Currently, the only curative treatment for primary melanoma is surgical excision. The thickness of the primary melanoma is the most important prognostic factor governing outcome in patients who do not have nodal disease. Patients with thin melanomas (American Joint Committee on Cancer [AJCC] stage I disease) have an excellent prognosis after surgical excision with adequate margins. However, in patients who have a melanoma thicker than 4 mm, nodal disease, or satellitosis (AJCC stage III disease), the rate of systemic recurrence is high, and prognosis is far worse; these patients have a 10-year survival rate of 20% to 40% after lymphadenectomy.
Postsurgical adjuvant therapy is important in patients who are at a high risk of relapse. Adjuvant radiotherapy or chemotherapy, has not had a substantial therapeutic impact in these patients, however.
Biological therapy using interferon-alfa-2b (Intron A) as a post surgical adjuvant has shown benefit in patients with node-positive melanoma in an Eastern Cooperative Oncology Group trial (EST 1684). This study demonstrated that therapy with interferon-alfa-2b after complete resection of nodal metastases improved disease-free survival from 1 to 1.7 years, compared with observation, and also increased overall survival from 2.8 to 3.8 years.
Unfortunately, recently presented results of the confirmatory intergroup trial (EST 1690) found no survival benefit from either high- or low-dose interferon, compared with observation; relapse-free survival was improved in the group treated with high-dose interferon, but there was no improvement in overall survival because delayed high-dose interferon administered after recurrence appeared to provide equivalent benefit.
Responses to chemotherapy in patients who have AJCC stage IV melanoma are also typically poor. Combination chemotherapy with or without biological therapy using interleukin or interferon, while achieving encouraging response rates, has not increased median survival compared to that achieved with single-agent dacarbazine (DTIC-Dome).[4-6] This lack of a survival benefit of combination regimens, coupled with their considerable systemic toxicity, indicate that alternative therapeutic approaches are urgently needed for patients with metastatic melanoma.
Immunotherapy as an adjuvant after surgical resection for stage III melanoma, or as primary therapy for AJCC stage IV disease, is receiving more attention because of exciting data from animal models.[7,8] Active specific immunotherapy using a vaccine has great appeal because of evidence that melanoma may respond to vaccines, without the toxicity that accompanies more conventional regimens. Encouraging results from phase II trials have paved the way for pivotal, phase III, randomized, controlled trials.
In the near future, research on cancer vaccines may finally provide dividends and make active specific immunotherapy a standard regimen for patients with high-risk melanoma. This review addresses the principles of cancer immunity and the goals of vaccine therapy; focuses on the results of clinical trials using different melanoma vaccines; and outlines novel approaches and future directions in melanoma immunotherapy.
Biological therapy is the use of natural physiologic substances produced by the cells of the immune system for treatment designed to enhance natural host defenses in order to produce an antitumor effect. Immunotherapy, one type of biological therapy, can be categorized into active and passive approaches.
Active immunotherapy is the use of agents that will cause the host to mount an immune response, which will lead to tumor cell growth arrest or death; this treatment can be further divided into specific or nonspecific methods. Specific immunotherapy, such as with tumor vaccines, is designed to elicit an immune response to one or more tumor antigens. Nonspecific agents, such as bacillus Calmette-Guérin (BCG) and levamisole (Ergamisol), and, more recently, cytokines, such as interferon and the interleukins, stimulate the immune system globally but do not recruit specific effector cells to produce antibodies or a T-cell response directed against a specific antigen.
In passive immunotherapy, agents, such as monoclonal antibodies and cells previously sensitized to host tumor antigens, are administered to a patient to directly or indirectly mediate tumor killing.
Unlike prophylactic vaccines directed against infectious agents, cancer vaccines are used therapeutically in patients whose tumor cells have already successfully evaded host immunity prior to vaccination. It, therefore, remains a significant obstacle to generate an immune response to transformed cells that are inherently able to escape immune surveillance. This failure to develop endogenous immunity against cells that undergo transformation to the malignant phenotype may be due to many mechanisms, such as loss of major histocompatibility complex (MHC) expression or downregulation of antigen processing.[9,10]
It is apparent that, without costimulatory signals from proinflammatory cytokines during antigen recognition (which, for instance, are present during bacterial infection), T-cells may become tolerant to specific tumor antigens. The potential for a tumor to not only evade the immune system but also prevent that system from mounting an antitumor response by inducing tolerance is a serious concern in active immunotherapy. In order for a vaccine to be effective, therefore, tolerance must be avoided or overcome.
