, Volume 71, Issue 10, pp 1233–1250 | Cite as

Novel Immunotherapeutic Agents and Small Molecule Antagonists of Signalling Kinases for the Treatment of Metastatic Melanoma

  • Nagendra Natarajan
  • Sucheta Telang
  • Donald Miller
  • Jason Chesney
Leading Article


Melanoma incidence is increasing annually and over 40 000 die of this disease each year worldwide. In this review, we discuss the rationale and recent trial results of several novel immunotherapeutic approaches and small molecule inhibitors of signalling kinases. Ipilimumab is a humanized anti-CTLA4 antibody that has been proven to increase the median overall survival of large cohorts of patients with unresectable melanoma in two phase III trials. OncoVEXGM-CSF is an oncolytic herpes simplex virus-1 recombined with granulocyte-macrophage colony-stimulating factor that has demonstrated durable objective responses in a phase II trial. Tumour-infiltrating lymphocytes given after lymphocyte depletion and followed by high-dose interleukin (IL)-2 yield durable complete responses in a significant percentage of melanoma patients. Lastly, denileukin diftitox, a fusion of IL-2 and diphtheria toxin, was recently observed to deplete regulatory T cells and cause durable partial responses, particularly in chemo/immune-naïve patients. These agents are enabling the rational design of novel combination trials to simultaneously increase antigen presentation, deplete regulatory T cells and block immune check-points in order to activate melanoma antigenspecific immunity.

Although melanoma metastases have been found to contain thousands of mutations, the V600E BRAF mutation is clearly a driver of the neoplastic phenotype and is present in 40–60% of melanomas. Two separate small molecule antagonists of B-Raf have been found to yield very high partial response rates in metastatic melanoma, and the B-Raf inhibitor, vemurafenib (PLX4032), was recently observed to increase median overall survival in an interim analysis. However, B-Raf inhibitor resistance through up-regulation or activating mutations of alternative oncogenic signalling receptors and enzymes is proving to be a major challenge. Inhibitors of c-Kit and mitogen-activated protein kinase (MEK) have also been found to have activity against melanomas and MEK inhibitors are now being examined as a strategy to overcome B-Raf inhibitor resistance.

In summary, these studies reveal that, for the first time, several immunotherapeutic and targeted agents are yielding dramatic clinical responses and improvements in overall survival in patients with unresectable stage III and IV melanoma.


  1. 1.
    Jemal A, Siegel R, Xu J, et al. Cancer statistics. CA Cancer J Clin 2010 Sep–Oct; 60(5): 277–300PubMedCrossRefGoogle Scholar
  2. 2.
    Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001 Aug 15; 19(16): 3635–48PubMedGoogle Scholar
  3. 3.
    Eggermont AM, Voit C. Management of melanoma: a European perspective. Surg Oncol Clin N Am 2008 Jul; 17(3): 635–48, xPubMedCrossRefGoogle Scholar
  4. 4.
    Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005 Feb 19; 365(9460): 687–701PubMedGoogle Scholar
  5. 5.
    Boon T, Coulie PG, Van den Eynde BJ, et al. cell responses against melanoma. Annu Rev Immunol 2006; 24: 175–208PubMedCrossRefGoogle Scholar
  6. 6.
    Aptsiauri N, Cabrera T, Garcia-Lora A, et al. MHC class I antigens and immune surveillance in transformed cells. Int Rev Cytol 2007; 256: 139–89PubMedCrossRefGoogle Scholar
  7. 7.
    Mendez R, Rodriguez T, Del Campo A, et al. Characterization of HLA class I altered phenotypes in a panel of human melanoma cell lines. Cancer Immunol Immunother 2008 May; 57(5): 719–29PubMedCrossRefGoogle Scholar
  8. 8.
    Cabrera T, Lara E, Romero JM, et al. HLA class I expression in metastatic melanoma correlates with tumor development during autologous vaccination. Cancer Immunol Immunother 2007 May; 56(5): 709–17PubMedCrossRefGoogle Scholar
  9. 9.
    Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 2001; 6(1): 34–55PubMedCrossRefGoogle Scholar
  10. 10.
    Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996 Jan; 14(1): 7–17PubMedGoogle Scholar
  11. 11.
    Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C 9190. J Clin Oncol 2000 Jun; 18(12): 2444–58PubMedGoogle Scholar
  12. 12.
    Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon formelanoma. Clin Cancer Res 2004 Mar 1; 10(5): 1670–7PubMedCrossRefGoogle Scholar
  13. 13.
    Eggermont AM, Suciu S, MacKie R, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet 2005 Oct 1; 366(9492): 1189–96PubMedCrossRefGoogle Scholar
  14. 14.
    Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 2008 Jul 12; 372(9633): 117–26PubMedCrossRefGoogle Scholar
  15. 15.
    Linsley PS, Brady W, Grosmaire L, et al. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 1991 Mar 1; 173(3): 721–30PubMedCrossRefGoogle Scholar
  16. 16.
    O'Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 2007 Dec 15; 110(12): 2614–27PubMedCrossRefGoogle Scholar
  17. 17.
    Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995 Nov; 3(5): 541–7PubMedCrossRefGoogle Scholar
  18. 18.
    Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 2006 Apr; 18(2): 206–13PubMedCrossRefGoogle Scholar
  19. 19.
    Bristol-Myers Squibb. Efficacy study of ipilimumab versus placebo to prevent recurrence after complete resection of high risk stage III melanoma [ClinicalTrials.gov identifier: NCT00636168]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  20. 20.
    Inaba K, Inaba M, Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colonystimulating factor. J Exp Med 1992 Dec 1; 176(6): 1693–702PubMedCrossRefGoogle Scholar
  21. 21.
    Xu Y, Zhan Y, Lew AM, et al. Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol 2007 Dec 1; 179(11): 7577–84PubMedGoogle Scholar
  22. 22.
    Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 1993 Apr 15; 90(8): 3539–43PubMedCrossRefGoogle Scholar
  23. 23.
    Spitler LE, Grossbard ML, Ernstoff MS, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 2000 Apr; 18(8): 1614–21PubMedGoogle Scholar
  24. 24.
    Lawson DH, Lee SJ, Tarhini AA, et al. E4697: Phase III cooperative group study of yeast-derived granulocyte macrophage colony-stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patients with completely resected stage III–IV melanoma [abstract no. 8504]. J Clin Oncol 2010; 28 Suppl. 15: 8504Google Scholar
  25. 25.
    Kim KB, Legha SS, Gonzalez R, et al. A randomized phase III trial of biochemotherapy versus interferon-alpha-2b for adjuvant therapy in patients at high risk for melanoma recurrence. Melanoma Res 2009 Feb; 19(1): 42–9PubMedCrossRefGoogle Scholar
  26. 26.
    James Graham Brown Cancer Center. Adjuvant, combined interleukin 2 (proleukin) and DTIC (dacarbazine) in high-risk melanoma patients [ClinicalTrials.gov identifier: NCT00553618]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  27. 27.
    Bilsborough J, Panichelli C, Duffour MT, et al. A MAGE-3 peptide presented by HLA-B44 is also recognized by cytolytic T lymphocytes on HLA-B 18. Tissue Antigens 2002 Jul; 60(1): 16–24PubMedCrossRefGoogle Scholar
  28. 28.
    Breckpot K, Heirman C, De Greef C, et al. Identification of new antigenic peptide presented by HLA-Cw7 and encoded by several MAGE genes using dendritic cells transduced with lentiviruses. J Immunol 2004 Feb 15; 172(4): 2232–7PubMedGoogle Scholar
  29. 29.
    Gaugler B, Van den Eynde B, van der Bruggen P, et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 1994 Mar 1; 179(3): 921–30PubMedCrossRefGoogle Scholar
  30. 30.
