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Melanoma

  • Akshay Gupta
  • John M. Kirkwood
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Summary

Melanoma is the fastest rising form of cancer among men and the second fastest rising form of cancer among women and has become an important public health hazard. There has been a 3–7% worldwide annual age standardized incidence increase over the past 5 decades. The current lifetime risk is 1.9% for men and 1.37% for women. Once the disease progresses in regional or distant sites, it is very difficult to treat—and when disseminated it is a devastating illness. Despite an epic number of clinical trials to test a wide variety of anticancer strategies, ranging from surgery to immuno-, radio- and chemotherapy, the average survival rate for patients with metastatic melanoma is still 6-to-10 months. The only 2 FDA approved agents for advanced melanoma are Decarbazine (DTIC) and interleukin-2 (IL-2). The overall response rate (RR) is 15% with the former and 15–20% with the latter. There have been several advances made in understanding the molecular pathways playing important roles in the pathophysiology and chemoresistance of melanoma. Based on this ongoing research, several current novel management strategies, such as immunomodulators, inhibitors of the Raf kinase signal transduction cascade, proapoptotic agents etc., have evolved targeting the molecular pathways critical for survival and progression of melanoma. This chapter reviews the current concepts in the molecular pathogenesis of melanoma, the current medical treatment alternatives and outlines the future directions of further improvement.

Key Words

Melanoma molecular pathogenesis targeting interferon STAT antisense Bc12 BRaf apoptosis cell cycle 

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references

  1. 1.
    de Vries, E., Bray, F. I., Coebergh, J. W. W., and Parkin, D. M. Changing epidemiology of malignant cutaneous melanoma in Europe 1953–1997: rising trends in incidence and mortality but recent stabilizations on western Europe and decreases in Scandinavia. Int. J. Cancer, 107: 119–126, 2003.PubMedGoogle Scholar
  2. 2.
    Manola, J., Atkins, M., Ibrahim, J., and Kirkwood, J. Prognostic factors in metastatic melanoma: a pooled analysis of eastern cooperative oncology group trials. J. Clin. Oncol., 18: 3782–3793, 2000.PubMedGoogle Scholar
  3. 3.
    Jemal, A., Thomas, A., Murray, T., and Thun, T. Cancer Statistics, 2002. CA Cancer J. Clin., 52: 23–47, 2002.PubMedGoogle Scholar
  4. 4.
    Li, G., Satyamoorthy, K., and Herlyn, M. Dynamics of cell interactions and communications during melanoma development. Crit. Rev. Oral Biol. Med., 13: 62–70, 2002.PubMedGoogle Scholar
  5. 5.
    Halaban, R. The regulation of normal melanocyte proliferation. Pig. Cell Res., 13: 4–14, 2000.Google Scholar
  6. 6.
    IARC. Solar and Ultraviolet Radiation. International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risk to Humans, Vol. 55. Lyon, France: International Agency for Research on Cancer, 1992.Google Scholar
  7. 7.
    Valery, C., Grob, J. J., and Verrando, P. Identification by cDNA microarray technology of genes modulated by artificial ultraviolet radiation in normal human melanocytes: relation to melanocarcinogenesis. J. Invest. Dermatol., 117: 1482, 2001.Google Scholar
  8. 8.
    Jean, S., Bideau, C., Bellon, L., Halimi, G., De Méo, M., Orsière, T., Dumenil, G., Bergé-Lefranc, J.-L., and Botta, A. The expression of genes induced in melanocytes by exposure to 35-nm UVA: study by cDNA arrays and real-time quantitative RT-PCR. Biochim. Biophys. Acta, 1522: 89–96, 2001.PubMedGoogle Scholar
  9. 9.
    Kadekaro, A. L., Kavanagh, R. J., Wakamatsu, K., Ito, S., Pipitone, M. A., and Abdel-Malek, Z. A. Cutaneous photobiology. The melanocyte vs. the sun: who will win the final round? Pig. Cell Res., 16: 434–447, 2003.Google Scholar
  10. 10.
    Noonan, F. P., Recio, J. A., and Takayama, H. Neonatal sunburn and melanoma in mice. Nature, 413: 271–272, 2001.PubMedGoogle Scholar
  11. 11.
    Jhappan, C., Noonan, F. P., and Merlino, G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene, 22: 3099–3112, 2003.PubMedGoogle Scholar
  12. 12.
    Kannan, K., Sharpless, N. E., Xu, J., O’Hagan, R. C., Bosenberg, M., and Chin, L. Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. Proc. Natl. Acad. Sci. U. S. A., 100: 1221–1225, 2003.Google Scholar
  13. 13.
    Dazard, J.-E., Gal, H., Amariglio, N., Rechavi, G., Domany, E., and Givol, D. Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer. Oncogene, 22: 2993–3006, 2003.PubMedGoogle Scholar
  14. 14.
    Clydesdale, G. J., Dandie, G. W., and Muller, H. K. Ultraviolet light induced injury: immunological and inflammatory effects. Immunol. Cell Biol., 79: 547–568, 2001.PubMedGoogle Scholar
  15. 15.
    Tada, A., Pereira, E., Beitner-Johnson, D., Kavanagh, R., and Abdel-Malek, Z. A. Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. J. Invest. Dermatol., 118: 316–322, 2002.PubMedGoogle Scholar
  16. 16.
    Jamal, S. and Schneider, R. UV-induction of keratinocyte endothelin-1 down regulates E-cadherin in melanocytes and melanoma cells. J. Clin. Invest., 110: 443–452, 2002.PubMedGoogle Scholar
  17. 17.