The development of melanoma vaccines has included attempts to define the most relevant antigens that may induce an immune response, with the goal of developing a univalent or an oligovalent vaccine composed of a purified, synthetic, or recombinant antigen. Unfortunately, while some antigens have been shown to be immunogenic in melanoma patients, the data linking response to a particular antigen with extended survival is weak. In addition, it seems that an immune response against multiple antigens induced by a polyvalent vaccine would be more likely to result in maximal tumor cell kill because different cell clones with selective antigen loss reside within a mass of tumor tissue.
At present, it is also unclear whether a T-cell or B-cell response is the optimal effect to strive for with a cancer vaccine. More than likely, stimulation of both T- and B-cell reactivity is beneficial in different tumors. T-cells recognize antigenic peptides that are expressed in association with MHC molecules on the cell surface. Both CD8+ T-cells, which recognize peptides bound to MHC class I molecules, and CD4+ T-cells, which recognize peptides bound to MHC class II molecules, are important for optimal cytotoxic and cytokine effector responses.
Since antigen recognition by T-lymphocytes depends on presentation of a peptide bound to a specific MHC molecule, peptides that do not bind to a host MHC molecule cannot produce a T-cell response. Therefore, only in patients of a specific human lymphocyte antigen (HLA) phenotype can a given peptide induce a significant immune response.
For example, MART-1/Melan-A is a well-defined protein antigen expressed by 80% of melanomas. The immunodominant peptide binds to HLA-A2, which provides MHC restriction to this antigenic peptide. Since only 45% of Caucasians express HLA-A2, only 36% (80% of 45%) will benefit from a MART-1/Melan-A vaccine composed of the immunodominant peptide.
To circumvent these problems, polyvalent vaccines have been developed that incorporate multiple antigens, which have complementary MHC restriction. Some of the known tumor antigens are listed in Table 1. These antigens are either tumor-associated antigens, which are shared by other tumors, or melanoma-associated antigens, which are found primarily in melanomas but also are seen in normal melanocytes.[14,15]
Some basic observations support the view that melanoma may be a good candidate for active specific immunotherapy. Approximately 15% of all melanomas present as metastases without clinical evidence of a primary tumor; such primaries have undergone regression, possibly due to destruction by cytotoxic T-lymphocytes. Histopathologic evidence of tumor regression also has been frequently observed within primary melanoma specimens.[16,17]
Furthermore, antibodies against tumor antigens from patients with melanoma, as well as cytotoxic T-lymphocytes derived from the tumor tissue itself, can produce in vitro destruction of melanoma cells.[18,19] Cytotoxic T-lymphocytes from the blood of healthy volunteers, after priming with melanoma peptides or viruses encoded to produce specific melanoma antigens, have also been demonstrated to induce melanoma cell destruction.[20,21]
1. Morton DL, Wanek L, Nizze JA et al: Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Ann Surg 214:491-501, 1991.
2. 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 14:7-17, 1996.
3. Kirkwood JM, Ibrahim J, Sondak V, et al: Role of high-dose interferon in high risk melanoma: Preliminary results of the E1690/S9111/C9190 US Intergroup postoperative adjuvant trial of high and low-dose interferon-alfa-2b in resected high-risk primary or regionally lymph node metastatic melanoma in relation to 10-year updated results of E1684. Presented at the Symposium on Advances in Biology and Treatment of Cutaneous Melanoma, Boston, Massachusetts, November 7, 1998.
4. Hill GJ, Krementz ET, Hill HZ: Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma: IV. Late results after complete response to chemotherapy. Cancer 53:1299, 1984.
5. Legha SS, Ring S, Bedikan A, et al: Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine, and dacarbazine (CVD) and biotherapy using interleukin-2 and interpheron-alfa. Ann Oncol 7:827-835, 1996.
6. McClay EF, Mastrangelo MJ, Berd D, et al: Effective combination chemo/hormonal therapy for malignant melanoma: Experience with three consecutive trials. Int J Cancer 50:553-556, 1992.
7. Shrayer DP, Bogaars H, Hearing VJ, et al: Immunization of mice with irradiated melanoma tumor cells transfected to secrete lymphokines and coupled with IL-2 or GM-CSF therapy. J Exp Ther Oncol 1:126-133, 1996.
8. Kobayashi M, Kobayashi H, Pollard RB, et al: A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma. J Immunol 160:5869-5873, 1998.
9. Wallich R, Bulbuc N, Hammerling GJ, et al: Abrogation of metastatic properties of tumour cells by de novo expression of H-2K antigens following H-2 gene transfection. Nature 315:301-305, 1985.
