Skip to main content
SpringerLink
Log in

Tumor Immunotherapy in Melanoma

Strategies for Overcoming Mechanisms of Resistance and Escape

  • Review Article
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

The incidence of melanoma has been steadily increasing over the last 3 decades. Currently, there are several approved treatments for metastatic melanoma, including chemotherapy and biologic therapy as both single treatments and in combination, but none is associated with a significant increase in survival. The chemotherapeutic agent dacarbazine is the standard treatment for metastatic melanoma, with a response rate of 15–20%, although most responses are not sustained. One of the main problems with melanoma treatment is chemotherapeutic resistance. The mechanisms of resistance of melanoma cells to chemotherapy have yet to be elucidated. Following treatment with dacarbazine, melanoma cells activate the extracellular signal-regulated kinase pathway, which results in over-expression and secretion of interleukin (IL)-8 and vascular endothelial growth factor. Melanoma cells utilize this mechanism to escape from the cytotoxic effect of the drug. We have previously reported on the development of fully human neutralizing antibodies against IL-8 (anti-IL-8-monoclonalantibody [ABX-IL8]). In preclinical studies, ABX-IL8 inhibited tumor growth, angiogenesis, and metastasis of human melanoma in vivo. We propose that combination treatment with dacarbazine and IL-8 will potentiate the cytotoxic effect of the drug. Furthermore, formation of metastasis is a multistep process that includes melanoma cell adhesion to endothelial cells. Melanoma cell adhesion molecule (MUC18) mediates these processes in melanoma and is therefore a good target for eliminating metastasis. We have developed a fully human antibody against MUC18 that has shown promising results in preclinical studies. Since resistance is one of the major obstacles in the treatment of melanoma, we propose that utilization of antibodies against IL-8 or MUC18 alone, or as part of a ‘cocktail’ in combination with dacarbazine, may be a new treatment modality for metastatic melanoma that overcomes resistance of the disease to chemotherapy and significantly improves survival of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bevona C, Sober AJ. Melanoma incidence trends. Dermatol Clin 2002; 20 (4): 589–95, vii

    Article  PubMed  Google Scholar 

  2. Howe HL, Wingo PA, Thun MJ, et al. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 2001; 93 (11): 824–42

    Article  PubMed  CAS  Google Scholar 

  3. Johnson TM, Yahanda AM, Chang AE, et al. Advances in melanoma therapy. J Am Acad Dermatol 1998; 38 (5 Pt 1): 731–41

    Article  PubMed  CAS  Google Scholar 

  4. Koh HK. Cutaneous melanoma. ZoN Engl J Med 1991; 325 (3): 171–82

    Article  CAS  Google Scholar 

  5. Sun W, Schuchter LM. Metastatic melanoma. Curr Treat Options Oncol 2001; 2 (3): 193–202

    Article  PubMed  CAS  Google Scholar 

  6. Becker JC, Kampgen E, Brocker E. Classical chemotherapy for metastatic melanoma. Clin Exp Dermatol 2000; 25 (6): 503–8

    Article  PubMed  CAS  Google Scholar 

  7. Cassel WA, Olkowski ZL, Murray DR. Immunotherapy in malignant melanoma [letter]. J Clin Oncol 1999; 17 (6): 1963

    PubMed  CAS  Google Scholar 

  8. Crosby T, Fish R, Coles B, et al. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; (2): CD001215

    PubMed  Google Scholar 

  9. Grossman D, Altieri DC. Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. Cancer Metastasis Rev 2001; 20 (1-2): 3–11

    Article  PubMed  CAS  Google Scholar 

  10. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17 (9): 2745–51

    PubMed  CAS  Google Scholar 

  11. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18 (1): 158–66

    PubMed  CAS  Google Scholar 

  12. Middleton MR, Lorigan P, Owen J, et al. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 2000; 82 (6): 1158–62

    Article  PubMed  CAS  Google Scholar 

  13. Atkins MB. Cytokine-based therapy and biochemotherapy for advanced melanoma. Clin Cancer Res 2006; 12 (7 Pt 2): 2353s–8s

    Article  PubMed  CAS  Google Scholar 

  14. Kirkwood JM, Moschos S, Wang W. Strategies for the development of more effective adjuvant therapy of melanoma: current and future explorations of antibodies, cytokines, vaccines, and combinations. Clin Cancer Res 2006; 12 (7 Pt 2): 2331s–6s

    Article  PubMed  CAS  Google Scholar 

  15. Sondak VK, Sabel MS, Mule JJ. Allogeneic and autologous melanoma vaccines: where have we been and where are we going? Clin Cancer Res 2006; 12 (7 Pt 2): 2337–41

    Article  Google Scholar 

  16. Leslie MC, Bar-Eli M. Regulation of gene expression in melanoma: new approaches for treatment. J Cell Biochem 2005; 94 (1): 25–38

    Article  PubMed  CAS  Google Scholar 

  17. Schadendorf D, Moller A, Algermissen B, et al. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 1993; 151 (5): 2667–75

    PubMed  CAS  Google Scholar 

  18. Lehmann JM, Riethmuller G, Johnson JP. MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci USA 1989; 86 (24): 9891–5

    Article  PubMed  CAS  Google Scholar 

  19. Koon HB, Atkins MB. Update on therapy for melanoma: opportunities for patient selection and overcoming tumor resistance. Expert Rev Anticancer Ther 2007; 7 (1): 79–88