    Hussussian, C. J., Struewing, J. P., Goldstein, A. M., Higgins, P. A., Ally, D. S., Sheahan, M. D., Clark, W. H., Tucker, M. A., and Dracopoli, N. C. Germline p16 mutations in familial melanoma. Nat. Genet., 8: 15–21, 1994.PubMedGoogle Scholar
  18. 18.
    Zuo, L., Weger, J., Yang, Z., et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat. Genet., 12: 97–99, 1996.PubMedGoogle Scholar
  19. 19.
    Castellano, M. and Parmiani, G. Genes involved in melanoma: an overview of INK4a and other loci. Melanoma Res., 9: 421–432, 1999.PubMedGoogle Scholar
  20. 20.
    Quelle, D. E., Zindy, F., Ashnum, R. A., and Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell, 83: 993–1000, 1995.PubMedGoogle Scholar
  21. 21.
    Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., Klehmann-Hieb, E., DePlaen, E., Hankeln, T., Meyer zum Buschenfelde, K. H., and Beach, D. A p161NK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science, 269: 1281–1284, 1995.PubMedGoogle Scholar
  22. 22.
    Honda, R. and Yasuda, H. Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J, 18: 22–27, 1999.PubMedGoogle Scholar
  23. 23.
    Gwosdz, C., Scheckenbach, K., Lieven, O., Reifenberger, J., Knopf, A., Bier, H., and Balz, V. Comprehensive analysis of the p53 status in mucosal and cutaneous melanomas. Int. J. Cancer, 118:577–582, 2006.PubMedGoogle Scholar
  24. 24.
    Sauter, E. R., Yeo, U.-C., von Stemm, A., Zhu, W., Litwin, S., Tichansky, D. S., Pistritto, G., Nesbit, M., Pinkel, D., Herlyn, M., and Bastian, B. C. Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res., 62: 3200–3206, 2002.PubMedGoogle Scholar
  25. 25.
    Nelson, M. A., Ariza, M. E., Yang, J. M., Thompson, F. H., Taetle, R., Trent, J. M., Wymer, J., Massey-Brown, K., Broome-Powel, M., Easton, J., Lahti, J. M., and Kidd, V. J. Abnormalities in the p34^cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma. Cancer Genet. Cytogenet., 108: 91–99, 1999.PubMedGoogle Scholar
  26. 26.
    Bales, E. S., Dietrich, C., Bandyopadhyay, D., Schwahn, D. J., Weidong, X., Didenko, V., Leiss, P., Conrad, N., Pereira-Smith, O., Orengo, I., and Medrano, E. E. High levels of expression of p27^KIP1 and cyclin E in invasive primary malignant melanomas. J. Invest. Dermatol., 113: 1039–1046, 1999.PubMedGoogle Scholar
  27. 27.
    Johnson, G. R. and Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinase. Science, 298: 1911–1912, 2002.PubMedGoogle Scholar
  28. 28.
    Busca, R., Abbe, P., Mantoux, F., Aberdam, E., Peyssonnaux, C., Eychène, A., Ortonne, J.-P., and Ballotti, R. Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERFs) in melanocytes. EMBO J., 19: 2900–2910, 2000.PubMedGoogle Scholar
  29. 29.
    Davies, H., Bignell, G., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M., Bottomley, W., Davis, N., Dicks, E., Ewing, R., Floyd, Y., Gray, K., Hall, S., Hawes, R., Hughes, J., Kosmidou, V., Menzies, A., Mould, C., Parker, A., Stevens, C., Watt, S., Hooper, S., Wilson, R., Jayatilake, H., Gusterson, B., Cooper, C., Shipley, J., Hargrave, D., Pritchard-Jones, K., Maitland, N., Chenevix-Trench, G., Riggins, G., Bigner, D., Palmieri, G., Cossu, A., Flanagan, A., Nicholson, A., Ho, J., Leung, S., Yuen, S., Weber, B., Seigler, H., Darrow, T., Paterson, H., Marais, R., Marshall, C., Wooster, R., Stratton, M., and Futreal, P. Mutations of the BRAF gene in human cancer. Nature, 417: 949–954, 2002.PubMedGoogle Scholar
  30. 30.
    Pollock, P. M., Harper, L., Hansen, K. S., Yudt, M. S., Robbins, C. R., Moses, T. Y., Galen, H., Wagner, U., Kakareka, J., Salem, G., Pohida, T., Heenan, P., Duray, P., Kallioniemi, O., Hayward, N. K., Trent, J. M., and Meltzer, P. S. High frequency of BRAF mutations in nevi. Nat. Genet., 33: 19–20, 2003.PubMedGoogle Scholar
  31. 31.
    Demunter, A., Stas, M., Degreef, H., De Wolf-Peeters, C., and van den Oord, J. J. Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma. J. Invest. Dermatol., 117: 1483–1489, 2001.PubMedGoogle Scholar
  32. 32.
    Powell, M. B., Hyman, P., Bell, O. D., Balmain, A., Brown, K., Alberts, D., and Bowden, G. T. Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter. Mol Carcinog., 12: 82–90, 1995.PubMedGoogle Scholar
  33. 33.
    Bastian, B. C. Hypothesis: A role for telomere crisis in spontaneous regression of melanoma. Arch. Dermatol., 139: 667–668, 2003.PubMedGoogle Scholar
  34. 34.