10. Restifo NP, Esquivel F, Asher AL, et al: Defective presentation of endogenous antigens by a murine sarcoma: Implications for the failure of an anti-tumor immune response. J Immunol 147:1453-1459, 1991.
11. Pardoll DM: Cancer vaccines. Nat Med 4:525-531, 1998.
12. Topalian S, Solomon D, Rosenberg SA: Tumour-specific lysis by lymphocytes infiltrating human melanomas. J Immunol 142:3714-3720, 1989.
13. Maeurer MJ, Storkus WJ, Kirkwood JM, et al: New treatment options for patients with melanoma: Review of melanoma-derived T-cell epitope-based peptide vaccines. Melanoma Res 6:11-24, 1996.
14. Morton DL, Barth A: Vaccine therapy for malignant melanoma. CA Cancer J Clin 46:225-244, 1996.
15. Ollila DW, Kelley MC, Gammon G, et al: Overview of melanoma vaccines: Active specific immunotherapy for melanoma patients. Semin Surg Oncol 14:328-336, 1998.
16. Trau H, Kopf AW, Riegel DS, et al: Regression in malignant melanoma. J Am Acad Dermatol 8:363-368, 1983.
17. Morton DL, Nizze A, Hoon D, et al: Improved survival of advanced stage IV melanoma following active immunotherapy: Correlation with immune response to melanoma vaccine (abstract). Proc Am Soc Clin Oncol 12:391, 1993.
18. Morton DL, Malmgren RA, Holmes EC, et al: Demonstration of antibodies against malignant melanoma by immunofluorescence. Surgery 64:233-240, 1968.
19. Mukherji B, Chakraborty NG, Sivanandham M: T-cell clones that react against autologous human tumors. Immunol Rev 116:33-62, 1990.
20. Tjandrawan T, Martin DM, Maeurer MJ, et al: Autologous human dendriphages pulsed with synthetic or natural tumor peptides elicit tumor-specific CTLs in vitro. J Immunother 2:149-157, 1998.
21. Zajac P, Oertli D, Spagnoli GC, et al: Generation of tumoricidal cytotoxic T lymphocytes from healthy donors after in vitro stimulation with a replication-incompetent vaccinia virus encoding MART-1/Melan-A 27-35 epitope. Int J Cancer 71:491-496, 1997.
22. Livingston PO, Natoli EJ, Calves MJ, et al: Vaccines containing purified GM2 ganglioside elicit GM2 antibodies in melanoma patients. Proc Natl Acad Sci USA 84:2911-2915, 1987.
23. Livingston PO, Ritter G, Srivastava P, et al: Characterization of IgG and IgM antibodies induced in melanoma patients by immunization with purified GM2 ganglioside. Cancer Res 49:7045-7050, 1989.
24. Hoon DS, Yuzuki D, Hayashida M, et al: Melanoma patients immunized with melanoma cell vaccine induce antibody responses to recombinant MAGE-1 antigen. J Immunol 154:730-737, 1995.
25. Morisaki T, Morton DL, Uchiyama A, et al: Characterization and augmentation of CD4+ cytotoxic T cell lines against melanoma. Cancer Immunol Immunother 39:172-178, 1994.
26. Chan A, Morton DL: Active immunotherapy with allogeneic tumor cell vaccines: Present status. Semin Oncol 25:611-622, 1998.
27. Ravidranath MH, Amiri AA, Bauer PM, et al: Endothelial-selectin ligands sialyl-Lewisx and sialyl-Lewisa are differentiation antigens immunogenic in human melanoma. Cancer 79:1686-1697, 1997.
28. Ravindranath MH, Kelley MC, Jones RC, et al: Ratio of IgG:IgM antibodies to sialyl Lewisx and GM3 correlates with tumor growth after immunization with melanoma-cell vaccine with different adjuvants in mice. Int J Cancer 75:117-124, 1998.
29. Morton DL, Foshag LJ, Hoon DS, et al: Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg 216:463-482, 1992.
30. Morton DL, Nizze A, Hoon D, et al: Improved survival of advanced stage IV melanoma following active immunotherapy: Correlation with immune response to melanoma vaccine (abstract). Proc Am Soc Clin Oncol 12:391, 1993.
31. Hsueh EC, Nizze A, Essner R, et al: Adjuvant immunotherapy with polyvalent melanoma cell vaccine (PMCV) prolongs survival after complete resection of distant melanoma metastases (abstract). Proc Am Soc Clin Oncol 16:492, 1997.
