Abstract
Treatment of advanced stage melanoma has recently undergone a revolutionary change. Prior to 2011 dacarbazine and interleukin-2 were the only treatment options with both demonstrating no impact on overall survival. However, the experience with and results with IL-2 therapy have stimulated development of novel immunotherapies in this disease. IL-2 was the first immunotherapy to be approved for patients with metastatic melanoma and produced durable complete remissions in about 6% of patients. The accompanying toxicity, however, limited the widespread use of IL-2 therapy. In contrast, interferon-alpha despite its important role in the adjuvant setting, never showed a significant response rate or any survival benefit in patients with stage IV disease.
Currently, due to the highly successful revival of immunotherapy with the development of immune checkpoint inhibitors targeting CTLA4 and PD1 on T-lymphocytes, the exploration of cytokines such as IL-2, IFN-a and others, now in conjunction with immune checkpoint inhibition or adoptive cell therapy has been rejuvenated in this disease.
This chapter summarizes the development and use of cytokines as single agents or in combination in the treatment of patients with advanced metastatic melanoma.
This is a preview of subscription content, log in via an institution.
References
Agarwala SS, Glaspy J, O’day SJ, Mitchell M, Gutheil J, Whitman E, Gonzalez R, Hersh E, Feun L, Belt R, Meyskens F, Hellstrand K, Wood D, Kirkwood JM, Gehlsen KR, Naredi P (2002) Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol 20:125–133
Ahmed FY, Leonard GA, A’hern R, Taylor AE, Lorentzos A, Atkinson H, Moore J, Nicolson MC, Riches PG, Gore ME (1996) A randomised dose escalation study of subcutaneous interleukin 2 with and without levamisole in patients with metastatic renal cell carcinoma or malignant melanoma. Br J Cancer 74:1109–1113
Alatrash G, Hutson TE, Molto L, Richmond A, Nemec C, Mekhail T, Elson P, Tannenbaum C, Olencki T, Finke J, Bukowski RM (2004) Clinical and immunologic effects of subcutaneously administered interleukin-12 and interferon alfa-2b: phase I trial of patients with metastatic renal cell carcinoma or malignant melanoma. J Clin Oncol 22:2891–2900
Albertini MR, Gan J, Jaeger P, Hank JA, Storer B, Schell K, Rivest T, Surfus J, Reisfeld RA, Schiller JH, Sondel PM (1996) Systemic interleukin-2 modulates the anti-idiotypic response to chimeric anti-GD2 antibody in patients with melanoma. J Immunother Emphasis Tumor Immunol 19:278–295
Albertini MR, Hank JA, Schiller JH, Khorsand M, Borchert AA, Gan J, Bechhofer R, Storer B, Reisfeld RA, Sondel PM (1997) Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients. Clin Cancer Res 3:1277–1288
Allegretta M, Atkins MB, Dempsey RA, Bradley EC, Konrad MW, Childs A, Wolfe SN, Mier JW (1986) The development of anti-interleukin-2 antibodies in patients treated with recombinant human interleukin-2 (IL-2). J Clin Immunol 6:481–490
Alpaugh RK, Von Mehren M, Palazzo I, Atkins MB, Sparano JA, Schuchter L, Weiner LM, Dutcher JP (1998) Phase IB trial for malignant melanoma using R24 monoclonal antibody, interleukin-2/alpha-interferon. Med Oncol 15:191–198
Alva A, Daniels GA, Wong MK, Kaufman HL, Morse MA, Mcdermott DF, Clark JI, Agarwala SS, Miletello G, Logan TF, Hauke RJ, Curti B, Kirkwood JM, Gonzalez R, Amin A, Fishman M, Agarwal N, Lowder JN, Hua H, Aung S, Dutcher JP (2016) Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunol Immunother 65:1533–1544
Angevin E, Valteau-Couanet D, Farace F, Dietrich PY, Lecesne A, Triebel F, Escudier B (1995) Phase I study of prolonged low-dose subcutaneous recombinant interleukin-2 (IL-2) in patients with advanced cancer. J Immunother Emphasis Tumor Immunol 18:188–195
Atkins MB, Gould JA, Allegretta M, Li JJ, Dempsey RA, Rudders RA, Parkinson DR, Reichlin S, Mier JW (1986) Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Clin Oncol 4:1380–1391
Atkins MB, Robertson MJ, Gordon M, Lotze MT, Decoste M, Dubois JS, Ritz J, Sandler AB, Edington HD, Garzone PD, Mier JW, Canning CM, Battiato L, Tahara H, Sherman ML (1997) Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3:409–417
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116
Atkins MB, Kunkel L, Sznol M, Rosenberg SA (2000) High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6(Suppl 1):S11–S14
Atkins MB, Redman B, Mier J, Gollob J, Weber J, Sosman J, Macpherson BL, Plasse T (2001) A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma. Clin Cancer Res 7:486–492
Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM, Eastern Cooperative Oncology, G (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
Atkins MB, Hodi FS, Thompson JA, Mcdermott DF, Hwu WJ, Lawrence DP, Dawson NA, Wong DJ, Bhatia S, James M, Jain L, Robey S, Shu X, Homet Moreno B, Perini RF, Choueiri TK, Ribas A (2018) Pembrolizumab plus pegylated interferon alfa-2b or ipilimumab for advanced melanoma or renal cell carcinoma: dose-finding results from the phase Ib KEYNOTE-029 study. Clin Cancer Res 24:1805–1815
Atzpodien J, Korfer A, Evers P, Franks CR, Knuver-Hopf J, Lopez-Hanninen E, Fischer M, Mohr H, Dallmann I, Hadam M et al (1990a) Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study. Mol Biother 2:18–26
Atzpodien J, Korfer A, Franks CR, Poliwoda H, Kirchner H (1990b) Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies. Lancet 335:1509–1512
Bajetta E, Del Vecchio M, Mortarini R, Nadeau R, Rakhit A, Rimassa L, Fowst C, Borri A, Anichini A, Parmiani G (1998) Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. Clin Cancer Res 4:75–85
Bajorin DF, Chapman PB, Wong G, Coit DG, Kunicka J, Dimaggio J, Cordon-Cardo C, Urmacher C, Dantes L, Templeton MA et al (1990) Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma. Cancer Res 50:7490–7495
Bergmann L, Weidmann E, Mitrou PS, Runne U, Keilholz U, Bartsch HH, Franks CR (1990) Interleukin-2 in combination with interferon-alpha in disseminated malignant melanoma and advanced renal cell carcinoma. A phase I/II study. Onkologie 13:137–140
Bernatchez CH, Haymaker CL, Hurwitz ME, Kluger HM, Tetzlaff MT, Jackson N, Gergel I, Tagliaferri MA, Zalevsky J, Hoch U, Fanton C, Iacucci E, Aung S, Imperiale M, Liao E, Bentebibel SE, Tannir NM, Hwu P, Sznol M, Diab A (2017) Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy. J Clin Oncol 35(suppl; abstr 2545)
Bindon C, Czerniecki M, Ruell P, Edwards A, Mccarthy WH, Harris R, Hersey P (1983) Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer 47:123–133