    Ramirez, R. D., D’Atri, S., Pagani, E., Faraggiana, T., Lacal, P. M., Taylor, R. S., and Shay, J. W. Progressive increase in telomerase activity from benign melanocytic conditions to malignant melanoma. Neoplasia (New York), 1: 42–49, 1999.Google Scholar
  35. 35.
    Zhai, S., Yaar, M., Doyle, S. M., and Gilchrest, B. A. Nerve growth factor rescues pigment cells from ultraviolet-induced apoptosis by upregulating BCL-2 levels. Exp. Cell Res., 224: 335–343, 1996.Google Scholar
  36. 36.
    Hodgkinson, C. A., Moore, K. J., Nakayama, A., Steingrimsson, E., Copeland, N. G., Jenkins, N. A., and Arnheiter, H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell, 74: 395–404, 1993.PubMedGoogle Scholar
  37. 37.
    Glinsky, G. V., Glinsky, V. V., Ivanova, A. B., and Hueser, C. J. Apoptosis and metastasis: increased apoptosis resistance of metastatic cancer cells is associated with the profound deficiency of apoptosis execution mechanisms. Cancer Lett., 115: 185–193, 1997.PubMedGoogle Scholar
  38. 38.
    Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J.-L., Schröter, M., Burns, K., Mattmann, C., Rimoldi, D., French, L. E., and Tschopp, J. Inhibition of death receptor signals by cellular FLIP. Nature, 388: 190–195, 1997.PubMedGoogle Scholar
  39. 39.
    Li, F., Ambrosini, G., Chu, E. Y., Plescia, J., Tognin, S., Marchisio, P. C., and Altieri, D. C. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature, 396: 580–584, 1998.PubMedGoogle Scholar
  40. 40.
    Ambrosini, G., Adida, C., Sirugo, G., and Altieri, D. C. Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J. Biol. Chem., 273: 11177–11182, 1998.PubMedGoogle Scholar
  41. 41.
    Vucic, D., Deshayes, K., Ackerly, H., Pisabarro, M. T., Kadkhokayan, S., Fairbrother, W. J., and Dixit, V. M. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP)*. J. Biol. Chem., 277: 12275–12279, 2002.PubMedGoogle Scholar
  42. 42.
    Bullani, R. R., Huard, B., Viard-Leveugle, I., Byers, H. R., Irmler, M., Saurat, J.-H., Tschopp, J., and French, L. E. Selective expression of FLIP in malignant melanocytic skin lesions. J. Invest. Dermatol., 117: 360–364, 2001.PubMedGoogle Scholar
  43. 43.
    Ugurel, S., Seiter, S., Rappl, G., Stark, A., Tilgen, W., and Reinhold, U. Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-y. Int. J. Cancer, 82: 727–736, 1999.PubMedGoogle Scholar
  44. 44.
    Soengas, M. S., Capodieci, P., Polsky, D., Mora, J., Esteller, M., Opitz-Araya, X., McCombie, R., Herman, J. G., Gerald, W. L., Lazebnik, Y. A., Cordón-Cardó, C., and Lowe, S. W. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature, 409: 207–211, 2001.PubMedGoogle Scholar
  45. 45.
    Birck, A., Ahrenkiel, V., Zeuthen, J., Hou-Jensen, K., and Guldberg, P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J. Invest. Dermatol., 114: 277–280, 2000.PubMedGoogle Scholar
  46. 46.
    Zhou, X.-P., Gimm, O., Hampel, H., Niemann, T., Walker, M. J., and Eng, C. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am. J. Pathol., 157: 1123–1128, 2000.PubMedGoogle Scholar
  47. 47.
    McNulty, S. E., Del Rosario, R., Cen, D., Meyskens, F. L., and Yang, S. Comparative expression of NF_KB proteins in melanocytes of normal skin vs. benign intradermal naevus and human metastatic melanoma biopsies. Pig. Cell Res., 17: 173–180, 2004.Google Scholar
  48. 48.
    McNulty, S. E., Tohidian, N. B., and Meyskens, F. L. RelA, p50 and Inhibitor of kappa B alpha are elevated in human metastatic melanoma cells and respond aberrantly to ultraviolet light B. Pig. Cell Res., 14: 456–465, 2001.Google Scholar
  49. 49.
    Buscà, R. and Ballotti, R. Cyclic AMP a key messenger in the regulation of skin pigmentation. Pig. Cell Res., 13: 60–69, 2000.Google Scholar
  50. 50.
    Harsanyi, Z. P., Post, P. W., Brinkmann, J. P., Chedekel, M. R., and Deibel, R. M. Mutagenicity of melanin from human red hair. Experientia, 36: 291–292, 1980.PubMedGoogle Scholar
  51. 51.
    Scot, M. C., Wakamatsu, K., Shosuke, I., Kadedaro, A. L., Kobayashi, N., Groden, J., Kavanagh, R., Takauwa, T., Virador, V., Hearing, V. J., and Abdel-Malek, Z. A. Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation. J. Cell Sci., 115: 2349–2355, 2002.Google Scholar
  52. 52.
    Box, N. F., Duffy, D. L., Chen, W., Stark, M., Martin, N. G., Sturm, R. A., and Hayward, N. K. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Am. J. Hum. Genet., 69: 765–773, 2001.PubMedGoogle Scholar
  53. 53.
    Aaronson, D. S. and Horvath, C. M. A road map for those who don’t know JAK-STAT. Science, 296: 1653–1655, 2002.PubMedGoogle Scholar
  54. 54.
    Yu, H. and Jove, R. The stats of cancer - new molecular targets come of age. Nat. Rev., 4: 97–105, 2004.Google Scholar
  55. 55.
