2329–2334.
Smith JW, Urba WJ, Clark JW, et al. Phase I Evaluation of Recombinant Tumor Necrosis Factor Given in Combination with Recombinant Interferon-gamma. Journal of Immunotherapy 1991;10: 355–362.
Schiller JH, Witt PL, Storer B, et al. Clinical and Biologic Effects of Combination Therapy with Gamma-Interferon and Tumor Necrosis Factor. Cancer 1992;69(2):562–571.
Lienard D, Lejeune F, Ewalenko I. In transit metastases of malignant melanoma treated by high dose rTNF-alpha in combination with interferon-gamma and melphalan in isolation perfusion. World Journal of Surgery 1992; 16:234–240.
Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: Results of a tumor necrosis factor dose-escalation study. J Clin Oncol 1996;14(2):479–489.
Olieman A, Lienard D, Eggermont A, et al. Hyperthermic isolated limb pefusion with tumor necrosis factor alpha, interferon gamma, and melphalan for locally advanced nonmelanoma skin tumors of the extremities. Arch Surg 1999;134:303–307.
Karpoff H, D’Angelica M, Blair S. Prevention of hepatic metastases in rats with herpes viral vaccines and gamma-interferon. J Clin Invest 1997;99:799–804.
Reinisch W, Holub M, Katz A, et al. Prospective Pilot Study of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor and Interferon-gamma in Patients with Inoperable Hepatocellular Carcinoma. Journal of Immunotherapy 2002;25(6):489–499.
Lummen G, Sperling H, Luboldt H, Otto T, Rubben H. Granulocyte-Macrophage Colony-Stimulating Factor and Interferon-Alpha 2B in Patients with Advanced Renal Cell Carcinoma. Int Urology 1998;61:215–219.
O’Donnell R, Dea G, Meyers F. A Phase II Trial of Concomitant Interferon-alpha-2b and Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Advanced Renal Cell Cancer. Journal of Immunotherapy 1995;17:58–61.
Shapiro J, Harold N, Takimoto C, et al. A Pilot Study of Interferon-alpha-2a, Fluoruracil, and Leucovorin Given with Granulocyte-Macrophage Colony Stimulating Factor in Advanced Gastrointestinal Adenocarcinoma. Clin Cancer Res 1999;5:2399–2408.
Krown S, Paredes J, Bundow D, Polsky B, Gold J, Flomenberg N. Interferon-alpha, Zidovudine, and Granulocyte-Macrophage Colony-Stimulating Factor: A Phase I AIDS Clinical Trials Group Study in Patients with Kaposi’s Sarcoma Associated with AIDS. Journal of Clinical Oncology 1992; 10(8): 1344–1351.
Yang S, Grimm E, Parkinson D, et al. Clinical and Immunomodulatory Effects of Combination Immunotherapy with Low-Dose Interleukin 2 and Tumor Necrosis Factor alpha in Patients with Advanced Non-Small Cell Lung Cancer: A Phase I Trial. Cancer Research 1991;51:3669–3676.
Schiller JH, Morgan-Ihrig C, Levitt M. Concomitant Aministration of Interleukin-2 Plus Tumor Necrosis Factor in Advanced Non-Small Cell Lung Cancer. American Journal of Clinical Oncology 1995;18(1):47–51.
Krigel R, Padavic-Schaller K, Toomey C, Comis R, Weiner L. Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2. J Immunother 1995;17: 161–170.
Krigel R, Padavic-Schaller K, Rudolph A, Konrad M, Bradley E, Comis R. Renal cell carcinoma: Treatment with recombinant interleukin-2 plus beta-interferon. J Clin Oncol 1990;8(3):460–467.
Duggan D, Santarelli M, Zamkoff K, et al. A phase ii study of recombinant interleukin-2 with or without recombinant interferon-beta in non-Hodgkin’s lymphoma. a study of the cancer and leukemia group B. J Immunother 1992; 12:115–122.
Tester W, Kim K, Krigel R, et al. A randomized Phase II study of interleukin-2 with and without betainterferon for patients with advanced non-small cell lung cancer. An Eastern Cooperative Oncology Group study (PZ586). Lung Cancer 1999;25:199–206.
Brunda M, Luistro L, Warrier T. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 1993;178:1223–1230.
Nastala C, Edington H, McKinney T. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 1994;153:1697–1706.