Boldt DH, Mills BJ, Gemlo BT, Holden H, Mier J, Paietta E, Mcmannis JD, Escobedo LV, Sniecinski I, Rayner AA et al (1988) Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Res 48:4409–4416
Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, Ferrone CR, Flaherty KT, Lawrence DP, Fisher DE, Tsao H, Wargo JA (2010) Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 70:5213–5219
Buchbinder EI, Gunturi A, Perritt J, Dutcher J, Aung S, Kaufman HL, Ernstoff MS, Miletello GP, Curti BD, Daniels GA, Patel SP, Kirkwood JM, Hallmeyer S, Clark JI, Gonzalez R, Richart JM, Lutzky J, Morse MA, Sullivan RJ, Mcdermott DF (2016) A retrospective analysis of high-dose interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma. J Immunother Cancer 4:52
Budd GT, Murthy S, Finke J, Sergi J, Gibson V, Medendorp S, Barna B, Boyett J, Bukowski RM (1992) Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy. J Clin Oncol 10:804–809
Bukowski RM, Murthy S, Sergi J, Budd GT, Mckeever S, Medendorp SV, Tubbs R, Gibson V, Finke J (1990) Phase I trial of continuous infusion recombinant interleukin-2 and intermittent recombinant interferon-alpha 2a: clinical effects. J Biol Response Mod 9: 538–545
Buter J, Janssen RA, Martens A, Sleijfer DT, De Leij L, Mulder NH (1993) Phase I/II study of low-dose intravenous OKT3 and subcutaneous interleukin-2 in metastatic cancer. Eur J Cancer 29A:2108–2113
Caligiuri MA, Murray C, Soiffer RJ, Klumpp TR, Seiden M, Cochran K, Cameron C, Ish C, Buchanan L, Perillo D et al (1991) Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity. J Clin Oncol 9:2110–2119
Castello G, Comella P, Manzo T, Napolitano M, Parziale AP, Galati MG, Daponte A, Casaretti R, Celentano E, Comella G (1993) Immunological and clinical effects of intramuscular rIFN alpha-2a and low dose subcutaneous rIL-2 in patients with advanced malignant melanoma. Melanoma Res 3:43–49
Cesana GC, Deraffele G, Cohen S, Moroziewicz D, Mitcham J, Stoutenburg J, Cheung K, Hesdorffer C, Kim-Schulze S, Kaufman HL (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
Chang E, Rosenberg SA (2001) Patients with melanoma metastases at cutaneous and subcutaneous sites are highly susceptible to interleukin-2-based therapy. J Immunother 24:88–90
Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, Sheng D, Liu X, Sims PW, Vanderveen LA, Ali CF, Chang TK, Konakova M, Pena RL, Kanhere RS, Kirksey YM, Ji C, Wang Y, Huang J, Sweeney TD, Kantak SS, Doberstein SK (2016) NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res 22:680–690
Charych D, Khalili S, Dixit V, Kirk P, Chang T, Langowski J, Rubas W, Doberstein SK, Eldon M, Hoch U, Zalevsky J (2017) Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One 12:e0179431
Choi BS, Sondel PM, Hank JA, Schalch H, Gan J, King DM, Kendra K, Mahvi D, Lee LY, Kim K, Albertini MR (2006) Phase I trial of combined treatment with ch14.18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma. Cancer Immunol Immunother 55:761–774
Cohen PJ, Lotze MT, Roberts JR, Rosenberg SA, Jaffe ES (1987) The immunopathology of sequential tumor biopsies in patients treated with interleukin-2. Correlation of response with T-cell infiltration and HLA-DR expression. Am J Pathol 129:208–216
Cole DJ, Sanda MG, Yang JC, Schwartzentruber DJ, Weber J, Ettinghausen SE, Pockaj BA, Kim HI, Levin RD, Pogrebniak HW et al (1994) Phase I trial of recombinant human macrophage colony-stimulating factor administered by continuous intravenous infusion in patients with metastatic cancer. J Natl Cancer Inst 86:39–45
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM, Goldman CK, Bryant BR, Decker JM, Chen J, Worthy TA, Figg WD Sr, Peer CJ, Sneller MC, Lane HC, Yovandich JL, Creekmore SP, Roederer M, Waldmann TA (2015) Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol 33:74–82
Cooper ZA, Frederick DT, Juneja VR, Sullivan RJ, Lawrence DP, Piris A, Sharpe AH, Fisher DE, Flaherty KT, Wargo JA (2013) BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology 2:e26615
Cormier JN, Hurst R, Vasselli J, Lee D, Kim CJ, Mckee M, Venzon D, White D, Marincola FM, Rosenberg SA (1997) A prospective randomized evaluation of the prophylactic use of low-dose dopamine in cancer patients receiving interleukin-2. J Immunother 20: 292–300
Creagan ET, Rowland KM Jr, Suman VJ, Kardinal CG, Marschke RF Jr, Marks RS, Maples WJ (1997) Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma. Am J Clin Oncol 20:490–492
Creekmore SP, Harris JE, Ellis TM, Braun DP, Cohen II, Bhoopalam N, Jassak PF, Cahill MA, Canzoneri CL, Fisher RI (1989) A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. J Clin Oncol 7:276–284
Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, Skak K, Lundsgaard D, Frederiksen KS, Thygesen P, Mcarthur GA (2007) An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 13:3630–3636
De Braud F, Biganzoli L, Bajetta E, Colleoni M, Zampino MG (1993) Subcutaneous low-dose interleukin-2 plus alpha interferon in advanced malignant melanoma. Tumori 79:187–190
Diab A, Tannir NM, Bernatchez C, Haymaker CL, Bentebibel SE, Curti BD, Wong MK, Gergel I, Tagliaferri MA, Zalevsky J, Hoch U, Aung S, Imperiale M, Cho DC, Tykodi SS, Puzanov I, Kluger HM, Hurwitz ME, Hwu P, Sznol MA (2017) Phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors. ASCO Annual Meeting, Chicago. J Clin Oncol 35(suppl; abstr e14040)
Diab A, Hurwitz ME, Cho DC, Papadimitrakopoulou V, Curti BD, Tykodi SS, Puzanov I, Ibrahim NK, Tolaney SM, Tripathy D, Gao J, Siefker-Radtke AO, Clemens W, Tagliaferri MA, Gettinger SN, Kluger HM, Larkin JM, Grignani G, Sznol M, Tannir NM (2018) NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. ASCO Annual Meeting, Chicago. J Clin Oncol 36(suppl; abstr 3006)
Dillman RO, Church C, Oldham RK, West WH, Schwartzberg L, Birch R (1993) Inpatient continuous-infusion interleukin-2 in 788 patients with cancer. The National Biotherapy Study Group experience. Cancer 71:2358–2370
Dillman RO, Wiemann MC, Vandermolen LA, Bury MJ, Depriest C, Church C (1997) Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic melanoma: a phase II trial of the Cancer Biotherapy Research Group (formerly the National Biotherapy Study Group). Cancer Biother Radiopharm 12:249–255
Dorval T, Mathiot C, Chosidow O, Revuz J, Avril MF, Guillaume JC, Tursz T, Brandely M, Pouillart P, Fridman WH (1992) IL-2 phase II trial in metastatic melanoma: analysis of clinical and immunological parameters. Biotechnol Ther 3:63–79
Doyle MV, Lee MT, Fong S (1985) Comparison of the biological activities of human recombinant interleukin-2(125) and native interleukin-2. J Biol Response Mod 4:96–109