32. Hsueh EC, Gupta RK, Qi K, et al: Correlation of specific immune responses with survival in melanoma patients with distant metastases receiving polyvalent melanoma cell vaccine. J Clin Oncol 16:2913-2920, 1998.
32a. Hsueh EC, Nathanson L, Foshag LJ, et al: Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases. Cancer 85:2160-2169, 1999,
33. Jones RC, Kelley M, Gupta RK, et al: Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: An immunologic survival model. Ann Surg Oncol 3:437-445, 1996.
34. Morton DL, Eilber FR, Holmes EC, et al: Preliminary results of a randomized trial of adjuvant immunotherapy in patients with malignant melanoma who have lymph node metastases. Aust NZ J Surg 48:49-52, 1978.
35. Cascinelli N, Rumke P, MacKie R, et al: The significance of conversion of skin reactivity to efficacy of bacillus Calmette-Guerin (BCG) vaccinations given immediately after radical surgery in stage II melanoma patients. Cancer Immunol Immunother 28:282-286, 1989.
36. Berd D, Mastrangelo MJ: Active immunotherapy of human melanoma exploiting the immunopotentiating effects of cyclophosphamide. Cancer Invest 6:337-349, 1988.
37. Peters LC, Brandhorst JS, Hanna MG Jr: Preparation of immunotherapeutic autologous tumor cell vaccines from solid tumors. Cancer Res 39:1353-1360, 1979.
38. Berd D, Maguire HC Jr, McCue P, et al: Treatment of metastatic melanoma with an autologous tumor-cell vaccine: Clinical and immunologic results in 64 patients. J Clin Oncol 8:1858-1867, 1990.
39. Berd D, Maguire HC Jr, Schucter LM, et al: Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases. J Clin Oncol 15:2359-2370, 1997.
40. Mitchell MS, Harel W, Kempf RA, et al: Active specific immunotherapy of melanoma. J Clin Oncol 10:1158-1164, 1992.
41. Wallack MK: Specific immunotherapy with vaccinia oncolysates. Cancer Immunol Immunother 12:1-4, 1981.
42. Hersey P: Evaluation of vaccinia viral lysates as therapeutic vaccines in the treatment of melanoma. Ann NY Acad Sci 690:167-177, 1993.
43. Wallack MK, Muthukumaran S, Balch CM, et al: Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg 187:69-79, 1998.
44. Roenigk HH Jr, Deodhar S, Jacques RS, et al: Immunotherapy of malignant melanoma with vaccinia virus. Arch Dermatol 109:668-673, 1974.
45. Hersey P: Active immunotherapy with viral lysates of micro-metastases following surgical removal of high-risk melanoma. World J Surg 16:251-260, 1992.
46. Hersey P, Coates A, Tyndall L: Is adjuvant therapy worthwhile? (abstract) Melanoma Res 7:22, 1997.
47. Mitchell MS, Harel W, Kempf RA, et al: Active specific immunotherapy of melanoma. J Clin Oncol 10:1158-1164, 1992.
48. Mitchell MS: Perspective on allogeneic melanoma lysates in active specific immunotherapy. Semin Oncol 25:623-635, 1998.
49. Elliot GT, McLeod RA, Perez J, et al: Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin Surg Oncol 9:264-272, 1993.
50. Mitchell MS, Von Eschen KB: Phase III trial of Melacine melanoma theraccine vs combination chemotherapy in the treatment of stage IV melanoma (abstract). Proc Am Soc Clin Oncol 16:1778, 1997.
51. Bystryn JC: Vaccines for melanoma: Design strategies and clinical results. Dermatol Clin 16:269-275, 1998.
52. Bystryn JC, Oratz R, Roses D, et al: Relation between immune response to melanoma vaccine immunization and clinical outcome in stage II malignant melanoma. Cancer 69:1157-1164, 1992.
53. Bystryn JC, Oratz R, Shapiro RL, et al: Phase III double-blind trial of a shed, polyvalent, melanoma vaccine in stage III melanoma (abstract). Proc Am Soc Clin Oncol 17:434a, 1998.
54. Tai T, Cahan LD, Tsuchida T, et al: Immunogenicity of melanoma-associated gangliosides in cancer patients. Int J Cancer 35:607-612, 1994.
55. Irie RF, Matsuki T, Morton DL: Human monoclonal antibody to ganglioside GM2 for melanoma treatment. Lancet 1:786-787, 1989.