    Yu, H. and Jove, R. The STATs of cancer–new molecular targets come of age. Nat Rev Cancer, 4: 97–105, 2004.PubMedGoogle Scholar
  56. 56.
    Wong, L. H., Krauer, K. G., Hatzinisiriou, I., Estcourt, M. J., Hersey, P., Tam, N. D., Edmondson, S., Devenish, R. J., and Ralph, S. J. Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3γ. J. Biol. Chem., 272: 28779–28785, 1997.PubMedGoogle Scholar
  57. 57.
    Niu, G., Bowman, T., Huang, M., Shivers, S., Reintgen, D., Daud, A., Chang, A., Kraker, A., Jove, R., and Yu, H. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene, 21: 7001–7010, 2002.PubMedGoogle Scholar
  58. 58.
    Xu, Q., Briggs, J., Park, S., Niu, G., Kortylewski, M., Zhang, S., Gritsko, T., Turkson, J., Kay, H., Semenza, G. L., Cheng, J. Q., Jove, R., and Yu, H. Targeting Stat3 blicks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene, 24: 5552–5560, 2005.PubMedGoogle Scholar
  59. 59.
    Xie, T.-X., Wei, D., Liu, M., Gao, A. C., Ali-Osman, F., Sawaya, R., and Huang, S. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 23: 3550–3560, 2004.PubMedGoogle Scholar
  60. 60.
    Wang, T., Niu, G., Kortylewski, M., Burdelya, L., Shain, K., Zhang, S., Bhattacharya, R., Gabrilovich, D., Heller, R., Coppola, D., Dalton, W., Jove, R., Pardoll, D., and Yu, H. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med., 10: 48–54, 2004.PubMedGoogle Scholar
  61. 61.
    Kortylewski, M., Jove, R., and Yu, H. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev., 24: 315–327, 2005.PubMedGoogle Scholar
  62. 62.
    Hsu, M. Y., Wheelock, M. J., Johnson, K. R., and Herlyn, M. Shifts in cadherin profiles between human normal melanocytes and melanomas. J. Investig. Dermatol. Symp. Proc., 1: 188–194, 1996.PubMedGoogle Scholar
  63. 63.
    Xie, S., Luca, M., Huang, S., Gutman, M., Reich, R., Johnson, J. P., and Bar-Eli, M. Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. Cancer Res., 57: 2295–2303, 1997.PubMedGoogle Scholar
  64. 64.
    Voura, E. B., Ramjeesingh, R. A., Montgomery, A. M. P., and Siu, C.-H. Involvement of integrin vα3 and cell adhesion molecule L1 in transendothelial migration of melanoma cells. Mol. Biol. Cell, 12: 2699–2710, 2001.PubMedGoogle Scholar
  65. 65.
    Ito, A., Katoh, F., Kataoka, T. R., Okada, M., Tsubota, N., Asada, H., Yoshikawa, K., Maeda, S., Kitamura, Y., Yamasaki, H., and Nojima, H. A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest., 105: 1189–1197, 2000.PubMedGoogle Scholar
  66. 66.
    Velazquez, O. C. and Herlyn, M. The vascular phenotype of melanoma metastasis. Clin. Exp. Metastasis, 20: 229–235, 2003.PubMedGoogle Scholar
  67. 67.
    Barnhill, R. L., Fandrey, K., Levy, M. A., Mihm, M. C., Jr., and Hyman, B. Angiogenesis and tumor progression of melanoma quantification of vascularity in melanocytic nevi and cutaneous malignant melanoma. Lab. Invest., 67: 331–337, 1992.PubMedGoogle Scholar
  68. 68.
    Srivastava, A., Laidler, P., Hughes, L. E., Woodcock, J., and Shedden, E. J. Neovascularization in human cutaneous melanoma: a quantitative morphological and Doppler ultrasound study. Eur. J. Cancer Clin. Oncol., 22: 1205–1209, 2003.Google Scholar
  69. 69.
    Massi, D., Franchi, A., Borgognoni, L., Paglierani, M., Reali, U. M., and Santucci, M. Tumor angiogenesis as a prognostic factor in thick cutaneous malignant melanoma. A quantitative morphologic analysis. Virchows Arch., 440: 22–28, 2002.Google Scholar
  70. 70.
    Kashani-Sabet, M., Sagebiel, R. W., Carlow, M., Ferreira, M., and Miller, J. R. Tumor vascularity in the prognostic assessment of primary cutaneous melanoma. J Clin Oncol, 20: 1826–1831, 2002.PubMedGoogle Scholar
  71. 71.
    Streit, M. and Detmar, M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene, 22: 3172–3179, 2003.PubMedGoogle Scholar
  72. 72.
    Seftor, E. A., Meltzer, P. S., Kirschmann, D. A., Peer, J., Maniotis, A. J., Trent, J. M., Folberg, R., and Hendrix, M. J. C. Molecular determinants of human uveal melanoma invasion and metastasis. Clin. Exp. Metastasis, 19: 233–246, 2002.PubMedGoogle Scholar
  73. 73.
    Hendrix, M. J. C., Seftor, E. A., Hess, A. R., and Seftor, R. E. B. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat. Rev. Cancer, 3: 411–421, 2003.PubMedGoogle Scholar
  74. 74.
    Van Belle, P. A., Elenitsas, R., Satyamoorthy, K., Wolfe, J. T., Guerry, D., Schuchter, L., Van Belle, T. J., Albelda, S., Tahin, P., Herlyn, M., and Elder, D. E. Progression-related expression of beta3 integrin in melanomas and nevi. Hum. Pathol., 30: 562–567, 1999.PubMedGoogle Scholar
  75. 75.