Du Bois JS, Trehu EG, Mier JW, Shapiro L, Epstein M, Klempner M, Dinarello C, Kappler K, Ronayne L, Rand W, Atkins MB (1997) Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma. J Clin Oncol 15:1052–1062
Engelhardt M, Wirth K, Mertelsmann R, Lindemann A, Brennscheidt U (1997) Clinical and immunomodulatory effects of repetitive 2-day cycles of high-dose continuous infusion IL-2. Eur J Cancer 33:1050–1054
Enk AH, Nashan D, Rubben A, Knop J (2000) High dose inhalation interleukin-2 therapy for lung metastases in patients with malignant melanoma. Cancer 88: 2042–2046
Eton O, Talpaz M, Lee KH, Rothberg JM, Brell JM, Benjamin RS (1996) Phase II trial of recombinant human interleukin-2 and interferon-alpha-2a: implications for the treatment of patients with metastatic melanoma. Cancer 77:893–899
Eton O, Buzaid AC, Bedikian AY, Smith TM, Papadopoulos NE, Ellerhorst JA, Hibberts JL, Legha SS, Benjamin RS (2000) A phase II study of “decrescendo” interleukin-2 plus interferon-alpha-2a in patients with progressive metastatic melanoma after chemotherapy. Cancer 88:1703–1709
Ettinghausen SE, Moore JG, White DE, Platanias L, Young NS, Rosenberg SA (1987) Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2 in cancer patients. Blood 69:1654–1660
Flaherty KT, Puzanov I, Kim KB, Ribas A, Mcarthur GA, Sosman JA, O’dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363: 809–819
Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP, Liu C, Peng W, Sullivan RJ, Lawrence DP, Hodi FS, Overwijk WW, Lizee G, Murphy GF, Hwu P, Flaherty KT, Fisher DE, Wargo JA (2013) BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 19:1225–1231
Fyfe GA, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC (1996) Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol 14:2410–2411
Galvani DW, Walton S, Davies JM, Owen RR, Carr R, Cawley JC, Sells RA (1992) Endolymphatic delivery of IL2 in patients with melanoma and lymphoma. Biotherapy 4:251–255
Gause BL, Sznol M, Kopp WC, Janik JE, Smith JW 2nd, Steis RG, Urba WJ, Sharfman W, Fenton RG, Creekmore SP, Holmlund J, Conlon KC, Vandermolen LA, Longo DL (1996) Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer. J Clin Oncol 14:2234–2241
Gemlo BT, Palladino MA Jr, Jaffe HS, Espevik TP, Rayner AA (1988) Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin 2 and lymphokine-activated killer cells. Cancer Res 48:5864–5867
Goldstein D, Sosman JA, Hank JA, Weil-Hillman G, Moore KH, Borchert A, Bechhofer R, Storer B, Kohler PC, Levitt D et al (1989) Repetitive weekly cycles of interleukin 2: effect of outpatient treatment with a lower dose of interleukin 2 on non-major histocompatibility complex-restricted killer activity. Cancer Res 49:6832–6839
Gollob JA, Mier JW, Veenstra K, Mcdermott DF, Clancy D, Clancy M, Atkins MB (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
Gollob JA, Veenstra KG, Parker RA, Mier JW, Mcdermott DF, Clancy D, Tutin L, Koon H, Atkins MB (2003) Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma. J Clin Oncol 21:2564–2573
Gratama JW, Bruin RJ, Lamers CH, Oosterom R, Braakman E, Stoter G, Bolhuis RL (1993) Activation of the immune system of cancer patients by continuous i.v. recombinant IL-2 (rIL-2) therapy is dependent on dose and schedule of rIL-2. Clin Exp Immunol 92:185–193
Green DS, Bodman-Smith MD, Dalgleish AG, Fischer MD (2007) Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol 156:337–345
Gustavson LE, Nadeau RW, Oldfield NF (1989) Pharmacokinetics of teceleukin (recombinant human interleukin-2) after intravenous or subcutaneous administration to patients with cancer. J Biol Response Mod 8:440–449
Gutwald JG, Groth W, Mahrle G (1994) Peritumoral injections of interleukin 2 induce tumour regression in metastatic malignant melanoma. Br J Dermatol 130:541–542
Hank JA, Albertini M, Wesly OH, Schiller JH, Borchert A, Moore K, Bechhofer R, Storer B, Gan J, Gambacorti C et al (1995) Clinical and immunological effects of treatment with murine anti-CD3 monoclonal antibody along with interleukin 2 in patients with cancer. Clin Cancer Res 1:481–491
Heimans JJ, Wagstaff J, Schreuder WO, Wolbers JG, Baars JW, Polman CH, Scharenberg JG, Scheper RJ, Palmer PA, Franks CR (1991) Treatment of leptomeningeal carcinomatosis with continuous intraventricular infusion of recombinant interleukin-2. Surg Neurol 35:244–247
Hellstrand K, Naredi P, Lindner P, Lundholm K, Rudenstam CM, Hermodsson S, Asztely M, Hafstrom L (1994) Histamine in immunotherapy of advanced melanoma: a pilot study. Cancer Immunol Immunother 39:416–419
Hidalgo OF, Aramendia JM, Alonso G, Foncillas JG, Brugarolas A (1996) Results of two sequential phase II studies of interleukin-2 (IL2) in metastatic renal cell carcinoma and melanoma: high-dose continuous intravenous IL2 infusion and subcutaneous IL2 administration in combination with alpha interferon. Rev Med Univ Navarra 40:6–12
Hodi FS, O’day SJ, Mcdermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723
Holmund JT, Kopp WC, Wiltrout RH, Longo DL, Urba WJ, Janik JE, Sznol M, Conlon KC, Fenton RG, Hornung R et al (1995) A phase I clinical trial of flavone-8-acetic acid in combination with interleukin 2. J Natl Cancer Inst 87:134–136
Huberman M, Bering H, Fallon B, Tessitore J, Sonnenborn H, Paul S, Zeffren J, Levitt D, Groopman J (1991) A phase I study of an outpatient regimen of recombinant human interleukin-2 and alpha-2a-interferon in patients with solid tumors. Cancer 68: 1708–1713
Jablons DM, Mule JJ, Mcintosh JK, Sehgal PB, May LT, Huang CM, Rosenberg SA, Lotze MT (1989) IL-6/IFN-beta-2 as a circulating hormone. Induction by cytokine administration in humans. J Immunol 142: 1542–1547
Jablons D, Bolton E, Mertins S, Rubin M, Pizzo P, Rosenberg SA, Lotze MT (1990) IL-2-based immunotherapy alters circulating neutrophil Fc receptor expression and chemotaxis. J Immunol 144:3630–3636
Joseph RW, Eckel-Passow JE, Sharma R, Liu P, Parker A, Jakob J, Buchbinder E, Bassett RL, Davies MA, Hwu P, Atkins MB, Sullivan RJ (2012a) Characterizing the clinical benefit of ipilimumab in patients who progressed on high-dose IL-2. J Immunother 35:711–715
Joseph RW, Sullivan RJ, Harrell R, Stemke-Hale K, Panka D, Manoukian G, Percy A, Bassett RL, Ng CS, Radvanyi L, Hwu P, Atkins MB, Davies MA (2012b) Correlation of NRAS mutations with clinical response to high-dose IL-2 in patients with advanced melanoma. J Immunother 35:66–72
Kammula US, White DE, Rosenberg SA (1998) Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer 83: 797–805
Karp SE (1998) Low-dose intravenous bolus interleukin-2 with interferon-alpha therapy for metastatic melanoma and renal cell carcinoma. J Immunother 21:56–61