Gollob J, Veenstra K, Parker R, et al. Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose il-2 in patients with melanoma or renal cell cancer. J Clin Oncol 2003;21(13):2564–2573.
Santoli D, Clark S, Kreider B, Maslin P, Rovera G. Amplification of IL-2-driven T cell proliferation by recombinant IL-3 and granulocyte-macrophage colony-stimulating factor. J Immunol 1988; 141:519–526.
Schiller JH, Hank J, Khorsand M, et al. Clinical and immunological effects of granulocytemacrophage colony-stimulating factor coadministered with interleukin-2: A phase IB study. Clin Cancer Res 1996;2:319–330.
Ryan C, Vogelzang N, Dumas M, Kuzel T, Stadler W. Granulocyte-macrophage-colony-stimulating factor in combination immunotherapy for patients with metastatic renal cell carcinoma. Cancer 2000; 88:1317–1324.
Smith JW, Kurt R, Baher A, et al. Immune effects of escalating doses of granulocyte-macrophage colony-stimulating factor added to a fixed, low-dose, inpatient interleukin-2 regimen: a randomized phase I trial in patients with metastatic melanoma and renal cell carcinoma. Journal of Immunotherapy 2003;26(2): 130–138.
O’Day S, Boasberg P, Piro L, et al. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res 2002;8:2775–2781.
Ridolfi L, Ridolfi R, Ascari-Raccagni A, et al. Intralesional GM-CSF followed by subcutaneous IL2 in metastatic melanoma. Journal of the European Academy of Dermatology and Venereology 2001; 15:218–223.
Kiertscher S, Roth M. Human CD14+ leukocytes acquire the phenotype and function of antigen-presenting dendritic cells when cultured in GM-CSF and IL-4. J Leukocyte Biol 1996;59:208–218.
Kiertscher S, Gitlitz B, Figlin R, Roth J. Granulocyte/macrophage-colony stimulating factor and interleukin-4 expand and activate type-1 dendritic cells (dcl) when administered in vivo to cancer patients. Int J Cancer 2003;107:256–261.
Gitlitz B, Figlin R, Kiertscher S, Moldawer N, Rosen F, Roth J. Phase I trial of granulocyte macrophage colony-stimulating factor and interleukin-4 as combined immunotherapy for patients with cancer. J Immunother 2003;26(2):171–178.
Tate J, Olencki T, Finke J, Kottke-Marchant K, Rybicki L, Bukowski R. Phase I trial of simultaneously administered GM-CSF and IL-6 in patients with renal-cell carcinoma: Clinical and laboratory effects. Ann Oncol 2001;12:655–659.
Hochster H, Speyer J, Mandeli J, et al. A phase II double-blind randomized study of the simultaneous administration of recombinant human interleukin-6 and recombinant human granulocyte colonystimulating factor following paclitaxel and carboplatin chemotherapy in patients with advanced epithelial ovarian cancer. Gyn Onc 1999;72:292–297.
Bracho F, Krailo M, Shen V, et al. A phase I clinical, pharmacological, and biological trial of interleukin 6 plus granulocyte-colony stimulating factor after ifosfamide, carboplatin, and etoiposide in children with recurrent/refractory solid tumors: Enhanced hematological responses but a high incidence of grade III/IV constitutional toxicities. Clin Cancer Res 2001;7:58–67.
Kawakami Y, Rosenberg SA, Lotze M. Interleukin-4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic form human autologous melanoma. Journal of Experimental Medicine 1988;168: 2183–2191.
Higuichi C, Thompson J, CG L. Induction of lymphokine-activated killer activity by interleukin-4 in human lymphocytes preactivated by interleukin-2 in vivo and in vitro. Cancer Res 1989;49: 6487–6492.
Sosman J, Fisher S, Kefer C, Fisher R, Ellis T. A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients. Annals of Oncology 1994;5: 447–452.
Sosman J, Bartemes K, Offord K, et al. Evidence for eosinophil activation in cancer patients receiving recombinant interleukin-4: Effects of interleukin-4 alone and following interleukin-2 administration. Clin Cancer Res 1995;1:805–812.
Whitehead R, Friedman K, Clark D, Pagani K, Rapp L. Phase I trial of simultaneous administration of interleukin-2 and interleukin-4 subcutaneously. Clin Cancer Res 1995;1:1145–1152.
Olencki T, Finke J, Tubbs R, et al. Immunomodulatory effects of interleukin-2 and interleukin-4 in patients with malignancy. J Immunother 1996;19(1):69–80.