    Mitjans, F., Meyer, T., Fittschen, C., Goodman, S., Jonczyk, A., Marshall, J. F., Reyes, G., and Piulats, J. In vivo therapy of malignant melanoma by means of antagonists of αv integrins. Int. J. Cancer, 87: 716–723, 2000.PubMedGoogle Scholar
  76. 76.
    Anichini, A., Vegetti, C., and Mortarini, R. The paradox of T cell-mediated antitumor immunity in spite of poor clinical outcome in human melanoma. Cancer Immunol. Immunother., 53: 855–864, 2004.PubMedGoogle Scholar
  77. 77.
    Agarwala, S. S. and Kirkwood, J. M. Adjuvant therapy of melanoma. Semin. Surg. Oncol., 14: 302–310, 1998.PubMedGoogle Scholar
  78. 78.
    Clemente, C. G., Mihm, M. C., Jr., Bufalino, R., Zurrida, S., Collini, P., and Cascinelli, N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer, 77: 1303–1310, 1996.PubMedGoogle Scholar
  79. 79.
    Marincola, F. M., Wang, E., Herlyn, M., Seliger, B., and Ferrone, S. Tumors as elusive targets of T-cell-based active immunotherapy. Trend Immunol., 24: 334–341, 2003.Google Scholar
  80. 80.
    Uyttenhove, C., Pilotte, L., Théate, I., Stroobant, V., Colau, D., Parmentier, N., Boon, T., and Van den Eynde, B. J. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med., 9: 1269–1274, 2005.Google Scholar
  81. 81.
    Murakami, T., Cardones, A. R., Finkelstein, S. E., Restifo, N. P., Klaunberg, B. A., Nestle, F. O., Castillo, S. S., Dennis, P. A., and Hwang, S. T. Immune evasion by murine melanoma mediated through CC chenokine recptor-10. J. Exp. Med., 198: 1337–1347, 2003.PubMedGoogle Scholar
  82. 82.
    Péguet-Navarro, J., Sportouch, M., Popa, I., Berthier, O., Schmitt, D., and Portoukalian, J. Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J. Immunol., 170: 3488–3494, 2003.PubMedGoogle Scholar
  83. 83.
    Geertsen, R. C., Hofbauer, G. F. L., Yue, F.-Y., Manolio, S., Berg, G., and Dummer, R. Higher frequency of selective losses of HLA-A and -B allospecificities in metastasis than in primary melanoma lesions. J. Invest. Dermatol., 111: 497–502, 1998.PubMedGoogle Scholar
  84. 84.
    Kageshita, T., Hirai, S., Ono, T., Hicklin, D. J., and Ferrone, S. Down-regulation of HLA class I antigen-processing molecules in malignant melanoma. Am. J. Pathol., 154: 745–754, 1999.PubMedGoogle Scholar
  85. 85.
    Dissemond, J., Kothen, T., Mörs, J., Weinann, T. K., Lindeke, A., Goos, M., and Wagner, S. N. Downregulation of tapasin expression in progressive human malignant melanoma. Arch. Dermatol. Res., 295: 43–49, 2003.PubMedGoogle Scholar
  86. 86.
    Mortarini, R., Piris, A., Maurichi, A., Molla, A., Bersani, I., Bono, A., Bartoli, C., Santinami, M., Lombardo, C., Ravagnani, F., Cascinelli, N., Parmiani, G., and Anichini, A. Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. Cancer Res., 63: 2535–2545, 2003.PubMedGoogle Scholar
  87. 87.
    Wang, H. Y., Lee, D. A., Peng, G., Guo, Z., Li, Y., Kiniwa, Y., Shevach, E. M., and Wang, R.-F. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity, 20: 107–118, 2004.PubMedGoogle Scholar
  88. 88.
    Buzaid, A. C., Ross, M. I., Balch, C. M., Soong, S.-J., McCarthy, W. H., Tinoco, L., Mansfield, P., Lee, J. E., Bedikian, A., Eton, O., Plager, C., Papadopoulos, N., Legha, S. S., and Benjamin, R. S. Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J. Clin. Oncol., 15: 1039–1051, 1997.PubMedGoogle Scholar
  89. 89.
    Kirkwood, J. M., Manola, J., Ibrahim, J., Sondak, V., Ernstoff, M. S., and Rao, U. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin.Cancer Res., 10: 1670–1677, 2004.PubMedGoogle Scholar
  90. 90.
    Kirkwood, J. M., Strawderman, M. H., Ernstoff, M. S., Smith, T. J., Borden, E. C., and Blum, R. H. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J. Clin. Oncol., 14: 7–17, 1996.PubMedGoogle Scholar
  91. 91.
    Kirkwood, J. M., Ibrahim, J. G., Sondak, V. K., Richards, J., Flaherty, L. E., Ernstoff, M. S., Smith, T. J., Rao, U. N. M., Steele, M., and Blum, R. H. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J. Clin. Oncol., 18: 2444–2458, 2000.PubMedGoogle Scholar
  92. 92.
    Kirkwood, J. M., Ibrahim, J., Lawson, D. H., Atkins, M. B., Agarwala, S. S., Collins, K., Mascari, R., Morrissey, D. M., and Chapman, P. B. High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the multicenter Eastern Cooperative Oncology Group phase II trial E2696. J. Clin. Oncol., 19: 1430–1436, 2001.PubMedGoogle Scholar
  93. 93.