Keilholz U, Eggermont AM (2000) The role of interleukin-2 in the management of stage IV melanoma: the EORTC melanoma cooperative group program. Cancer J Sci Am 6(Suppl 1):S99–S103
Keilholz U, Scheibenbogen C, Tilgen W, Bergmann L, Weidmann E, Seither E, Richter M, Brado B, Mitrou PS, Hunstein W (1993) Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials. Cancer 72:607–614
Keilholz U, Goey SH, Punt CJ, Proebstle TM, Salzmann R, Scheibenbogen C, Schadendorf D, Lienard D, Enk A, Dummer R, Hantich B, Geueke AM, Eggermont AM (1997) Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 15:2579–2588
Kilbourn RG, Fonseca GA, Trissel LA, Griffith OW (2000) Strategies to reduce side effects of interleukin-2: evaluation of the antihypotensive agent NG-monomethyl-l-arginine. Cancer J Sci Am 6(Suppl 1):S21–S30
Kim CJ, Taubenberger JK, Simonis TB, White DE, Rosenberg SA, Marincola FM (1996) Combination therapy with interferon-gamma and interleukin-2 for the treatment of metastatic melanoma. J Immunother Emphasis Tumor Immunol 19:50–58
Klasa RJ, Silver HK, Kong S (1990) In vivo induction of lymphokine-activated killer cells by interleukin-2 splenic artery perfusion in advanced malignancy. Cancer Res 50:4906–4910
Klempner MS, Noring R, Mier JW, Atkins MB (1990) An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med 322:959–965
Konrad MW, Hemstreet G, Hersh EM, Mansell PW, Mertelsmann R, Kolitz JE, Bradley EC (1990) Pharmacokinetics of recombinant interleukin 2 in humans. Cancer Res 50:2009–2017
Konrad MW, Dewitt SK, Bradley EC, Goodman G, Groves EC, Hersh EM, Krigel RL, Rudolph A (1992) Interferon-gamma induced by administration of recombinant interleukin-2 to patients with cancer: kinetics, dose dependence, and correlation with physiological and therapeutic response. J Immunother (1991) 12: 55–63
Kradin RL, Kurnick JT, Preffer FI, Dubinett SM, Dickersin GR, Pinto C (1989) Adoptive immunotherapy with IL-2 results in the loss of delayed-type hypersensitivity responses and the development of immediate hypersensitivity to recall antigens. Clin Immunol Immunopathol 50:184–195
Kragel AH, Travis WD, Feinberg L, Pittaluga S, Striker LM, Roberts WC, Lotze MT, Yang JJ, Rosenberg SA (1990) Pathologic findings associated with interleukin-2-based immunotherapy for cancer: a postmortem study of 19 patients. Hum Pathol 21:493–502
Krigel RL, Padavic-Shaller KA, Rudolph AR, Litwin S, Konrad M, Bradley EC, Comis RL (1988) A phase I study of recombinant interleukin 2 plus recombinant beta-interferon. Cancer Res 48:3875–3881
Krigel RL, Padavic-Shaller K, Toomey C, Comis RL, Weiner LM (1995) Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2. J Immunother Emphasis Tumor Immunol 17:161–170
Krouse RS, Royal RE, Heywood G, Weintraub BD, White DE, Steinberg SM, Rosenberg SA, Schwartzentruber DJ (1995) Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Emphasis Tumor Immunol 18:272–278
Kruit WH, Goey SH, Calabresi F, Lindemann A, Stahel RA, Poliwoda H, Osterwalder B, Stoter G (1995) Final report of a phase II study of interleukin 2 and interferon alpha in patients with metastatic melanoma. Br J Cancer 71:1319–1321
Kruit WH, Punt CJ, Goey SH, De Mulder PH, Gratama JW, Eggermont AM, Bolhuis RL, Stoter G (1996) Dose efficacy study of two schedules of high-dose bolus administration of interleukin 2 and interferon alpha in metastatic melanoma. Br J Cancer 74:951–955
Lange JR, Raubitschek AA, Pockaj BA, Spencer WF, Lotze MT, Topalian SL, Yang JC, Rosenberg SA (1992) A pilot study of the combination of interleukin-2-based immunotherapy and radiation therapy. J Immunother (1991) 12:265–271
Leahy MG, Pitfield D, Popert S, Gallagher CJ, Oliver RT (1992) Phase I study comparing continuous infusion of recombinant interleukin-2 by subcutaneous or intravenous administration. Eur J Cancer 28A:1049–1051
Lee KH, Talpaz M, Rothberg JM, Murray JL, Papadopoulos N, Plager C, Benjamin R, Levitt D, Gutterman J (1989) Concomitant administration of recombinant human interleukin-2 and recombinant interferon alpha-2A in cancer patients: a phase I study. J Clin Oncol 7:1726–1732
Lee DS, White DE, Hurst R, Rosenberg SA, Yang JC (1998) Patterns of relapse and response to retreatment in patients with metastatic melanoma or renal cell carcinoma who responded to interleukin-2-based immunotherapy. Cancer J Sci Am 4:86–93
Legha SS, Gianan MA, Plager C, Eton OE, Papadopoulous NE (1996) Evaluation of interleukin-2 administered by continuous infusion in patients with metastatic melanoma. Cancer 77:89–96
Lindemann A, Hoeffken K, Schmidt RE, Diehl V, Kloke O, Gamm H, Hayungs J, Oster W, Boehm M, Franks CR et al (1989) A multicenter trial of interleukin-2 and low-dose cyclophosphamide in highly chemotherapy-resistant malignancies. Cancer Treat Rev 16(Suppl A): 53–57
Lindner P, Rizell M, Mattsson J, Hellstrand K, Naredi P (2004) Combined treatment with histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma. Anticancer Res 24:1837–1842
Lindsey KR, Rosenberg SA, Sherry RM (2000) Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2. J Clin Oncol 18:1954–1959
Lissoni P, Barni S, Cazzaniga M, Ardizzoia A, Rovelli F, Brivio F, Tancini G (1994) Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone. Oncology 51:344–347
Lissoni P, Fumagalli L, Paolorossi F, Rovelli F, Roselli MG, Maestroni GJ (1997) Anticancer neuroimmunomodulation by pineal hormones other than melatonin: preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin. J Biol Regul Homeost Agents 11:119–122
List J, Moser RP, Steuer M, Loudon WG, Blacklock JB, Grimm EA (1992) Cytokine responses to intraventricular injection of interleukin 2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and soluble interleukin 2 receptor (Mr 55,000 protein). Cancer Res 52: 1123–1128
Lotze MT, Robb RJ, Sharrow SO, Frana LW, Rosenberg SA (1984) Systemic administration of interleukin-2 in humans. J Biol Response Mod 3: 475–482
Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CA, Custer MC, Rosenberg SA (1985) In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 135:2865–2875
Lotze MT, Custer MC, Rosenberg SA (1986a) Intraperitoneal administration of interleukin-2 in patients with cancer. Arch Surg 121:1373–1379
Lotze MT, Matory YL, Rayner AA, Ettinghausen SE, Vetto JT, Seipp CA, Rosenberg SA (1986b) Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer 58:2764–2772
Lotze MT, Custer MC, Sharrow SO, Rubin LA, Nelson DL, Rosenberg SA (1987) In vivo administration of purified human interleukin-2 to patients with cancer: development of interleukin-2 receptor positive cells and circulating soluble interleukin-2 receptors following interleukin-2 administration. Cancer Res 47:2188–2195