Blay J, Pallardy M, Ravaud A. Serum VEGF is an independent prognostic factor in patients with metastatic renal cell carcinoma, treated with IL2 and/or IFN: Analysis of the Crecy trial. Proc Am Ass Clin Oncol 1997;18:1669 (abstract).
Lissoni P, Rovelli F, Baiocco N, Tangini G, Fumagalli L. A Phase II study of subcutaneous low-dose interleukin-2 plus erythropoietin in metastatic renal cell carcinoma progressing on interleukin-2 alone. Anticancer Res 2001;21:777–780.
Iogo M, Sakurai M, Tamura T. In vivo antitumor activity of multiple injections of recombinant interleukin 2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors. Cancer Res 1988;48:260–264.
Rosenberg SA, Schwartz S, Spiess P. Combination immunotherapy for cancer: Synergistic antitumor interactions of interleukin-2, alfa interferon, and tumor-infiltrating lymphocytes. J Natl Cancer Inst 1988;80:1393–1397.
Cameron R, McIntosh J, Rosenberg S. Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2and a recombinant hybrid alpha-interferon in the treatment of established murine hepatic metastases. Cancer Res 1988;48:5810–5817.
Rosenberg SA, Lotze M, Yang J, et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 1989;7(12):1863–1874.
Marincola F, White D, Wise A, Rosenberg SA. Combination therapy with interferon alpha-2a and interleukin-2 for the treatment of metastatic cancer. J Clin Oncol 1995;13(5): 1110–1122.
Huberman M, Bering H, Fallon B, et al. A phase I study of an outpatient regimen of recombinant human interleukin-2 and alpha-2a-interferon in patients with solid tumors. Cancer 1991;68:1708–1713.
Ratain M, Priest E, Janisch L, Vogelzang N. A phase I study of subcutaneous recombinant interleukin-2 and interferon alfa-2a. Cancer 1992;71:2371–2376.
Rosso R, Sertoli M, Queirolo P, et al. An outpatient phase I study of a subcutaneous interleukin-2 and intramuscular alpha-2a-interferon combination in advanced malignancies. Ann Oncol 1992;3: 559–563.
Budd G, Murthy S, Finke J, et al. Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy. J Clin Oncol 1992;10(5):804–809.
Schiller JH, Hank J, Storer B, et al. A direct comparison of immunological and clinical effects of interleukin 2 with a without interferon-alpha in humans. Cancer Res 1993;53:1286–1292.
Gause B, Sznol M, Kapp W, et al. Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer. J Clin Oncol 1996;14(8):2234–2241.
Atzpodien J, Kirchner H, Jonas U, et al. Interleukin-2 and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: A prospectively randomized trial of the german cooperative renal carcinoma chemoimmunotherapy group. J Clin Oncol 2004;22(7): 1188–1194.
Vogelzang N, Lipton A, Figlin R. Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: An outpatient multicenter trial. J Clin Oncol 1993; 11(9): 1809–1816.
Atkins M, Sparano J, Fisher R, et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol 1993; 11(4):661–670.
Stadler W, Kuzel T, Dumas M, Vogelzang N. Multicenter phase II trial of interleukin-2, interferonalpha, and 13-cis-retinoic acid in patients with metastatic renal-cell carcinoma. J Clin Oncol 1998; 16(5):1820–1825.
Tourani J-M, Pfister C, Berdah J-F. Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: Results of a sequential nonrandomized phase II study. J Clin Oncol 1998;16(7):2505–2513.
Figlin R, Belldegrun A, Moldawer N, Zeffren J, deKernion J. Concomitant administration of recombinant human interleukin-2 and recombinant interferon alfa-2a: An active outpatient regimen in metastatic renal cell carcinoma. J Clin Oncol 1992;10(3):414–421.
Facendola G, Locatelli M, Pizzocaro G, et al. Subcutaneous administration of interleukin 2 and interferonj-alpha-2b in advanced renal cell carcinoma: A confirmatory study. Br J Cancer 1995;72(6): 1531–1535.
Ravaud A, Negrier S, Cany L, et al. Subcutaneous low-dose recombinant interleukin 2 and alphainterferon in patients with metastatic renal cell carcinoma. Br J Cancer 1994;69:1111–1114.
Ravaud A, Audhuy B, Gomez F, et al. Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: A multicenter phase II trial. J Clin Oncol 1998;16(8):2728–2732.