    Kirkwood, J. M., Bender, C., Agarwala, S. S., Tarhini, A., Shipe-Spotloe, J., Smith, D., Smelko, B., Donnelly, S., and Stover, L. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J. Clin. Oncol., 20: 3703–3718, 2002.PubMedGoogle Scholar
  94. 94.
    Caraglia, M., Marra, M., Pelaia, G., Maselli, R., Caputi, M., Marsico, S. A., and Abbruzzese, A. Alpha-interferon and its effects on signal transduction pathways. J. Cell. Physiol., 202: 323–335, 2005.PubMedGoogle Scholar
  95. 95.
    Belardelli, F., Ferrantini, M., Proietti, E., and Kirkwood, J. M. Interferon-alpha in tumor immunity and immunotherapy. Cytokine Growth Factor Rev., 13: 119–134, 2002.PubMedGoogle Scholar
  96. 96.
    Beadling, C., Guschin, D., Witthuhn, B. A., Ziemiecki, A., Ihle, J. N., Kerr, I. M., and Cantrell, D. A. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon α, but not the T cell antigen receptor, in human T lymphocytes. EMBO J., 13: 5605–5615, 1994.PubMedGoogle Scholar
  97. 97.
    Yang, C.-H., Murti, A., and Pfeffer, L. M. STAT3 complements defects in an interferon-resistant cell line: Evidence for an essential role for STAT3 in interferon signaling and biological activities. Proc. Natl. Acad. Sci. U. S. A., 95: 5568–5572, 1998.Google Scholar
  98. 98.
    Fish, E. N., Uddin, S., Korkmaz, M., Majchrzak, B., Druker, B. J., and Platanias, L. C. Activation of a CrkL-stat5 signaling complex by type I interferons. J. Biol. Chem., 274: 571–573, 1999.PubMedGoogle Scholar
  99. 99.
    Sangfelt, O., Erickson, S., Castro, J., Heiden, T., Einhorn, S., and Grander, D. Induction of apoptosis and inhibition of cell growth are independent responses to interferon-alpha in hematopoietic cell lines. Cell Growth Differ., 8: 343–352, 1997.PubMedGoogle Scholar
  100. 100.
    Thyrell, L., Erickson, S., Zhivotovsky, B., Pokrovskaja, K., Sangfelt, O., Castro, J., Einhorn, S., and Grander, D. Mechanisms of Interferon-alpha induced apoptosis in malignant cells. Oncogene, 21: 1251–1262, 2002.PubMedGoogle Scholar
  101. 101.
    Panaretakis, T., Pokrovskaja, K., Shoshan, M., and Grandér, D. Interferon-α-induced apoptosis in U266 cells is associated with activation of the proapoptotic Bcl-2 family members Bak and Bax. Oncogene, 22: 4543–4556, 2003.PubMedGoogle Scholar
  102. 102.
    David, M., Petricoin, E., III, Benjamin, C., Pine, R., Weber, M. J., and Larner, A. C. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science, 269: 1721–1723, 1995.PubMedGoogle Scholar
  103. 103.
    Gil, J. and Esteban, M. Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action. Apoptosis, 5: 107–114, 2000.PubMedGoogle Scholar
  104. 104.
    Moschos, S. J., Edington, H. D., Land, S. R., Rao, U. N., Jukic, D., Shipe-Spotloe, J., and Kirkwood, J. M. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J. Clin. Oncol., 24: 3164–3171, 2006.PubMedGoogle Scholar
  105. 105.
    Wang, W., Edington, H., Rao, U., Jukic, D., Moschos, S., Mascari, R., Sander, C., Becker, D., Ferrone, S., and Kirkwood, J. M. Effects of neoadjuvant high-dose interferon (IFNα2β) upon STAT signaling, IFNαRβ, MHC and Tap expression in lymph node metastatic melanoma (UPCI 008). Proc. Am. Assoc. Cancer Res., 13: 1523–31, 2005.Google Scholar
  106. 106.
    Collisson, E. A., De, A., Suzuki, H., Gambhir, S. S., and Kolodney, M. S. Treatment of metastatic melanoma with an orally available inhibitor of the Ras-Raf-MAPK cascade. Cancer Res., 63: 5669–5673, 2003.PubMedGoogle Scholar
  107. 107.
    Karasarides, M., Chiloeches, A., Hayward, R., Niculescu-Duvaz, D., Scanlon, I., Friedlos, F., Ogilvie, L., Hedley, D., Martin, J., Marshall, C. J., Springer, C. J., and Marais, R. B-RAF is a therapeutic target in melanoma. Oncogene, 23: 6292–6298, 2004.PubMedGoogle Scholar
  108. 108.
    Ahmad, T., Marais, R., Pyle, L., James, M., Schwartz, B., Gore, M., and Eiden, T. BAY 43–9006 in patients with advanced melanoma: the Royal Marsden experience. Proc. Am. Soc. Clin. Oncol., 22(14S): 711s, 2004.Google Scholar
  109. 109.
    Flaherty, K. T., Brose, M., Schuchter, L., Tuveson, D., Lee, R., Schwartz, B., Lathia, C., Weber, B., and O’Dwyer, P. Phase I/II trial of BAY 43–9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. Proc. Am. Soc. Clin. Oncol., 22(14S): 711s, 2004.Google Scholar
  110. 110.
    Morgan, G. J., Krishnan, B., Jenner, M., and Davies, F. E. Advances in oral therapy for multiple myeloma. Lancet Oncol., 7: 316–325, 2006.PubMedGoogle Scholar
  111. 111.
