When will melanoma vaccines be proven effective?

For more than 40 years, investigators have provided countless rationales for the use of cancer vaccines in the prevention and treatment of human cancer [1,2]. No disease has been more targeted for active specific immunotherapy than melanoma. This fascination with melanoma has grown out of a variety of observations, including the rare occurrence of spontaneous clinical remissions, the frequent infiltration of lymphocytes at the primary site of the cancer and its potential prognostic significance, the evidence for objective tumor regressions with cytokines such as interferon alfa and interleukin-2 (presumably through an immune mechanism), and the isolation of functional T cells that recognize melanoma antigens from melanoma patients that can be activated by the same tumor stimuli [3-6]. In addition, there is the virtual absence of any effective nonsurgical treatment for disseminated disease [6a]. During this same time frame, our knowledge of cellular and molecular immunology has progressed from the simple description of different immune cells, such as monocytes and lymphocytes, to the identification of numerous cancer-associated antigens, the T cells that recognize them, and the antigen-presenting cells (APC) that present these cancer antigens to the T lymphocyte [2]. The depth of our understanding and extent of our technical ability now makes it feasible to isolate peptide fragments derived from proteins present within cancer cells that are bound to the major histocompatibity complex (MHC) and presented to the T-cell receptor binding complex on cognate T cells. We now understand the critical role of other cell-surface (“costimulatory”) molecules on both the APC and the T lymphocyte [7]. Finally, we understand better the most effective APC, the dendritic cell, and the importance of its state of maturation to an effective immune response [8]. The disheartening part of these exciting advances in our understanding of the tumor-specific immune response is the lack of corresponding progress in developing vaccines with proven clinical efficacy against melanoma or any other form of cancer [1]. This should be qualified by acknowledging the advances in vaccine development against two cancer-causing viruses— human papilloma virus (type 16) and hepatitis B. Vaccines against these viruses demonstrate that they may prevent development of cervical cancer and hepatocellular cancer, respectively [9,10]. The underlying reasons for this glaring clinical deficiency is likely not due to the lack of cancer-associated antigens to target or the absence of T lymphocytes that can recognize the cancer antigen–MHC complex through their T-cell receptor. Rather, in patients with advanced cancer, the problem is likely attributable to a dysfunctional host immune response secondary to the tumor’s “evade and escape” tactics [11-13]. However, those tactics are not as obvious an explanation for our inability to demonstrate clinically effective vaccines in the adjuvant setting following surgical resection. At present, there is a large body of literature related to the adjuvant use of several different melanoma vaccines. The publication by Berd et al [14] in this issue of the Journal of Clinical Oncology retrospectively summarizes their extensive and unique experience with dinitrophenyl(DNP-) modified autologous melanoma vaccines after complete surgical resection of bulky regional lymph node disease. Their treatment of 214 melanoma patients throughout 10 years is a very impressive accomplishment. But do these vaccines work? In this nonrandomized experience, the 214 patients treated with various vaccination schedules had a 5-year relapse-free survival of 33% and an overall survival of 44%. Considering that all patients had to have palpable nodal JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 3 FEBRUARY 1 2004