    Herman J, van der Bruggen P, Luescher IF, et al. A peptide encoded by the human MAGE3 gene and presented by HLA-B44 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE 3. Immunogenetics 1996; 43(6): 377–83PubMedCrossRefGoogle Scholar
  31. 31.
    Kawashima I, Hudson SJ, Tsai V, et al. The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors. Hum Immunol 1998 Jan; 59(1): 1–14PubMedCrossRefGoogle Scholar
  32. 32.
    Kruit WH, Suciu S, Dreno B, et al. 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 (16032–18031) [abstract]. J Clin Oncol 2008; 26 Suppl. 15: 9065Google Scholar
  33. 33.
    GlaxoSmithKline. A phase III study to test the benefit of a new kind of anti-cancer treatment in patients with melanoma, after surgical removal of their tumor [ClinicalTrials.gov identifier: NCT00796445]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  34. 34.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008 Mar–Apr; 58(2): 71–96PubMedCrossRefGoogle Scholar
  35. 35.
    Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 2008 Feb 1; 26(4): 527–34PubMedCrossRefGoogle Scholar
  36. 36.
    Smith KA. Interleukin-2: inception, impact, and implications. Science 1988 May 27; 240(4856): 1169–76PubMedCrossRefGoogle Scholar
  37. 37.
    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 Jul; 17(7): 2105–16PubMedGoogle Scholar
  38. 38.
    Novartis Pharmaceuticals. Aldesleukin in patients with metastatic renal cell carcinoma and metastatic melanoma [ClinicalTrials.gov identifier: NCT00414765]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  39. 39.
    Slingluff Jr CL, Yamshchikov G, Neese P, et al. Phase I trial of a melanoma vaccine with gp100(280–288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes. Clin Cancer Res 2001 Oct; 7(10): 3012–24PubMedGoogle Scholar
  40. 40.
    Schwartzentruber DJ, Lawson D, Richards J, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011; 364(22): 2119–27PubMedCrossRefGoogle Scholar
  41. 41.
    Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 1998 May; 16(5): 1752–9PubMedGoogle Scholar
  42. 42.
    McDermott DF, Mier JW, Lawrence DP, 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 Jun; 6(6): 2201–8PubMedGoogle Scholar
  43. 43.
    Atkins MB, Hsu J, Lee S, et al. 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 2008 Dec 10; 26(35): 5748–54PubMedCrossRefGoogle Scholar
  44. 44.
    Hamm C, Verma S, Petrella T, et al. Biochemotherapy for the treatment of metastatic malignant melanoma: a systematic review. Cancer Treat Rev 2008 Apr; 34(2): 145–56PubMedCrossRefGoogle Scholar
  45. 45.
    Ives NJ, Stowe RL, Lorigan P, et al. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 2007 Dec 1; 25(34): 5426–34PubMedCrossRefGoogle Scholar
  46. 46.
    O'Day SJ, Atkins MB, Boasberg P, et al. Phase II multicenter trial of maintenance biotherapy after induction concurrent biochemotherapy for patients with metastatic melanoma. J Clin Oncol 2009 Dec 20; 27(36): 6207–12PubMedCrossRefGoogle Scholar
  47. 47.
    Moroz A, Eppolito C, Li Q, et al. 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 Jul 15; 173(2): 900–9PubMedGoogle Scholar
  48. 48.
    Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000 Nov 2; 408(6808): 57–63PubMedCrossRefGoogle Scholar
  49. 49.
    Parrish-Novak J, Foster DC, Holly RD, et al. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol 2002 Nov; 72(5): 856–63PubMedGoogle Scholar
  50. 50.
    Peluso I, Fantini MC, Fina D, et al. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 2007 Jan 15; 178(2): 732–9PubMedGoogle Scholar
  51. 51.
    Davis ID, Skrumsager BK, Cebon J, et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 2007 Jun 15; 13(12): 3630–6PubMedCrossRefGoogle Scholar
  52. 52.