    Trisciuoglio, D., Desideri, M., Ciuffreda, L., Mottolese, M., Ribatti, D., Vacca, A., Del Rosso, M., Larcocci, L., Zupi, G., and Del Bufalo, D. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. J. Cell. Physiol., 205: 141–421, 2005.Google Scholar
  112. 112.
    Jansen, B., Wacheck, V., Heere-Ress, E., Schlagbauer-Wadl, H., Hoeller, C., Lucas, T., Hoermann, M., Hollenstein, U., Wolff, K., and Pehamberger, H. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet, 356: 1728–1733, 2000.PubMedGoogle Scholar
  113. 113.
    Kirkwood, J. M., Bedikian, A. Y., Millward, M. J., Conry, R. M., Gore, M. E., Pehamberger, H. E., Sterry, W., Pavlick, A. C., DeConti, R. C., and Itri, L. M. Long-term survival results of a randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM). Proc. Am. Soc. Clin. Oncol., 23(16S): 711s, 2005.Google Scholar
  114. 114.
    Eisen, T., Boshoff, C., Mak, I., Sapunar, F., Vaughan, M. M., Pyle, L., Johnston, S. R. D., Ahern, R., Smith, I. E., and Gore, M. E. Continuous low dose thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br. J. Cancer, 82: 812–817, 2000.PubMedGoogle Scholar
  115. 115.
    Danson, S., Lorigan, P., Arance, A., Clamp, A., Ranson, M., Hodgetts, J., Lomax, L., Ashcroft, L., Thatcher, N., and Middleton, M. R. Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma. J. Clin. Oncol., 21: 2551–2557, 2003.PubMedGoogle Scholar
  116. 116.
    Hwu, W.-J., Krown, S. E., Menell, J. H., Panageas, K. S., Merrell, J., Lamb, L. A., Williams, L. J., Quinn, C. J., Foster, T., Chapman, P. B., Livingston, P. O., Wolchok, J. D., and Houghton, A. N. Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J. Clin.Oncol., 21: 3351–3356, 2003.PubMedGoogle Scholar
  117. 117.
    Wu, H., Beuerlein, G., Nie, Y., Smith, H., Lee, B. A., Hensler, M., Huse, W. D., and Watkins, J. D. Stepwise in vitro affinity maturation of Vitaxin, an αvβ3-specific humanized mAb. Proc. Natl. Acad. Sci. U. S. A., 95: 6037–6042, 1998.Google Scholar
  118. 118.
    Bartlett, J. B., Michael, A., Clarke, I. A., Dredge, K., Nicholson, S., Kristeleit, H., Polychronis, A., Pandha, H., Muller, G. W., Stirling, D. I., Zeldis, J., and Dalgleish, A. G. Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br. J. Cancer, 90: 955–961, 2004.PubMedGoogle Scholar
  119. 119.
    Peterson, A. C., Swiger, S., Stadler, W. M., Medved, M., Karczmar, G., Gajewski, T. F. Phase II study of the Flk-1 TK inhibitor SU5416 in patients with advanced melanoma. Proc. Am. Soc. Clin. Oncol., 22: 712, 2003.Google Scholar
  120. 120.
    Carson, W. E., Biber, J., Shah, N., Reddy, K., Kefauver, C., Leming, P. D., Kendre, K., and Walker, M. A phase 2 trial of a recombinant humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody in patients with malignant melanoma. Proc. Am. Soc. Clin. Oncol., 22: 715, 2003.Google Scholar
  121. 121.
    Asea, A., Hermodsson, S., and Hellstrand, K. Histaminergic regulation of natural killer cell-mediated clearance of tumor cells in mice. Scand. J. Immunol., 43: 9–15, 1996.PubMedGoogle Scholar
  122. 122.
    Hellstrand, K., Naredi, P., Lindner, P., Lundholm, K., Rudenstam, C. M., Hermodsson, S., Asztely, M., and Hafstrom, L. Histamine in immunotherapy of advanced melanoma: a pilot study. Cancer Immunol. Immunother., 39: 416–419, 1994.PubMedGoogle Scholar
  123. 123.
    Agarwala, S. S., Glaspy, J., O’Day, S. J., Mitchell, M., Gutheil, J., Whitman, E., Gonzalez, R., Hersh, E., Feun, L., Belt, R., Meyskens, F., Hellstrand, K., Wood, D., Kirkwood, J. M., Gehlsen, K. R., and Naredi, P. 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, 2002.PubMedGoogle Scholar
  124. 124.
    Hauschild, A. First analysis of international M-02 trial: histamine, interferon alpha-2b (IFN), interleukin (IL)-2 vs dacarbazine (DTIC). Proceedings of perspectives in Melanoma Management, Tampa, Florida, 2003 (abstr.).Google Scholar
  125. 125.
    Kawakami, Y., Eliyahu, S., Delgado, C. H., Robbins, P. F., Rivoltini, L., Topalian, S. L., Miki, T., and Rosenberg, S. A. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl. Acad. Sci. U. S. A., 91: 3515–3519, 1994.Google Scholar
  126. 126.
    Livingston, P. O., Wong, G. Y. C., Adluri, S., Tao, Y., Padavan, M., Parente, R., Hanlon, C., Calves, M. J., Helling, F., Ritter, G., Oettgen, H. F., and Old, L. J. Improved survival in stage III melanoma patients with gm2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J. Clin. Oncol., 12: 1036–1044, 1994.PubMedGoogle Scholar
  127. 127.
