Immunotherapy. Part2
Several centers have investigated the immunogenicity of lysates derived from tumor cells infected with Newcastle disease virus, vaccinia virus, and vesicular stomatitis virus. A multicenter randomized controlled prospective clinical trial that enrolled 250 patients with resected moderate- to high-risk melanoma was recently reported demonstrating the lack of any therapeutic benefit of immunization with the Newcastle disease virus viral oncolysate approach. This is the only randomized controlled multicenter trial of a melanoma tumor cell vaccine reported in the literature. Our understanding of molecular biology of immune response to melanoma has increased greatly since the design of this trial. We know the importance of tumor cell expression of histocompatibility antigens (e.g., HLA-A2) that were lacking in this tumor vaccine, or costimulatory molecules (B7.1) that may have been suboptimal in the vaccine. Yet this trial demonstrates the approach that will be necessary to evaluate the most promising vaccine candidates in the adjuvant setting. As with the SWOG 9035 trial (see later), the eligibility criteria for this trial included T3 (AJCC IIA) lesions for which prognosis is more heterogeneous than for stage IIb or a stage III disease, and the sample size was insufficient to detect small benefits.
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The allogeneic tumor cell vaccine reported first by Mitchell and colleagues, admixed with the immunologic adjuvant Detox (Ribi Immunochem Res, Hamilton, MT) has been studied in a second large multicenter randomized trial that is enrolling moderate-risk T3 N0 patients, and will be completed in 2006. This study has been enlarged from its original goal to 600 patients to increase the power of the trial, and its ability to detect more subtle movements in relapse-free survival. In addition, the understanding of the nature of melanoma antigens recognized has moved forward rapidly, including the discovery of a number of peptide antigens whose recognition is restricted by the HLA-A2 allele, which was absent in the tumor cell lines employed in this vaccine trial.
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Another approach to increasing immune response has been to alter tumor cells by binding haptens to autologous tumor cells. Pilot single-institution data with haptenated autologous tumor cells have been intriguing but, to date, this type of vaccine has not been evaluated in a randomized controlled or multicenter trial, owing in part to the difficulty of manipulating autologous tumor cells for the vaccine.
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A variety of efforts are also underway to immunize melanoma patients with purified or partially purified preparations of potentially immunogenic molecules from melanoma cells. The rationale for this approach comes from the identification of antigens on melanoma cells that can be recognized by antibodies in sera or lymphocytes from patients with melanoma. A large experience using partially purified cultured allogeneic tumor cell antigens has been the stimulus for the initiation of controlled trials of one vaccine preparation derived from shed antigens of cultured melanoma cell lines. Gangliosides have been shown to induce antibody responses after immunization. Of particular interest is that the ganglioside GM2 induces IgM antibody responses in more than 80% of patients immunized with GM2 and BCG following cyclophosphamide treatment at low dose as an immunomodulator. A prospective randomized study evaluated the role of vaccination for 6 months against GM2 with BCG, in comparison to BCG alone, using low-dose cyclophosphamide pretreatment in both groups.
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Serologic studies have shown a favorable prognostic significance for the presence of anti-GM2 ganglioside antibodies, suggesting that the induction of antibodies against gangliosides may confer protection from relapse and mortality due to melanoma. However, native autologous antibody reactivity against GM2 is infrequently detected in patients with melanoma. A variety of vaccination programs utilizing intact autologous and allogeneic cells, and cell fractions derived from allogeneic melanoma cell lines, have been employed to increase immune responses to autologous melanoma cells. The most promising results from randomized controlled trials of vaccination have emerged from studies of purified ganglioside GM2. Livingston and colleagues have performed a series of trials employing autologous tumor cells, and more recently purified ganglioside preparations, with various immunologic adjuvants. The combination of BCG given together with ganglioside GM2 has been shown to induce the formation of increased titers of IgM antibodies in the majority of patients immunized (33 of 44).