Macfarlane MP, Yang JC, Guleria AS, White RL Jr, Seipp CA, Einhorn JH, White DE, Rosenberg SA (1995) The hematologic toxicity of interleukin-2 in patients with metastatic melanoma and renal cell carcinoma. Cancer 75:1030–1037
Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA (2005) Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 12:1005–1016
Margolin KA, Doroshow JH, Akman SA, Leong LA, Morgan RJ, Raschko J, Somlo G, Mills B, Goldberg D, Sniecinski I (1992) Phase I trial of interleukin-2 plus gamma-interferon. J Immunother (1991) 11:50–55
Margolin K, Aronson FR, Sznol M, Atkins MB, Gucalp R, Fisher RI, Sunderland M, Doroshow JH, Ernest ML, Mier JW et al (1994) Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma. J Immunother Emphasis Tumor Immunol 15:147–153
Margolin K, Atkins M, Sparano J, Sosman J, Weiss G, Lotze M, Doroshow J, Mier J, O’boyle K, Fisher R, Campbell E, Rubin J, Federighi D, Bursten S (1997) Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma. Clin Cancer Res 3:565–572
Marincola FM, Shamamian P, Rivoltini L, Salgaller M, Cormier J, Restifo NP, Simonis TB, Venzon D, White DE, Parkinson DR (1995a) HLA associations in the antitumor response against malignant melanoma. J Immunother Emphasis Tumor Immunol 18:242–252
Marincola FM, White DE, Wise AP, Rosenberg SA (1995b) Combination therapy with interferon alfa-2a and interleukin-2 for the treatment of metastatic cancer. J Clin Oncol 13:1110–1122
Marolda R, Belli F, Prada A, Villani F, Gambacorti-Passerini C, Galazka A, Parmiani G, Cascinelli N (1987) A phase I study of recombinant interleukin 2 in melanoma patients. Toxicity and clinical effects. Tumori 73:575–584
Marroquin CE, White DE, Steinberg SM, Rosenberg SA, Schwartzentruber DJ (2000) Decreased tolerance to interleukin-2 with repeated courses of therapy in patients with metastatic melanoma or renal cell cancer. J Immunother 23:387–392
Mavroukakis SA, Muehlbauer PM, White RL Jr, Schwartzentruber DJ (2001) Clinical pathways for managing patients receiving interleukin 2. Clin J Oncol Nurs 5:207–217
Maxwell W, Mcdevitt J, Reid I, Sharpe I, Feighery C, Tanner WA, Emmons R, Monson JR (1993) Changes in immunological parameters during interleukin 2 and interferon 2 alpha treatment of recurrent renal cell carcinoma and malignant melanoma. Eur J Surg Oncol 19:265–272
Mcdermott DF, Trehu EG, Mier JW, Sorce D, Rand W, Ronayne L, Kappler K, Clancy M, Klempner M, Atkins MB (1998) A two-part phase I trial of high-dose interleukin 2 in combination with soluble (Chinese hamster ovary) interleukin 1 receptor. Clin Cancer Res 4:1203–1213
Middleton M, Hauschild A, Thomson D, Anderson R, Burdette-Radoux S, Gehlsen K, Hellstrand K, Naredi P (2007) Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin-2, interferon-{alpha}2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma. Ann Oncol 18:1691–1697
Mier JW, Vachino G, Van Der Meer JW, Numerof RP, Adams S, Cannon JG, Bernheim HA, Atkins MB, Parkinson DR, Dinarello CA (1988) Induction of circulating tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients. J Clin Immunol 8:426–436
Mier JW, Vachino G, Klempner MS, Aronson FR, Noring R, Smith S, Brandon EP, Laird W, Atkins MB (1990) Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects. Blood 76:1933–1940
Mitchell MS, Kempf RA, Harel W, Shau H, Boswell WD, Lind S, Bradley EC (1988) Effectiveness and tolerability of low-dose cyclophosphamide and low-dose intravenous interleukin-2 in disseminated melanoma [corrected]. J Clin Oncol 6:409–424
Mittelman A, Huberman M, Puccio C, Fallon B, Tessitore J, Savona S, Eyre R, Gafney E, Wick M, Skelos A et al (1990) A phase I study of recombinant human interleukin-2 and alpha-interferon-2a in patients with renal cell cancer, colorectal cancer, and malignant melanoma. Cancer 66:664–669
Mooradian MJ, Reuben A, Prieto PA, Hazar-Rethinam M, Frederick DT, Nadres B, Piris A, Juneja V, Cooper ZA, Sharpe AH, Corcoran RB, Flaherty KT, Lawrence DP, Wargo JA, Sullivan RJ (2018) A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma. Oncoimmunology 7:e1423172
Morgan DA, Ruscetti FW, Gallo R (1976) Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193:1007–1008
Naing A, Papadopoulos KP, Autio KA, Ott PA, Patel MR, Wong DJ, Falchook GS, Pant S, Whiteside M, Rasco DR, Mumm JB, Chan IH, Bendell JC, Bauer TM, Colen RR, Hong DS, Van Vlasselaer P, Tannir NM, Oft M, Infante JR (2016) Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol 34:3562–3569
Nasi ML, Meyers M, Livingston PO, Houghton AN, Chapman PB (1997) Anti-melanoma effects of R24, a monoclonal antibody against GD3 ganglioside. Melanoma Res 7(Suppl 2):S155–S162
Negrier MS, Pourreau CN, Palmer PA, Ranchere JY, Mercatello A, Viens P, Blaise D, Jasmin C, Misset JL, Franks CR et al (1992) Phase I trial of recombinant interleukin-2 followed by recombinant tumor necrosis factor in patients with metastatic cancer. J Immunother (1991) 11:93–102
Nicholson S, Guile K, John J, Clarke IA, Diffley J, Donnellan P, Michael A, Szlosarek P, Dalgleish AG (2003) A randomized phase II trial of SRL172 (Mycobacterium vaccae) +/− low-dose interleukin-2 in the treatment of metastatic malignant melanoma. Melanoma Res 13:389–393
O’brien GC, Cahill RA, Bouchier-Hayes DJ, Redmond HP (2006) Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma. Ir J Med Sci 175:10–14
Ogilvie AC, Baars JW, Eerenberg AJ, Hack CE, Pinedo HM, Thijs LG, Wagstaff J (1994) A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2. Br J Cancer 69:596–598
Oldham RK, Stark J, Barth NM, Hoogstraten B, Brown CH, O’connor T, Dupere S, Birch R (1991) Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. Mol Biother 3:74–78
Oldham RK, Blumenschein G, Schwartzberg L, Birch R, Arnold J (1992) Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group Trial. Mol Biother 4:4–9
Olencki T, Finke J, Tubbs R, Tuason L, Greene T, Mclain D, Swanson SJ, Herzog P, Stanley J, Edinger M, Budd GT, Bukowski RM (1996) Immunomodulatory effects of interleukin-2 and interleukin-4 in patients with malignancy. J Immunother Emphasis Tumor Immunol 19:69–80
Oliver RT, Crosby D, Nouri A, Scott E, Galazka A (1989) Evaluation of the effect of continuous infusion recombinant interleukin-2 (bioleukin) on peripheral blood leucocytes of patients with terminal malignancy. Br J Cancer 60:934–937
O’reilly SM, Rustin GJ, Farmer K, Burke M, Hill S, Denekamp J (1993) Flavone acetic acid (FAA) with recombinant interleukin-2 (rIL-2) in advanced malignant melanoma: I. Clinical and vascular studies. Br J Cancer 67:1342–1345
