ABSTRACT: Investigation into the therapeutic use of vaccines in patients with metastatic melanoma is critically important because of the lack of effective conventional modalities. The most extensively studied melanoma vaccines in clinical trials are whole-cell preparations or cell lysates that contain multiple antigens capable of stimulating an immune response. Unfortunately, in the majority of studies, immune responses to these vaccines have not translated into a survival advantage. Advances in tumor cell immunology have led to the identification of candidate tumor cell antigens that can stimulate an immune response; this, in turn, has allowed for refinements in vaccine design. However, the exact tumor antigens that should be targeted with a specific vaccine are unknown. The univalent antigen vaccines, which have greater purity, ease of manufacturing, and reproducibility compared with polyvalent vaccines, may suffer from poorer efficacy due to immunoselection and appearance of antigen-negative clones within the tumor. Novel approaches to vaccine design using gene transfection with cytokines and dendritic cells are all promising. However, the induction of immune responses does not necessarily confer a therapeutic benefit. Therefore, these elegant newer strategies need to be studied in carefully designed clinical trials so that outcomes can be compared objectively with standard therapy. If survival is improved with these vaccine approaches, their ease of administration and lack of toxicity will firmly entrench active specific vaccine immunotherapy as a standard modality in the treatment of the melanoma patient.[ONCOLOGY 13(11):1561-1574, 1999].
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]
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