    Article  PubMed  CAS  Google Scholar 

  20. La Porta CA. Drug resistance in melanoma: new perspectives. Curr Med Chem 2007; 14 (4): 387–91

    Article  PubMed  Google Scholar 

  21. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353 (20): 2135–47

    Article  PubMed  CAS  Google Scholar 

  22. von Gise A, Lorenz P, Wellbrock C, et al. Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. Mol Cell Biol 2001; 21 (7): 2324–36

    Article  Google Scholar 

  23. R¨ockmann H, Schadendorf D. Drug resistance in human melanoma: mechanisms and therapeutic opportunities. Onkologie 2003; 26 (6): 581–7

    Article  Google Scholar 

  24. Lev DC, Ruiz M, Mills L, et al. Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther 2003; 2 (8): 753–63

    PubMed  CAS  Google Scholar 

  25. Lev DC, Onn A, Melinkova VO, et al. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 2004; 22 (11): 2092–100

    Article  PubMed  CAS  Google Scholar 

  26. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol 1994; 102 (3): 285–90

    Article  PubMed  CAS  Google Scholar 

  27. Hazan RB, Kang L, Roe S, et al. Vinculin is associated with the E-cadherin adhesion complex. J Biol Chem 1997; 272 (51): 32448–53

    Article  PubMed  CAS  Google Scholar 

  28. Jafari M, Papp T, Kirchner S, et al. Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol 1995; 121 (1): 23–30

    Article  PubMed  CAS  Google Scholar 

  29. Satyamoorthy K, Li G, Gerrero MR, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res 2003; 63 (4): 756–9

    PubMed  CAS  Google Scholar 

  30. Okano J, Rustgi AK. Paclitaxel induces prolonged activation of the Ras/MEK/ERK pathway independently of activating the programmed cell death machinery. J Biol Chem 2001; 276 (22): 19555–64

    Article  PubMed  CAS  Google Scholar 

  31. Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer 2007; 109 (3): 455–64

    Article  PubMed  CAS  Google Scholar 

  32. Kunz M, Goebeler M, Brocker EB, et al. IL-8 mRNA expression in primary malignant melanoma mRNA in situ hybridization: sensitivity, specificity, and evaluation of data. J Pathol 2000; 192 (3): 413–5

    Article  PubMed  CAS  Google Scholar 

  33. Nurnberg W, Tobias D, Otto F, et al. Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma. J Pathol 1999; 189 (4): 546–51

    Article  PubMed  CAS  Google Scholar 

  34. Singh RK, Gutman M, Radinsky R, et al. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 1994; 54 (12): 3242–7

    PubMed  CAS  Google Scholar 

  35. Singh RK, Gutman M, Reich R, et al. Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. Cancer Res 1995; 55 (16): 3669–74

    PubMed  CAS  Google Scholar 

  36. Singh RK, Varney ML, Bucana CD, et al. Expression of interleukin-8 in primary and metastatic malignant melanoma of the skin. Melanoma Res 1999; 9 (4): 383–7

    Article  PubMed  CAS  Google Scholar 

  37. Scheibenbogen C, Mohler T, Haefele J, et al. Serum interleukin-8 (IL-8) is elevated in patients with metastatic melanoma and correlates with tumour load. Melanoma Res 1995; 5 (3): 179–81

    Article  PubMed  CAS  Google Scholar 

  38. Ugurel S, Rappl G, Tilgen W, et al. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 2001; 19 (2): 577–83

    PubMed  CAS  Google Scholar 

  39. Luca M, Huang S, Gershenwald JE, et al. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol 1997; 151 (4): 1105–13

    PubMed  CAS  Google Scholar 

  40. Yoshida S, Ono M, Shono T, et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 1997; 17 (7): 4015–23

    PubMed  CAS  Google Scholar 

  41. Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 2002; 161 (1): 125–34

    Article  PubMed  CAS  Google Scholar 

  42. Xie S, Luca M, Huang S, et al. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res 1997; 57 (11): 2295–303

    PubMed  CAS  Google Scholar 

  43. Shih IM, Speicher D, Hsu MY, et al. Melanoma cell-cell interactions are mediated through heterophilic Mel-CAM/ligand adhesion. Cancer Res 1997; 57 (17): 3835–40

    PubMed  CAS  Google Scholar 

  44. Anfosso F, Bardin N, Frances V, et al. Activation of human endothelial cells via Sendo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK). J Biol Chem 1998; 273 (41): 26852–6

    Article  PubMed  CAS  Google Scholar 

  45. Satyamoorthy K, Muyrers J, Meier F, et al. Mel-CAM-specific genetic suppressor elements inhibit melanoma growth and invasion through loss of gap junctional communication. Oncogene 2001; 20 (34): 4676–84

    Article  PubMed  CAS  Google Scholar 

  46. Mills L, Tellez C, Huang S, et al. Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma. Cancer Res 2002; 62 (17): 5106–14

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by US National Institutes of Health grants CA76098 and P50CA093459. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA

    Maya Zigler, Gabriel J. Villares, Dina C. Lev, Vladislava O. Melnikova &  Menashe Bar-Eli

Authors
  1. Maya Zigler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel J. Villares
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dina C. Lev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vladislava O. Melnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Menashe Bar-Eli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Menashe Bar-Eli.

Additional information

* Both the first and second authors contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zigler, M., Villares, G.J., Lev, D.C. et al. Tumor Immunotherapy in Melanoma. Am J Clin Dermatol 9, 307–311 (2008). https://doi.org/10.2165/00128071-200809050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00128071-200809050-00004

Keywords

Search

Navigation