Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Interleukin-2 and experimental immunotherapy approaches for advanced melanoma

Jeffrey A Sosman, MD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD


Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. For localized melanomas, surgical excision is curative in most cases, and patients at high risk of developing metastatic disease may benefit from adjuvant therapy. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant immunotherapy for melanoma".)

Historically, high-dose interleukin-2 (IL-2) was the first immunotherapy approach to produce durable remissions in patients with advanced disease. However, these benefits were limited to a small fraction of patients and treatment was associated with substantial toxicity. The use of high-dose IL-2 has now been supplanted by immunotherapy with checkpoint inhibitors directed against programmed death protein-1 or CTLA-4. In addition, targeted therapy directed against the MAP kinase pathway has provided an additional important treatment option for patients with advanced disease and a V600 mutation of BRAF.

The results with high-dose IL-2 and the potential role of other experimental immunotherapy approaches are reviewed here.

Other related topics include:

(See "Principles of cancer immunotherapy".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: May 6, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Rosenberg SA, Mulé JJ, Spiess PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985; 161:1169.
  2. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994; 271:907.
  3. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
  4. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000; 6 Suppl 1:S11.
  5. Yang JC, Abad J, Sherry R. Treatment of oligometastases after successful immunotherapy. Semin Radiat Oncol 2006; 16:131.
  6. Mier JW, Vachino G, van der Meer JW, et al. 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 1988; 8:426.
  7. Phan GQ, Attia P, Steinberg SM, et al. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 2001; 19:3477.
  8. Joseph RW, Sullivan RJ, Panka GD, et al. Effect of mutational status on response, PFS, or OS after treatment with IL-2 for metastatic melanoma. J Clin Oncol 2010; 28:15s.
  9. Atkins MB. Immunotherapy and experimental approaches for metastatic melanoma. Hematol Oncol Clin North Am 1998; 12:877.
  10. Sabatino M, Kim-Schulze S, Panelli MC, et al. Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 2009; 27:2645.
  11. Wang E, Miller LD, Ohnmacht GA, et al. Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 2002; 62:3581.
  12. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316:889.
  13. Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 1994; 86:1159.
  14. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17:4550.
  15. Dummer R, Garbe C, Thompson JA, et al. Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma. J Clin Oncol 2006; 24:1188.
  16. Agarwala SS, Kirkwood JM. Interferons in melanoma. Curr Opin Oncol 1996; 8:167.
  17. Creagan ET, Ahmann DL, Frytak S, et al. Phase II trials of recombinant leukocyte A interferon in disseminated malignant melanoma: results in 96 patients. Cancer Treat Rep 1986; 70:619.
  18. Agarwala SS, Kirkwood JM. Adjuvant interferon treatment for melanoma. Hematol Oncol Clin North Am 1998; 12:823.
  19. Petrella TM, Tozer R, Belanger K, et al. Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J Clin Oncol 2012; 30:3396.
  20. Alatrash G, Hutson TE, Molto L, et al. 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 2004; 22:2891.
  21. Younes A, Pro B, Robertson MJ, et al. Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease. Clin Cancer Res 2004; 10:5432.
  22. Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 2008; 26:5896.
  23. Nawrocki S, Murawa P, Malicki J, et al. Genetically modified tumour vaccines (GMTV) in melanoma clinical trials. Immunol Lett 2000; 74:81.
  24. Szabolcs P, Moore MA, Young JW. Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-alpha. J Immunol 1995; 154:5851.
  25. Lawson DH, Lee SJ, Tarhini AA, et al. Phase III cooperative group study of yeast-derived granulocyte macrophage colony stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patients with completely resected stage III_IV melanoma. J Clin Oncol 2010; 28:612s.
  26. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA 2014; 312:1744.