    Petrella R, Tozer K, Belanger KJ, et al. Interleukin-21 (IL-21) activity in patients with metastic melanoma [abstract no. 8507]. J Clin Oncol 2010; 28 Suppl. 15: 8507Google Scholar
  53. 53.
    NCIC Clinical Trials Group. A randomized phase II study of interleukin-21 (rIL-21) versus dacarbazine (DTIC) in patients with metastatic or recurrent melanoma [ClinicalTrials.gov identifier: NCT01152788]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  54. 54.
    Dubois S, Patel HJ, Zhang M, et al. Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol 2008 Feb 15; 180(4): 2099–106PubMedGoogle Scholar
  55. 55.
    Epardaud M, Elpek KG, Rubinstein MP, et al. Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res 2008 Apr 15; 68(8): 2972–83PubMedCrossRefGoogle Scholar
  56. 56.
    National Cancer Institute. A phase I study of intravenous recombinant human IL-15 in adults with refractory metastatic malignant melanoma and metastatic renal cell cancer [ClinicalTrials.gov identifier: NCT01021059]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  57. 57.
    Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2009; 11(2): 155–64PubMedCrossRefGoogle Scholar
  58. 58.
    Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711–23PubMedCrossRefGoogle Scholar
  59. 59.
    Robert S, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. Epub 2011 Jun 5Google Scholar
  60. 60.
    Eggermont AM, Suciu S, Rutkowski P, et al. 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 [abstract]. J Clin Oncol 2010; 28 Suppl. 15: 8505Google Scholar
  61. 61.
    Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2011; 107(9): 4275–80CrossRefGoogle Scholar
  62. 62.
    Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007 Jul; 27(1): 111–22PubMedCrossRefGoogle Scholar
  63. 63.
    Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007 Jul; 19(7): 813–24PubMedCrossRefGoogle Scholar
  64. 64.
    Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28(19): 3167–75PubMedCrossRefGoogle Scholar
  65. 65.
    Bristol-Myers Squibb. Dose-escalation study of combination BMS-936558 (MDX-1106) and ipilimumab in subjects with unresectable stage III or stage IV malignant melanoma [ClinicalTrials.gov identifier: NCT01024231]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  66. 66.
    H. Lee Moffitt Cancer Center and Research Institute. Monoclonal antibody therapy and vaccine therapy in treating patients with stage IV melanoma that has been removed by surgery [ClinicalTrials.gov identifier: NCT01176474]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  67. 67.
    H. Lee Moffitt Cancer Center and Research Institute. Vaccine therapy and monoclonal antibody therapy in treating patients with stage III or stage IV melanoma that cannot be removed by surgery [ClinicalTrials.gov identifier:NCT01 176461]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  68. 68.
    van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol 2000 Jan; 67(1): 2–17PubMedGoogle Scholar
  69. 69.
    von Leoprechting A, van der Bruggen P, Pahl HL, et al. Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocytemediated lysis and induces apoptosis. Cancer Res 1999 Mar 15; 59(6): 1287–94Google Scholar
  70. 70.
    Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 2007 Mar 1; 25(7): 876–83PubMedCrossRefGoogle Scholar
  71. 71.
    Abramson Cancer Center of the University of Pennsylvania. Tremelimumab and CP-870,893 in patients with metastatic melanoma [ClinicalTrials.gov identifier: NCT01103635]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  72. 72.
    Shao Z, Schwarz H. CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J Leukoc Biol 2011; 89(1): 21–9PubMedCrossRefGoogle Scholar
  73. 73.
    Sun Y, Chen JH, Fu Y. Immunotherapy with agonistic anti-CD 137: two sides of a coin. Cell Mol Immunol 2004 Feb; 1(1): 31–6PubMedGoogle Scholar
  74. 74.
    Sznol M, Hodi FS, Margolin K, et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients with advanced cancer [abstract]. J Clin Oncol 2008; 26 Suppl.: 3007Google Scholar
  75. 75.
    Bristol-Myers Squibb. Phase II, 2nd line melanoma — RAND monotherapy [ClinicalTrials.gov identifier: NCT00612664]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  76. 76.