Palmieri G, Morabito A, Lauria R, Montesarchio V, Matano E, Memoli B, Libetta C, Rea A, Merola C, Correale P et al (1993) Low-dose dopamine induces early recovery of recombinant interleukin-2--impaired renal function. Eur J Cancer 29A:1119–1122
Papa MZ, Mule JJ, Rosenberg SA (1986) Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo: successful immunotherapy of established pulmonary metastases from weakly immunogenic and nonimmunogenic murine tumors of three district histological types. Cancer Res 46: 4973–4978
Parkinson DR, Abrams JS, Wiernik PH, Rayner AA, Margolin KA, Van Echo DA, Sznol M, Dutcher JP, Aronson FR, Doroshow JH et al (1990) Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. J Clin Oncol 8:1650–1656
Perez EA, Scudder SA, Meyers FA, Tanaka MS, Paradise C, Gandara DR (1991) Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study. J Immunother (1991) 10:57–62
Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA (2001) Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477–3482
Pichert G, Jost LM, Fierz W, Stahel RA (1991) Clinical and immune modulatory effects of alternative weekly interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma and melanoma. Br J Cancer 63:287–292
Punt KC, Jansen RL, De Mulder PH, Batchelor D, Galazka A, Bolhuis RL, Stoter G (1992) Repetitive weekly cycles of 4-day continuous infusion of recombinant interleukin-2: a phase I study. J Immunother (1991) 12:277–284
Quan WD Jr, Quan FM (2003) Outpatient experience with moderate dose bolus interleukin-2 in metastatic malignant melanoma and kidney cancer. J Immunother 26:286–290
Quan W Jr, Ramirez M, Taylor C, Quan F, Vinogradov M, Walker P (2005) Administration of high-dose continuous infusion interleukin-2 to patients age 70 or over. Cancer Biother Radiopharm 20:11–15
Quan WD Jr, Milligan KS, Quan FM, Cuenca RE, Khan N, Liles DK, Walker PR (2006) Continuous infusion interleukin-2 and intravenous famotidine in metastatic melanoma. Cancer Biother Radiopharm 21:607–612
Radny P, Caroli UM, Bauer J, Paul T, Schlegel C, Eigentler TK, Weide B, Schwarz M, Garbe C (2003) Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer 89:1620–1626
Rao RD, Anderson PM, Arndt CA, Wettstein PJ, Markovic SN (2003) Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol 26:493–498
Richards JM, Barker E, Latta J, Ramming K, Vogelzang NJ (1988) Phase I study of weekly 24-hour infusions of recombinant human interleukin-2. J Natl Cancer Inst 80:1325–1328
Ridolfi L, Ridolfi R, Ascari-Raccagni A, Fabbri M, Casadei S, Gatti A, Trevisan G, Righini MG (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
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, Mcneil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015a) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, Mcneil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, Investigators, K (2015b) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532
Robertson MJ, Mier JW, Logan T, Atkins M, Koon H, Koch KM, Kathman S, Pandite LN, Oei C, Kirby LC, Jewell RC, Bell WN, Thurmond LM, Weisenbach J, Roberts S, Dar MM (2006) Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res 12:4265–4273
Rosenberg SA, White DE (1996) Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy. J Immunother Emphasis Tumor Immunol 19:81–84
Rosenberg SA, Grimm EA, Mcgrogan M, Doyle M, Kawasaki E, Koths K, Mark DF (1984) Biological activity of recombinant human interleukin-2 produced in Escherichia coli. Science 223:1412–1414
Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485–1492
Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210:474–484; discussion 484–5
Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271:907–913
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998a) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327
Rosenberg SA, Yang JC, White DE, Steinberg SM (1998b) Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 228:307–319
Rosenberg SA, Sportes C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL, Stetler-Stevenson M, Morton KE, Mavroukakis SA, Morre M, Buffet R, Mackall CL, Gress RE (2006) IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother 29:313–319
Rosener M, Schwulera U, Menke G, Thrun A, Lissner R, Krauseneck P, Bogdahn U, Martin R (1993) Tolerance and cerebrospinal fluid pharmacokinetics of intrathecally administered human natural interleukin-2: a phase I trial. Eur Cytokine Netw 4:189–195
Rosenthal NS, Hank JA, Kohler PC, Minkoff DZ, Moore KH, Bechhofer R, Hong R, Storer B, Sondel PM (1988) The in vitro function of lymphocytes from 25 cancer patients receiving four to seven consecutive days of recombinant IL-2. J Biol Response Mod 7:123–139
Rosso R, Sertoli MR, Queirolo P, Sanguineti O, Barzacchi MC, Mariani GL, Miglio L, Venturini M, Toma S (1992) An outpatient phase I study of a subcutaneous interleukin-2 and intramuscular alpha-2a-interferon combination in advanced malignancies. Ann Oncol 3:559–563
Royal RE, Steinberg SM, Krouse RS, Heywood G, White DE, Hwu P, Marincola FM, Parkinson DR, Schwartzentruber DJ, Topalian SL, Yang JC, Rosenberg SA (1996) Correlates of response to IL-2 therapy in patients treated for metastatic renal cancer and melanoma. Cancer J Sci Am 2:91–98
Rubin JT, Elwood LJ, Rosenberg SA, Lotze MT (1989) Immunohistochemical correlates of response to recombinant interleukin-2-based immunotherapy in humans. Cancer Res 49:7086–7092
Rubin JT, Day R, Duquesnoy R, Simonis B, Adams S, Lee J, Lotze MT (1995) HLA-DQ1 is associated with clinical response and survival of patients with melanoma who are treated with interleukin-2. Ther Immunol 2:1–6
Sabatino M, Kim-Schulze S, Panelli MC, Stroncek D, Wang E, Taback B, Kim DW, Deraffele G, Pos Z, Marincola FM, Kaufman HL (2009) Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 27:2645–2652
Safwat A, Schmidt H, Bastholt L, Fode K, Larsen S, Aggerholm N, Von Der Maase H (2005) A phase II trial of low-dose total body irradiation and subcutaneous interleukin-2 in metastatic melanoma. Radiother Oncol 77:143–147
Salvo G, Samoggia P, Masciulli R, Boccoli G, Allavena P, Mariani G, Bullo A, Montesoro E, Bulgarini D, Carlini P et al (1992) Interleukin-2 bolus therapy induces immediate and selective disappearance from peripheral blood of all lymphocyte subpopulations displaying natural killer activity: role of cell adhesion to endothelium. Eur J Cancer 28A:818–825
Samlowski WE, Park KJ, Galinsky RE, Ward JH, Schumann GB (1993) Intrathecal administration of interleukin-2 for meningeal carcinomatosis due to malignant melanoma: sequential evaluation of intracranial pressure, cerebrospinal fluid cytology, and cytokine induction. J Immunother Emphasis Tumor Immunol 13:49–54