  27. Liénard D, Eggermont AM, Koops HS, et al. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 1999; 9:491.
  28. Sosman JA, Carrillo C, Urba WJ, et al. Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. J Clin Oncol 2008; 26:2292.
  29. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res 2008; 14:5610.
  30. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011; 364:2119.
  31. Vantomme V, Dantinne C, Amrani N, et al. Immunologic analysis of a phase I/II study of vaccination with MAGE-3 protein combined with the AS02B adjuvant in patients with MAGE-3-positive tumors. J Immunother 2004; 27:124.
  32. Louahed J, Gruselle O, Gaulis S. Expression of defined genes identified by pretreatment tumor profiling: Association with clinical responses to the GSK MAGE - A3 immunotherapeutic in metastatic melanoma patients. J Clin Oncol 2008; 26:494s.
  33. Kruit WH, Suciu S, Dreno B. Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: A randomized open-label phase II study of the EORTC Melanoma Group. J Clin Oncol 2008; 26:494s.
  34. National Institutes of Health Clinical Trials database http://www.clinicaltrials.gov/ (Accessed on April 08, 2011).
  35. Jones PC, Sze LL, Liu PY, et al. Prolonged survival for melanoma patients with elevated IgM antibody to oncofetal antigen. J Natl Cancer Inst 1981; 66:249.
  36. Livingston PO, Natoli EJ, Calves MJ, et al. Vaccines containing purified GM2 ganglioside elicit GM2 antibodies in melanoma patients. Proc Natl Acad Sci U S A 1987; 84:2911.
  37. Livingston PO, Wong GY, Adluri S, et al. Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 1994; 12:1036.
  38. Helling F, Zhang S, Shang A, et al. GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 1995; 55:2783.
  39. Livingston PO, Adluri S, Helling F, et al. Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 1994; 12:1275.
  40. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001; 19:2370.
  41. Eggermont AM, Suiciu S, Rutkowski P. Randomized phase III trial comparing postoperative adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation in stage II (T3-T4N0M0) melanoma: Final results of study EORTC 18961. J Clin Oncol 2010; 28:612s.
  42. Eggermont A, Suciu S, Rutkowski P, et al. Adjuvant Ganglioside GM2-KLH/QS-21 Vaccination Versus Observation After Resection of Primary Tumor > 1.5 mm in Patients With Stage II Melanoma: Results of the EORTC 18961 Randomized Phase III Trial. J Clin Oncol 2013.
  43. Morton DL, Hoon DS, Nizze JA, et al. Polyvalent melanoma vaccine improves survival of patients with metastatic melanoma. Ann N Y Acad Sci 1993; 690:120.
  44. DiFronzo LA, Gupta RK, Essner R, et al. Enhanced humoral immune response correlates with improved disease-free and overall survival in American Joint Committee on Cancer stage II melanoma patients receiving adjuvant polyvalent vaccine. J Clin Oncol 2002; 20:3242.
  45. Lotem M, Peretz T, Drize O, et al. Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on Cancer. Br J Cancer 2002; 86:1534.
  46. Berd D, Maguire HC Jr, Schuchter LM, et al. Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases. J Clin Oncol 1997; 15:2359.
  47. Berd D, Sato T, Maguire HC Jr, et al. Immunopharmacologic analysis of an autologous, hapten-modified human melanoma vaccine. J Clin Oncol 2004; 22:403.
  48. Mitchell MS. Perspective on allogeneic melanoma lysates in active specific immunotherapy. Semin Oncol 1998; 25:623.
  49. Morton DL, Mozzillo N, Thompson JF. An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J Clin Oncol 2007; 25:474s.
  50. Sosman JA. Unpublished data. March 9, 2005.
  51. Ross M, Camacho LH, Hersh EM. Clinical and Immunological responses in patients with malignant melanoma treated with a dendritic cell-based vaccine. Preliminary report from a multi-institutional phase II clinical trial. J Clin Oncol 2007; 25:478s.
  52. López MN, Pereda C, Segal G, et al. Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol 2009; 27:945.
  53. Wolchok JD, Yuan J, Houghton AN, et al. Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma. Mol Ther 2007; 15:2044.
  54. Andtbacka RH, Collichio FA, Amatruda T, et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma (abstract #LBA9008). J Clin Oncol 2013.
  55. Bedikian AY, Richards J, Kharkevitch D, et al. A phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res 2010; 20:218.
  56. Testori A, Faries MB, Thompson JF, et al. Local and intralesional therapy of in-transit melanoma metastases. J Surg Oncol 2011; 104:391.