    Gonzalez R, Hutchins L, Nemunaitis J, et al. Phase 2 trial of Allovectin-7 in advanced metastatic melanoma. Melanoma Res 2006 Dec; 16(6): 521–6PubMedCrossRefGoogle Scholar
  77. 77.
    Vical. A phase 3 pivotal trial comparing Allovectin-7® alone vs chemotherapy alone in patients with stage 3 or stage 4 melanoma [ClinicalTrials.gov identifier: NCT00395070]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  78. 78.
    Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther 2003 Feb; 10(4): 292–303PubMedCrossRefGoogle Scholar
  79. 79.
    Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colonystimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol 2009 Dec 1; 27(34): 5763–71PubMedCrossRefGoogle Scholar
  80. 80.
    BioVex Limited. Efficacy and safety study of oncoVEXGMCSF compared to GM-CSF in melanoma [ClinicalTrials. gov identifier: NCT00769704]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  81. 81.
    Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008 Nov 10; 26(32): 5233–9PubMedCrossRefGoogle Scholar
  82. 82.
    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. Epub 2011 May 11Google Scholar
  83. 83.
    Johnson LA, Morgan RA, Dudley ME, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 2009 Jul 16; 114(3): 535–46PubMedCrossRefGoogle Scholar
  84. 84.
    Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006 Oct 6; 314(5796): 126–9PubMedCrossRefGoogle Scholar
  85. 85.
    Hong JJ, Rosenberg SA, Dudley ME, et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res 2010; 16(19): 4892–8PubMedCrossRefGoogle Scholar
  86. 86.
    Jones E, Dahm-Vicker M, Golgher D, et al. CD25+ regulatory T cells and tumor immunity. Immunol Lett 2003 Jan 22; 85(2): 141–3PubMedCrossRefGoogle Scholar
  87. 87.
    Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005 Apr 1; 105(7): 2862–8PubMedCrossRefGoogle Scholar
  88. 88.
    Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002 Feb 22; 2: 1PubMedGoogle Scholar
  89. 89.
    Turk MJ, Guevara-Patino JA, Rizzuto GA, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004 Sep 20; 200(6): 771–82PubMedCrossRefGoogle Scholar
  90. 90.
    Viguier M, Lemaitre F, Verola O, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 2004 Jul 15; 173(2): 1444–53PubMedGoogle Scholar
  91. 91.
    Berger CL, Tigelaar R, Cohen J, et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 2005 Feb 15; 105(4): 1640–7PubMedCrossRefGoogle Scholar
  92. 92.
    Rasku MA, Clem AL, Telang S, et al. Transient T cell depletion causes regression of melanoma metastases. J Transl Med 2008 Mar 11; 6(1): 1–18CrossRefGoogle Scholar
  93. 93.
    Chesney J, Rasku M, Klarer AC, et al. Effect of denileukin diftitox on serum GM-CSF and clinical responses in stage IV melanoma. J Clin Oncol 2011; 29 Suppl.: 2507CrossRefGoogle Scholar
  94. 94.
    Eisai Inc. Study of ONTAK in patients with stage IIIC and stage IV melanoma [ClinicalTrials.gov identifier: NCT01127451]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  95. 95.
    Avruch J, Khokhlatchev A, Kyriakis JM, et al. Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res 2001; 56: 127–55PubMedCrossRefGoogle Scholar
  96. 96.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002 Jun 27; 417(6892): 949–54PubMedCrossRefGoogle Scholar
  97. 97.
    Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br J Cancer 2006 Sep 4; 95(5): 581–6PubMedCrossRefGoogle Scholar
  98. 98.
    McDermott DF, Sosman JA, Gonzalez R, et al. Doubleblind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. J Clin Oncol 2008 May 1; 26(13): 2178–85PubMedCrossRefGoogle Scholar
  99. 99.
    Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363(9): 809–19PubMedCrossRefGoogle Scholar
  100. 100.