Jayson G, Middleton M, Lee S, Ashcroft L, Thatcher N. A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer. Br J Cancer 1998;78(3):366–369.
Naglieri E, Lopez M, Lelli G, et al. Interleukin-2, interferon-alpha, and medroxyprogesterone acetate in metastatic renal cell carcinoma. Anticancer Res 2002;22:3045–3052.
Mittelman A, Puccio C, Ahmed T, Zeffren J, Choudhury A, Arlin Z. A phase II trial of interleukin-2 by continuous infusion and interferon by intramuscular injection in patients with renal cell cancer. Cancer 1991;68:1699–1702.
Canobbio L, Curotto A, Cannata D, et al. Combination therapy with subcutaneous interleukin-2 and interferon-alpha in advanced renal cancer patients with poor prognostic factors. Anticancer Res 1996;16:541–544.
Ellerhorst J, Sella A, Amato R, et al. Phase II trial of 5-fluorouracil, interferon-alpha and conmtinuous infusion interleukin-2 for patients with metastatic renal cell carcinoma. Cancer 1997;80:128–132.
Bergmann L, Fenchel K, Weidmann E, et al. Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. Cancer 1993;72(5): 1734–1742.
Ravaud A, Delva R, Gomez F, et al. Subcutaneous interleukin-2 and interferon alpha in the treatment of patients with metastatic renal cell carcinoma—less efficacy compared with intravenous interleukin-2 and interferon alpha. Cancer 2002;95:2324–2330.
Atzpodien J, Hoffmann R, Franzke M, Stief C, Wandert T, Reitz M. Thirteen-year, long-term efficacy of interferon 2alpha and interleukin 2-based home therapy in patients with advanced renal cell carcinoma. Cancer 2002;95:1045–1050.
Ryan C, Vogelzang N, Stadler W. A phase II trial of intravenous gemcitabine and 5-fluorouracil with subcutaneous interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma. Cancer 2002;94:2602–2609.
Buzio C, Andrulli S, Santi R, et al. Long-term immunotherapy with low-dose interleukin-2 and interferon-alpha in the treatment of patients with advanced renal cell carcinoma. Cancer 2001; 92: 2286–2296.
Elias L, Lew D, Figlin R, et al. Infusional interleukin-2 and 5-fluorouracil with subcutaneous interferon-alpha in the treatment of patients with advanced renal cell carcinoma. Cancer 2000;89: 597–603.
Gez E, Rubinov R, Gaitini D, et al. Interleukin-2, interferon-alpha, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma. Cancer 2002;95:1644–1649.
Piga A, Giordani P, Quattrone A, et al. A phase II study of interferon alpha and low-dose interleukin-2 in advanced renal cell carcinoma. Cancer Immunol Immunother 1997;44:348–351.
Rogers E, Bredin H, Butler M, et al. Combined subcutaneous recombinant alpha-interferon and interleukin-2 in metastatic renal cell cancer: Results of the Multicentre All Ireland Immunotherapy Study Group. European Urol 2000;37:261–266.
Fossa S, Aune H, Baggerud E, Granerud T, Heilo A, Theodorsen L. Continuous intravenous interleukin-2 infusion and subcutaneous interferon-alpha in metastatic renal cell carcinoma. Eur J Cancer 1993;29A(9):1313–1315.
Besana C, Borri A, Bucci E, et al. Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon. Eur J Cancer 1994;30A(9): 1292–1298.
Pectasides D, Vartalitis J, Kostopoulou M, et al. An outpatient phase ii study of subcutaneous interleukin-2 and interferon-alpha-2b in combination with intravenous vinblastine in metastatic renal cell cancer. Oncology 1998;55:10–15.
Lissoni P, Barni S, Ardizzola A, et al. A randomized study of low-dose interleukin-2 subcutaneous immunotherapy versus interleukin-2 plus interferon-alpha as first-line threapy for metastatic renal cell carcinoma. Tumori 1993;79:397–400.
Boccardo F, Rubagotti A, Canobbio L, et al. Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. a randomized phase II trial. Tumori 1998;84:534–539.
Lummen G, Goepel M, Mollhoff S, Hinke A, Otto T, Rubben H. Phase II study of interferon-gamma versus interleukin-2 and interferon-alpha2B in metastatic renal cell carcinoma. J Urol 1996;155:455–458.