Sanda MG, Yang JC, Topalian SL, Groves ES, Childs A, Belfort R, De Smet MD, Schwartzentruber DJ, White DE, Lotze MT et al (1992) Intravenous administration of recombinant human macrophage colony-stimulating factor to patients with metastatic cancer: a phase I study. J Clin Oncol 10:1643–1649
Sarna G, Machleder H, Collins J, Bonavida B, Jacobs E, Hawkins R, Golub S, Shau H, Fahey J, Popow J et al (1994) A comparative study of intravenous versus intralymphatic interleukin-2, with assessment of effects of interleukin-2 on both peripheral blood and thoracic-duct lymph. J Immunother Emphasis Tumor Immunol 15:140–146
Schaafsma MR, Falkenburg JH, Landegent JE, Duinkerken N, Osanto S, Ralph P, Kaushansky K, Wagemaker G, van Damme J, Willemze R et al (1991) In vivo production of interleukin-5, granulocyte-macrophage colony-stimulating factor, macrophages colony-stimulating factor, and interleukin-6 during intravenous administration of high-dose interleukin-2 in cancer patients. Blood 78:1981–1987
Schmidt H, Larsen S, Bastholt L, Fode K, Rytter C, von der Maase H (2002) A phase II study of outpatient subcutaneous histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma. Ann Oncol 13:1919–1924
Schwartzentruber DJ (1993) In vitro predictors of clinical response in patients receiving interleukin-2-based immunotherapy. Curr Opin Oncol 5:1055–1058
Schwartzentruber DJ (2000) Interleukin-2: clinical applications. Principles of administration and management of side effects. In: Rosenberg SA (ed) Principles and practice of the biologic therapy of cancer. Lippincott Williams & Wilkins, Philadelphia
Schwartzentruber DJ (2001) Guidelines for the safe administration of high-dose interleukin-2. J Immunother 24:287–293
Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P (2011) gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364: 2119–2127
Smith IJ, Kurt RA, Baher AG, Denman S, Justice L, Doran T, Gilbert M, Alvord WG, Urba WJ (2003) 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. J Immunother 26:130–138
Smith FO, Goff SL, Klapper JA, Levy C, Allen T, Mavroukakis SA, Rosenberg SA (2007) Risk of bowel perforation in patients receiving interleukin-2 after therapy with anti-CTLA 4 monoclonal antibody. J Immunother 30:130
Soiffer RJ, Chapman PB, Murray C, Williams L, Unger P, Collins H, Houghton AN, Ritz J (1997) Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma. Clin Cancer Res 3:17–24
Sondel PM, Kohler PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B (1988) Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Cancer Res 48:2561–2567
Sosman JA, Kohler PC, Hank J, Moore KH, Bechhofer R, Storer B, Sondel PM (1988) Repetitive weekly cycles of recombinant human interleukin-2: responses of renal carcinoma with acceptable toxicity. J Natl Cancer Inst 80:60–63
Sosman JA, Weiss GR, Margolin KA, Aronson FR, Sznol M, Atkins MB, O’boyle K, Fisher RI, Boldt DH, Doroshow J et al (1993) Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects. J Clin Oncol 11:1496–1505
Sosman JA, Kefer C, Fisher RI, Jacobs CD, Pumfery P, Ellis TM (1995) A phase IA/IB trial of anti-CD3 murine monoclonal antibody plus low-dose continuous-infusion interleukin-2 in advanced cancer patients. J Immunother Emphasis Tumor Immunol 17:171–180
Sosman JA, Aronson FR, Sznol M, Atkins MB, Dutcher JP, Weiss GR, Isaacs RE, Margolin KA, Fisher RI, Ernest ML, Mier J, Oleksowicz L, Eckhardt JR, Levitt D, Doroshow JH (1997) Concurrent phase I trials of intravenous interleukin 6 in solid tumor patients: reversible dose-limiting neurological toxicity. Clin Cancer Res 3:39–46
Sosman JA, Carrillo C, Urba WJ, Flaherty L, Atkins MB, Clark JI, Dutcher J, Margolin KA, Mier J, Gollob J, Kirkwood JM, Panka DJ, Crosby NA, O’boyle K, Lafleur B, Ernstoff MS (2008) 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 26:2292–2298
Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR et al (1993) 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 11:1969–1977
Stein RC, Malkovska V, Morgan S, Galazka A, Aniszewski C, Roy SE, Shearer RJ, Marsden RA, Bevan D, Gordon-Smith EC et al (1991) The clinical effects of prolonged treatment of patients with advanced cancer with low-dose subcutaneous interleukin-2 [corrected]. Br J Cancer 63:275–278
Sullivan RJ, Hoshida Y, Logan T, Khushalani NI, Giobbie-Hurder A, Margolin KA, Roder J, Bhatt R, Koon H, Olencki T, Hutson T, Curti B, Blackmon S, Mier JW, Roder H, Stewart J, Amin A, Ernstroff M, Clark J, Atkins MB, Kaufman H, Sosman J, Signoretti S, Mcdermott DF (2016) High Dose Interleukin 2 (HD IL-2) Select Trial in Melanoma: A tissue and blood collection protocol to identify predictive biomarkers of response to HD IL-2 in patients with advanced melanoma. Society of Immunotherapy in Cancer Annual Meeting, National Harbor
Sznol M, Mier JW, Sparano J, Gaynor ER, Weiss GR, Margolin KA, Bar MH, Hawkins MJ, Atkins MB, Dutcher JP et al (1990) A phase I study of high-dose interleukin-2 in combination with interferon-alpha 2b. J Biol Response Mod 9:529–537
Tagliaferri P, Barile C, Caraglia M, Guarrasi R, Morelli D, Ricciardi B, Martignetti A, Librera MT, Matano E, Della Vecchia A, Catalano G, Famiani M, Palmieri G, Correale P, Bianco AR (1998) Daily low-dose subcutaneous recombinant interleukin-2 by alternate weekly administration: antitumor activity and immunomodulatory effects. Am J Clin Oncol 21:48–53
Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J (1983) Structure and expression of a cloned cDNA for human interleukin-2. Nature 302:305–310
Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS (2007) Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J Clin Oncol 25:3802–3807
Tartour E, Blay JY, Dorval T, Escudier B, Mosseri V, Douillard JY, Deneux L, Gorin I, Negrier S, Mathiot C, Pouillart P, Fridman WH (1996) Predictors of clinical response to interleukin-2--based immunotherapy in melanoma patients: a French multiinstitutional study. J Clin Oncol 14:1697–1703
Taylor CW, Chase EM, Whitehead RP, Rinehart JJ, Neidhart JA, Gonzalez R, Bunn PA, Hersh EM (1992) 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 (1991) 11:176–183
Thatcher N, Dazzi H, Johnson RJ, Russell S, Ghosh AK, Moore M, Chadwick G, Craig RD (1989) Recombinant interleukin-2 (rIL-2) given intrasplenically and intravenously for advanced malignant melanoma. A phase I and II study. Br J Cancer 60:770–774
Thatcher N, Dazzi H, Mellor M, Ghosh A, Carrington B, Johnson RJ, Loriaux EM, Craig RP (1990) Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: a phase II study. Br J Cancer 61:618–621