    Sosman J, Kim K, Schuchter LM, et al. An open-label, multicenter phase II study of continuous oral dosing of RG7204 (PLX4032) in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [abstract 30] Pigment Cell Melanoma Res 2010. 23 Suppl.: 912Google Scholar
  101. 101.
    Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. Epub 2011 Jun 5Google Scholar
  102. 102.
    Kefford RF, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors [abstract]. J Clin Oncol 2010; 28 Suppl. 15: 8503Google Scholar
  103. 103.
    GlaxoSmithKline. A study comparing GSK2118436 to dacarbazine (DTIC) in previously untreated subjects with BRAF mutation positive advanced (stage III) or metastatic (stage IV) melanoma [ClinicalTrials.gov identifier: NCT01227889]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  104. 104.
    Poulikakos PI, Rosen N. Mutant BRAF melanomas: dependence and resistance. Cancer Cell 2011; 19(1): 11–5PubMedCrossRefGoogle Scholar
  105. 105.
    Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med 2011; 364(8): 772–4PubMedCrossRefGoogle Scholar
  106. 106.
    Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468(7326): 973–7PubMedCrossRefGoogle Scholar
  107. 107.
    Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468(7326): 968–72PubMedCrossRefGoogle Scholar
  108. 108.
    Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010; 18(6): 683–95PubMedCrossRefGoogle Scholar
  109. 109.
    Haass NK, Sproesser K, Nguyen TK, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res 2008 Jan 1; 14(1): 230–9PubMedCrossRefGoogle Scholar
  110. 110.
    Banerji U, Camidge DR, Verheul HM, et al. The first-inhuman study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 2010; 16(5): 1613–23PubMedCrossRefGoogle Scholar
  111. 111.
    LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 2010; 16(6): 1924–37PubMedCrossRefGoogle Scholar
  112. 112.
    Thompson DS, Flaherty KT, Messersmith W, et al. A three-part, phase I, dose escalation study of GSK1120212, a potent MEK inhibitor, administered orally to subjects with solid tumors or lymphoma. J Clin Oncol 2009; 27 Suppl.: e14584Google Scholar
  113. 113.
    GlaxoSmithKline. Investigate safety, pharmacokinetics and pharmacodynamics of GSK2118436 & GSK1120212 [ClinicalTrials.gov identifier: NCT01072175]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Jun 23]
  114. 114.
    Davies MA, Samuels Y. Analysis of the genome to personalize therapy for melanoma. Oncogene 2010; 29(41): 5545–55PubMedCrossRefGoogle Scholar
  115. 115.
    Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 2008 Sep 2; 99(5): 734–40PubMedCrossRefGoogle Scholar
  116. 116.
    Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005 Apr 25; 92(8): 1398–405PubMedCrossRefGoogle Scholar
  117. 117.
    Wyman K, Atkins MB, Prieto V, et al. Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006 May 1; 106(9): 2005–11PubMedCrossRefGoogle Scholar
  118. 118.
    Handolias D, Hamilton AL, Salemi R, et al. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br J Cancer 2010; 102(8): 1219–23PubMedCrossRefGoogle Scholar
  119. 119.
    Fisher DE, Barnhill R, Hodi FS, et al. Melanoma from bench to bedside: meeting report from the 6th International Melanoma Congress. Pigment Cell Melanoma Res 2010; 23(1): 14–26PubMedCrossRefGoogle Scholar
  120. 120.
    Clem BF, Clem AL, Yalcin A, et al. A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene. Epub 2011 Mar 21Google Scholar
  121. 121.
    Yalcin A, Clem B, Makoni S, et al. Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling. Oncogene 2010; 29(1): 139–49PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Nagendra Natarajan
    • 1
  • Sucheta Telang
    • 1
  • Donald Miller
    • 1
  • Jason Chesney
    • 1
  1. 1.Department of Medicine, Division of Medical Oncology/HematologyUniversity of Louisville School of Medicine, James Graham Brown Cancer CenterLouisvilleUSA

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