    Kirkwood, J. M., Ibrahim, J., Sosman, J. A., Sondak, V. K., Agarwala, S. S., Ernstoff, M. S., and Rao, U. 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., 19: 2370–2380, 2001.PubMedGoogle Scholar
  128. 128.
    Cebon, J., Jäger, E., Shackleton, M. J., Gibbs, P., Davis, I. D., Hopkins, W., Gibbs, S., Chen, Q., Karbach, J., Jackson, H., MacGregor, D. P., Sturrock, S., Vaughan, H., Maraskovisky, E., Neumann, A., Hoffman, E., Sherman, M., and Knuth, A. Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma. Cancer Immun., 3: 7, 2003.PubMedGoogle Scholar
  129. 129.
    Kirkwood, J. M., Lee, S., Land, S., Sander, C., Mascari, R., Weiner, L. M., and Whiteside, T. L. E1696: Final analysis of the clinical and immunological results of a multicenter ECOG phase II trial of multi-epitope peptide vaccination for stage IV melanoma with MART-1 (27–35), gp100 (209–217, 210M), and tyrosinase (368–376, 370D) (MGT) =/- IFNα2b and GM-CSF. Proc. Am. Soc. Clin. Oncol., 22(14S): 145. 2004.Google Scholar
  130. 130.
    Sosman, J. A., Weeraratna, A. T., and Sondak, V. K. When will melanoma vaccines be proven effective. J. Clin. Oncol., 22: 387–389, 2004.PubMedGoogle Scholar
  131. 131.
    Chan, A. D. and Morton, D. L. Active immunotherapy with allogeneic tumor cell vaccines: present status. Semin. Oncol., 25: 611–622, 1998.PubMedGoogle Scholar
  132. 132.
    Sondak, V. K. and Sosman, J. A. Results of clinical trials with an allogenic melanoma tumor cell lysate vaccine: MelacineˆledR. Semin. Cancer Biol., 13: 409–415, 2003.PubMedGoogle Scholar
  133. 133.
    Belli, F., Testori, A., Rivoltini, L., Maio, M., Andreola, G., Sertoli, M., Gallino, G., Piris, A., Cattelan, A., Lazzari, I., Carrabba, M., Scita, G., Santantonio, C., Pilla, L., Tragni, G., Lombardo, C., Arienti, F., Marchiano, A., Queirolo, P., Bertolini, F., Cova, A., Lamaj, E., Ascani, L., Camerini, R., Corsi, M., Cascinelli, N., Lewis, J., Srivastava, P., and Parmiani, G. Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J. Clin. Oncol., 20: 4169–4180, 2002.PubMedGoogle Scholar
  134. 134.
    Soiffer, R., Hodi, F. S., Haluska, F., Jung, K., Gillessen, S., Singer, S., Tanabe, K., Duda, R., Mentzer, S., Jaklitsch, M., Bueno, R., Clift, S., Hardy, S., Neuberg, D., Mulligan, R., Webb, I., Mihm, M., and Dranoff, G. Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J. Clin. Oncol., 21: 3343–3350, 2003.PubMedGoogle Scholar
  135. 135.
    Smith, C. L. Results of a phase I study evaluating “prime-boost” therapeutic vaccination strategies using a string of melanoma-derived CD8+ T cell epitopes in stage II/III/IV melanoma patients. Proc. Am. Soc. Clin. Oncol., 22, 175. 2003.Google Scholar
  136. 136.
    Bedrosian, I., Mick, R., Xu, S., Nisenbaum, H., Faries, M., Zhang, P., Cohen, P. A., Koski, G., and Czerniecki, B. J. Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J. Clin. Oncol., 21: 3826–3835, 2003.PubMedGoogle Scholar
  137. 137.
    Schadendorf, D., Nestle, F. O., Broecker, E.-B., Enk, A., Grabbe, S., Ugurel, S., Edler, L., Schuler, G., and DeCPG-DC Stidu Group. Dacarbacine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) as first-line treatment of patients with metastatic melanoma: results of a prospective-randomized phase III study. Proc. Am. Soc. Clin. Oncol., 22(14S). 2005.Google Scholar
  138. 138.
    Dudley, M., Wunderlich, J., Robbins, P., Yang, J., Hwu, P., Schwartzentruber, D., Topalian, S., Sherry, R., Restifo, N., Hubicki, A., Robinson, M., Raffeld, M., Duray, P., Seipp, C., Rogers-Freezer, L., Morton, K., Mavroukakis, S., White, D., and Rosenberg, S. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science, 289: 850–854, 2002.Google Scholar
  139. 139.
    Leach, D. R., Krummel, M. F., and Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271: 1734–1736, 1996.PubMedGoogle Scholar
  140. 140.
    van Elsas, A., Hurwitz, A. A., and Allison, J. P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med., 190: 355–366, 1999.PubMedGoogle Scholar
  141. 141.
    Phan, G. Q., Yang, J. C., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Freezer, L. J., Morton, K. E., Mavroukakis, S. A., Duray, P. H., Steinberg, S. M., Allison, J. P., and Davis, T. A. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl. Acad. Sci. U. S. A., 100: 8372–8377, 2003.Google Scholar
  142. 142.
    Schneeberger, A., Wagner, C., Zemann, A., Lührs, P., Kutil, R., Goos, M., Stingl, G., and Wagner, S. N. CpG motifs are efficient adjuvants for DNA cancer vaccines. J. Invest. Dermatol., 123: 371–379, 2004.PubMedGoogle Scholar

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© Humana Press 2008

Authors and Affiliations

  • Akshay Gupta
  • John M. Kirkwood

There are no affiliations available

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