Thomas H, Barton C, Saini A, Dalgleish A, Waxman J (1992) Sequential interleukin-2 and alpha interferon for renal cell carcinoma and melanoma. Eur J Cancer 28A:1047–1049
Thompson JA, Lee DJ, Cox WW, Lindgren CG, Collins C, Neraas KA, Dennin RA, Fefer A (1987) Recombinant interleukin 2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial. Cancer Res 47:4202–4207
Thompson JA, Lee DJ, Lindgren CG, Benz LA, Collins C, Levitt D, Fefer A (1988) Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation. J Clin Oncol 6:669–678
Tilg H, Shapiro L, Atkins MB, Dinarello CA, Mier JW (1993) Induction of circulating and erythrocyte-bound IL-8 by IL-2 immunotherapy and suppression of its in vitro production by IL-1 receptor antagonist and soluble tumor necrosis factor receptor (p75) chimera. J Immunol 151:3299–3307
Tilg H, Atkins MB, Dinarello CA, Mier JW (1995) Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy. Cytokine 7:734–739
Trehu EG, Mier JW, Dubois JS, Sorce D, Klempner MS, Epstein M, Dinarello CA, Shapiro L, Kappler K, Ronayne L, Atkins MB (1996) Phase I trial of interleukin 2 in combination with the soluble tumor necrosis factor receptor p75 IgG chimera. Clin Cancer Res 2:1341–1351
Triozzi PL, Kim JA, Martin EW, Young DC, Benzies T, Villasmil PM (1995) Phase I trial of escalating doses of interleukin-1 beta in combination with a fixed dose of interleukin-2. J Clin Oncol 13:482–489
Tritarelli E, Rocca E, Testa U, Boccoli G, Camagna A, Calabresi F, Peschle C (1991) Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level. Blood 77:741–749
Urba WJ, Steis RG, Longo DL, Kopp WC, Maluish AE, Marcon L, Nelson DL, Stevenson HC, Clark JW (1990) Immunomodulatory properties and toxicity of interleukin 2 in patients with cancer. Cancer Res 50:185–192
van Haelst Pisani C, Kovach JS, Kita H, Leiferman KM, Gleich GJ, Silver JE, Dennin R, Abrams JS (1991) Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer. Blood 78:1538–1544
Veelken H, Rosenthal FM, Schneller F, von Schilling C, Guettler IC, Herrmann F, Mertelsmann R, Lindemann A (1992) Combination of interleukin-2 and interferon-alpha in renal cell carcinoma and malignant melanoma: a phase II clinical trial. Biotechnol Ther 3:1–14
Verdi CJ, Taylor CW, Croghan MK, Dalke P, Meyskens FL, Hersh EM (1992) Phase I study of low-dose cyclophosphamide and recombinant interleukin-2 for the treatment of advanced cancer. J Immunother (1991) 11:286–291
Vetto JT, Papa MZ, Lotze MT, Chang AE, Rosenberg SA (1987) Reduction of toxicity of interleukin-2 and lymphokine-activated killer cells in humans by the administration of corticosteroids. J Clin Oncol 5: 496–503
Viens P, Blaise D, Stoppa AM, Brandely M, Baume D, Olive D, Resbeut M, Delpero JR, Lopez M, Aubert C et al (1992) Interleukin-2 in association with increasing doses of interferon-gamma in patients with advanced cancer. J Immunother (1991) 11:218–224
Vlasveld LT, Rankin EM, Hekman A, Rodenhuis S, Beijnen JH, Hilton AM, Dubbelman AC, Vyth-Dreese FA, Melief CJ (1992) A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part I: clinical aspects. Br J Cancer 65:744–750
Vlasveld LT, Horenblas S, Hekman A, Hilton AM, Dubbelman AC, Melief CJ, Rankin EM (1994) Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer. Ann Oncol 5:179–181
Vuoristo M, Jantunen I, Pyrhonen S, Muhonen T, Kellokumpu-Lehtinen P (1994) A combination of subcutaneous recombinant interleukin-2 and recombinant interferon-alpha in the treatment of advanced renal cell carcinoma or melanoma. Eur J Cancer 30A:530–532
Weber J, Yang JC, Topalian SL, Parkinson DR, Schwartzentruber DS, Ettinghausen SE, Gunn H, Mixon A, Kim H, Cole D et al (1993) Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol 11:499–506
Weber J, Gunn H, Yang J, Parkinson D, Topalian S, Schwartzentruber D, Ettinghausen S, Levitt D, Rosenberg SA (1994) A phase I trial of intravenous interleukin-6 in patients with advanced cancer. J Immunother Emphasis Tumor Immunol 15:292–302
Weidmann E, Bergmann L, Stock J, Kirsten R, Mitrou PS (1992) Rapid cytokine release in cancer patients treated with interleukin-2. J Immunother (1991) 12:123–131
Weiner LM, Padavic-Shaller K, Kitson J, Watts P, Krigel RL, Litwin S (1991) Phase I evaluation of combination therapy with interleukin 2 and gamma-interferon. Cancer Res 51:3910–3918
Weinreich DM, Rosenberg SA (2002) Response rates of patients with metastatic melanoma to high-dose intravenous interleukin-2 after prior exposure to alpha-interferon or low-dose interleukin-2. J Immunother 25:185–187
Whitehead RP, Ward D, Hemingway L, Hemstreet GP 3rd, Bradley E, Konrad M (1990) Subcutaneous recombinant interleukin 2 in a dose escalating regimen in patients with metastatic renal cell adenocarcinoma. Cancer Res 50:6708–6715
Whitehead RP, Kopecky KJ, Samson MK, Costanzi JJ, Natale RB, Feun LG, Hersh EM, Rinehart JJ (1991) Phase II study of intravenous bolus recombinant interleukin-2 in advanced malignant melanoma: Southwest Oncology Group study. J Natl Cancer Inst 83:1250–1252
Whitehead RP, Figlin R, Citron ML, Pfile J, Moldawer N, Patel D, Jones G, Levitt D, Zeffren J (1993) A phase II trial of concomitant human interleukin-2 and interferon-alpha-2a in patients with disseminated malignant melanoma. J Immunother Emphasis Tumor Immunol 13:117–121
Wiebke EA, Rosenberg SA, Lotze MT (1988) Acute immunologic effects of interleukin-2 therapy in cancer patients: decreased delayed type hypersensitivity response and decreased proliferative response to soluble antigens. J Clin Oncol 6:1440–1449
Yang JC, Rosenberg SA (1997) An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer. Cancer J Sci Am 3(Suppl 1):S79–S84
Yang JC, Topalian SL, Schwartzentruber DJ, Parkinson DR, Marincola FM, Weber JS, Seipp CA, White DE, Rosenberg SA (1995) The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2. Cancer 76:687–694
Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA (2003) Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127–3132
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this entry
Cite this entry
Haanen, J.B.A.G., Sullivan, R.J., Kirkwood, J., Atkins, M.B., Schwartzentruber, D.J. (2019). Cytokines (IL-2, IFN GM-CSF etc) Melanoma. In: Balch, C., et al. Cutaneous Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-319-46029-1_56-1
Download citation
DOI: https://doi.org/10.1007/978-3-319-46029-1_56-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-46029-1
Online ISBN: 978-3-319-46029-1
eBook Packages: Springer Reference MedicineReference Module Medicine