56. Irie RF, Morton DL: Regression of cutaneous metastatic melanoma by intralesional injection with human monoclonal antibody to ganglioside GD2. Proc Natl Acad Sci USA 83:8694-8698, 1986.
57. 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 12:1036-1044, 1994.
58. Livingston PO: Ganglioside vaccines with emphasis on GM2. Semin Oncol 25:636-645, 1998.
59. Kitamura K, Livingston PO, Fortunato SR, et al: Serological response patterns of melanoma patients immunized with a GM2 ganglioside conjugate vaccine. Proc Natl Acad Sci USA 92:2805-2809, 1995.
60. Tsuchida T, Saxton RE, Morton DL, et al: Gangliosides of human melanoma. J Natl Cancer Inst 78:45-54, 1987.
61. Ravidranath MH, Morton DL, Irie RF: An epitope common to gangliosides O-acetyl-GD3 and GD3 recognized by antibodies in melanoma patients after active specific immunotherapy. Cancer Res 49:3891-3897, 1989.
62. Traversari C, van der-Bruggen P, Luescher IF, et al: A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic T lymphocytes directed against tumor antigen MZ2-E. J Exp Med 176:1453-1457, 1992.
63. van der-Bruggen P, Bastin J, Gajewski T, et al: A peptide encoded by human gene MAGE-3 and presented by HLA-A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE-3. Eur J Immunol 24:3038-3043, 1994.
64. Zhai Y, Yang JC, Kawakami Y, et al: Antigen-specific tumor vaccines: Development and characterization of recombinant adenoviruses encoding MART-1 or gp100 for cancer therapy. J Immunol 156:700-710, 1996.
65. Cormier JN, Salgaller ML, Prevette T, et al: Enhancement of cellular immunity in melanoma patients immunized with a peptide from MART/Melan-A. Cancer J Sci Am 3:37-44, 1997.
66. Takechi Y, Hara I, Naftzger C, et al: A melanosomal membrane protein is a cell surface target for melanoma therapy. Clin Cancer Res 2:1837-1842, 1996.
67. Bakker ABH, Schreurs MWJ, de Boer AJ, et al: Melanocyte lineage specific gp100 is recognized by melanoma derived tumor infiltrating lymphocytes. J Exp Med 179:1005-1009, 1994.
68. Pass HA, Schwarz SL, Wunderlich JR, et al: Immunization of patients with melanoma peptide vaccines: Immunologic assessment using the ELISPOT assay. Cancer J Sci Am 4:316-323, 1998.
69. Wolfel T, Van Pel A, Brichard V, et al: Two tyrosinase nonapeptides recognized on HLA-A2 melanomas by autologous cytolytic T lymphocytes. Eur J Immunol 24:759-764, 1994.
70. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321-327, 1998.
71. Marchand M, Weynants P, Rankin E: Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 63:883-885, 1995.
72. Menoret A, Chandawarkar R: Heat-shock protein-based anticancer immunotherapy: An idea whose time has come. Semin Oncol 25:654-660, 1998.
73. Fu TM, Ulmer JB, Caulfield MJ: Priming of cytotoxic T lymphocytes by DNA vaccines: Requirement for professional antigen presenting cells and evidence for antigen transfer from myocytes. Mol Med 3:362-371, 1997.
74. Ulmer JB, Deck RR, DeWitt CM, et al: Expression of a viral protein by muscle cells in vivo induces protective cell-mediated immunity. Vaccine 15:839-841, 1997.
75. Borysiewicz LK, Fiander A, Nimako M, et al: A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet 347:1523-1527, 1996.
76. Schreurs MW, de Boer AJ, Figdor CG, et al: Genetic vaccination against the melanocyte lineage-specific antigen gp100 induces cytotoxic T lymphocyte-mediated tumor protection. Cancer Res 58:2509-2514, 1998.
77. Sun T, Carr-Brendel V, De Zoeten EF, et al: Immunization with interleukin-2-secreting allogeneic cells transfected with DNA from mouse melanoma cells induces immune responses that prolong the lives of mice with melanoma. Cancer Gene Ther 5:110-118, 1998.
78. Mayordomo JI, Zorina T, Storkus WJ, et al: Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med 1:1297-1302, 1995.
79. Hsu FJ, Benike C, Fagnoni F, et al: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52-58, 1996.
80. Gong J, Chen D, Kashiwaba M, et al: Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells. Nat Med 3:558-561, 1997.
81. Nestle FO, Alijagic S, Gilliet M, et al: Vaccination of melanoma patients with peptide- or tumor lysate pulsed dendritic cells. Nat Med 4:328-332, 1998.