Hofmockel G, Langer W, Theiss M, Gruss A, Frohmuller H. Immunochemotheapy for metastatic renal cell carcinoma using a regimen of interleukin-2, interferon-alpha, and 5-fluorouracil. J Urol 1996;156:18–21.
Clark J, Kuzel T, Lsetingi T, et al. A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon alpha-2b in advanced renal cell carcinoma: Major durable responses in a less highly selected patient population. Ann Oncol 2002;13:606–613.
Atzpodien J, Kuchler T, Wandert T, Reitz M. Rapid deterioration in quality of life during interleukin-2 and alpha-interferon-based home therapy of renal cell carcinoma is assocaited with a good outcome. Br J Cancer 2003;89:50–54.
Tourani J-M, Pfister C, Tubiana N, et al. Subcutaneous interleukin-2 and interferon alfa administration in patients with metastatic renal cell carcinoma: Final results of SCAPP III, a large, multicenter, phase II, nonrandomized study with sequential analysis design—The subcutaneous administration propeukin Program Cooperative Group. J Clin Oncol 2003;21(21):3987–3994.
Rathmell W, Malkowicz S, Holroyde C, Luginbuhl W, Vaughn D. Phase II trial of 5-fluorouracil and leucovorin in combination with interferon-alpha and interleukin-2 for advanced renal cell cancer. Am J Clin Oncol 2004;27:109–112.
Ravaud A, Trufflandier N, Ferriere J, et al. Subcutaneous interleukin-2, interferon-alpha-2b and 5-fluorouracil in metastatic renal cell carcinoma as second-line treatment after failure of previous immunotherapy: A phase II trial. Br J Cancer 2003;89:2213–2218.
Neri B, Doni L, Gemelli M, et al. Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer. J Urol 2002;168: 956–958.
Atzpodien J, Kirchner H, Illiger H, et al. IL-2 in combination with IFN-alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: Long-term results of a controlled randomized clinical trial. Br J Cancer 2001; 85(8): 1130–1136.
Clark J, Gaynor E, Martone B, et al. Daily subcutaneous ultra-low-dose interleukin 2 with daily lowdose interferon-alpha in patients with advanced renal cell carcinoma. Clin Cancer Res 1999; 5:2374–2380.
Dutcher J, Logan T, Gordon M, et al. Phase II trial of interleukin-2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: A cytokine working group study. Clin Cancer Res 2000; 6:3442–3450.
Allen M, Vaughan M, Webb A, et al. Protracted venous infusion 5-fluorouracil in combination with subcutaneous interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer. Br J Cancer 2000;83(8):980–985.
Negrier S, Caty A, Lesimple T, et al. Treatment of patients with metastatic renal cell carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil. J Clin Oncol 2000;18(24):4009–4015.
van Herpen C, Jansen R, Kruit W, et al. Immunochemotherapy with interleukin-2, interferon-alpha and 5-fluorouracil for progressive metastatic renal cell carcinoma: A multicenter phase II study. Br J Cancer 2000;82(4):772–776.
Atzpodien J, Kirchner H, Hanninen E, Deckert M, Fenner M, Poliwada H. Interleukin-2 in combination with interferon-alpha and 5-fluorouracil for metastatic renal cell cancer. Eur J Cancer 1993;29A:S6–S8.
Whitehead R, Figlin R, Citron M, et al. A phase II trial of concomitant human interleukin-2 and interferon-alpha-2a in patients with disseminated malignant melanoma. J Immunother 1993;13:117–121.
Richards J, Mehta N, Ramming K, Skosey P. Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol 1992;10(8):1338–1343.
Khayat D, Borel C, Tourani J-M, et al. Sequential chemoimmunotherapy with cisplatin, interleukin-2, and interferon alfa-2a for metastatic melanoma. J Clin Oncol 1993;11(11):2173–2180.
Keilholz U, Scheibenbogen C, Tilgen W, et al. Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Cancer 1993;72:607–614.
Kruit W, Goey S, Calabresi F, et al. Final report of a phase II study of interleukin 2 and interferon alpha with metastatic melanoma. Br J Cancer 1995;71:1319–1321.
Eton O, Talpaz M, Lee K, Rothberg J, Brell J, Benjamin R. Phase II trial of recombinant human interleukin-2 and interferon-alpha-2a. Cancer 1995;77:893–899.
Atzpodien J, Hanninen E, Kirchner H, et al. Chemoimmunotherapy of advanced malignant melanoma: Sequential administration of subcutaneous interleukin-2 and interferon-alpha after intravenous dacarbazine and carboplatinor intravenous dacarbazine, cisplatin, carmustine, and tamoxifen. Eur J Cancer 1995;31A(6):876–881.
Proebstle T, Scheibenbogen C, Sterry W, Keilholz U. A phase ii study of dacarbazine, cisplatin, interferon-alpha and high-dose interleukin-2 in ‘poor-risk’ metastatic melanoma. Eur J Cancer 1996;32A(9): 1530–1533.
Legha S, Ring S, Bedikian A, et al. Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol 1996;7(8):827–835.
Eton O, Buzaid A, Bedikian A, et al. A phase II study of “decrescendo” interleukin-2 plus interferonalpha-2a in patients with progressive metastatic melanoma after chemotherapy. Cancer 1999;88: 1703–1709.
Richards J, Gale D, Mehta N, Lestigni T. Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 1999;17(2):651–657.
McDermott D, Mier J, Lawrence D, et al. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res 2000;6:2201–2208.
Flaherty L, Atkins M, Sosman J, et al. Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: Results of two phase II cytokine working group trials. J Clin Oncol 2001;19(13):3194–3202.
Donskov F, von der Maase H, Henriksson R, et al. Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma: Results of an open single-armed multicentre phase II study. Ann Oncol 2002; 13:441–449.
Schmidt H, Larsen S, Bastholt L, Fode K, Rytter C, von der Maase H. A phase II study of outpatient subcutaneous histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma. Ann Oncol 2002;13:1919–1924.
Hauschild A, Weichenthal M, Balda B, et al. Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for resected intermediate-and high-risk primary melanoma without clinically detectable node metastasis. J Clin Oncol 2003;21(15):2883–2888.
Atkins M, Gollob J, Sosman J, et al. 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 2002;8:3075–3081.
Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. New Engl J Med 1998;338:1272–1278.
Sparano J, Fisher R, Sunderland M, et al. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 1993;11(10):1969–1977.
Rosenberg SA, Yang J, Schwartzentruber J, et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999;17(3):968–975.
Hauschild A, Garbe C, Stolz W, et al. Dacarbazine and interferon-alpha with or without interleukin-2 in metastatic melanoma: A randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 2001;84(8):1036–1042.
Atzpodien J, Neuber K, Kamanabrou D, et al. Combination chemotherapy with or without s.c. IL-2 and IFN-alpha: Results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM). Br J Cancer 2002;86:179–184.
Dorval T, Negrier S, Chevreau C, et al. Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: A Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study. Cancer 1998;85:1060–1066.
Ridolfi R, Chiarion-Sileni V, Guida M, et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: Results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol 2002;20(6): 1600–1607.
Tummarello D, Graziano F, Isidori P, et al. Consolidation biochemotherapy for patients with advanced nonsmall cell lung carcinoma responding to induction PVM (cisplatin, vinblastine, mitomycin-C) regimen. A phase II study. Cancer 1996;77:2251–2257.
Jansen R, Slingerland R, Hoo Goey S, Franks C, Bolhuis R, Stoter G. Interleukin-2 and interferonalpha in the treatment of patients with advanced non-small-cell lung cancer. J Immunother 1992; 12: 70–73.
Atzpodien J, Kirchner H, Hanninen E, et al. Treatment of metastatic colorectal cancer patients with 5-fluorouracil in combination with recombinant subcutaneous human interleukin-2 and alpha-interferon. Oncology 1994;51:273–275.
Chang A, Cameron M, Sondak V, Geiger J, Van der Woude D. A phase II trial of interleukin-2 and interferon-alpha in the treatment of metastatic colorectal carcinoma. J Immunother 1996;18(4): 253–262.
Walters R, Theriault R, Holmes F, Esparza L, Hortobagyi G. Phase II study of recombinant alphainterferon and recombinant interleukin-2 metastatic breast cancer. J Immunother 1994;16:303–305.
Kimmick G, Ratain M, Berry D, Woolf S, Norton L, Muss H. Subcutaneously administered recombinant human interleukin-2 and interferon alfa-2a for advanced breast cancer: A phase II study of the Cancer and Leukemia Group B (CALGB 9041). Invest New Drugs 2004;22:83–89.
Urba S, Forastiere A, Wolf G, Amrein P. Intensive recombinant interleukin-2 and alpha-interferon therapy in patients with advanced head and neck squamous carcinoma. Cancer 1993;71:2326–2331.
Eskander E, Harvey H, Givant E, Lipton A. Phase I study combining tumor necrosis factor with interferon-alpha and interleukin-2. Am J Clin Oncol 1997;20(5):511–514.
Itoh K, Shiiba K. Generation of activated killer (AK) cells by recombinant interleukin-2 (rIL-2) in collaboration with interferon-gamma (IFN-gamma). J Immunol 1985;134:3124–3129.
Weiner L, Padavic-Schaller K, Kitson J, Watts P, Krigel R, Litwin S. Phase I evaluation of combination therapy with interleukin-2 and gamma-interferon. Cancer Res 1991;51:3910–3918.
Taylor C, Chase E, Whitehead R, et al. A Southwest Oncology Group phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. J Immunother 1992;11:176–183.
Margolin K, Doroshow J, Akman S, et al. Phase I study of interleukin-2 plus interferon-gamma. J Immunother 1992; 11:50–55.
Baars J, Wagstaff J, Boven E, et al. Phase I study on the sequential administration of recombinant human interferon-gamma and recombinant human interleukin-2 in patients with metastatic solid tumors. J Natl Cancer Inst 1991; 83(19): 1408–1410.
Reddy S, Harwood R, Moore D, Grimm E, Murray J, Vadhan-Raj S. Recombinant interleukin-2 in combination with recombinant interferon-gamma in patients with advanced malignancy: A phase I study. J Immunother 1997;20(1):79–87.
Escudier B, Farace F, Angevin E, et al. Combination of interleukin-2 and gamma-interferon in metastatic renal cell carcinoma. Eur J Cancer 1993;29A(5):724–728.
Schmidinger M, Steger G, Wenzel C, et al. Sequential administration of interferon-gamma and interleukin-2 in metastatic renal cell carcinoma: Results of a phase II trial. Cancer Immunol Immunother 2000;49:395–400.
Schmidinger M, Steger G, Wenzel C, et al. Sequential administration of interferon-gamma, gm-csf, and interleukin-2 in patients with metastatic renal cell carcinoma: Results of a phase II trial. J Immunother 2001;24(3):257–262.
de Gast G, Klumpen H, Vyth-Dreese F, et al. Phase I Trial of combined immunotherapy with subcutaneous granulocyte macrophage colony-stimulating factor, low-dose interleukin 2, and interferon alpha in progressive metastatic melanoma and renal cell carcinoma. Clin Cancer Res 2000;6: 1267–1272.
Westermann J, Reich G, Kopp J, Haus U, Dorken B, Pezzutto A. Granulocyte/macrophage-colonystimulating-factor plus interleukin-2 plus interferon-alpha in the treatment of metastatic renal cell carcinoma: A pilot study. Cancer Immunol Immunother 2001;49:613–620.
Verra N, Jansen R, Groenewegen G, et al. Immunotherapy with concurrent subcutaneous GM-CSF, low-dose IL2 and IFN-alpha in patients with progressive metastatic renal cell carcinoma. Br J Cancer 2003;88:1346–1351.
Vaughan M, Moore J, Riches P, et al. GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): A phase I trial in melanoma. Annals of Oncology 2000; 11:1183–1189.
Groenewegen G, Bloem A, de Gast G. Phase I/II study of sequential chemoimmunotherapy (SCIT) for metastatic melanoma: Outpatient treatment with dacarbazine, granulocyte-macrophage colonystimulating factor, low-dose interleukin-2, and interferon-alpha. Cancer Immunol Immunother 2002;51:630–636.
Takeda K, Tsutsui H, Yoshimoto T, et al. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 1998;8(3):383–390.
Moroz A, Eppolito C, Li Q, Tao J, Clegg C, Shrikant P. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: Comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 2004;173(2):900–909.
Maruyama S, Yagita A, Sukegawa Y Significance of gefitinib combined with immunotherapy in tumor-bearing mice (in Japanese). Gan To Kagaku Ryoho 2003;30(11):1773–1775.
Rini B, Halabi S, Taylor J, Small E, RL S. Cancer and Leukemia Group B 90206: A randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma. Clin Cancer Res 2004;10(8):2584–2586.
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Cohen, S.M., Kaufman, H.L. (2007). Combination Cytokine Therapy. In: Caligiuri, M.A., Lotze, M.T. (eds) Cytokines in the Genesis and Treatment of Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-455-1_20
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