Results of clinical trials with an allogeneic melanoma tumor cell lysate vaccine: Melacine®
Introduction
The concept that vaccines can trigger a therapeutic immune response to cancer has been the basis for many clinical trials over a number of years [1], [2]. Experiments with allogeneic and xenogeneic cancers in mice showed that cancers could be rejected and subsequent tumor challenge induced a brisk anamnestic immune response [2], [3]. Human cancers have been shown to express antigens that can be recognized by autologous or HLA-matched T cells and induce an immune response [1], [4]. Of the many human cancers studied, melanoma has demonstrated a plethora of different tumor antigens including unique specific cancer antigens, cancer-testis antigens (found only in germ line tissues and cancers), and tissue-restricted differentiation antigens [4], [5], [6], [7], [8], [9], [10], [11], [12]. This observation has led to clinical trials of immunotherapy with an enormous variety of defined antigen vaccines, but as yet none of these vaccines have demonstrated high levels of antitumor activity [2]. We must acknowledge that our current state of knowledge is insufficient to allow us to predict which individual antigens are necessary and sufficient to generate a therapeutic antitumor immune response [13].
On the other hand, the cellular vaccines present a large number of antigens, any one or more of which may be critical to mediating tumor rejection. Our clinical history in tumor immunology has engendered a sense of failure in cancer vaccines [2]. However, much of the problem may lie in the fact that few cancer vaccines have been tested in a setting that would provide the greatest likelihood to demonstrate benefit in a scientifically sound way. There has been an overemphasis on using vaccines to treat widely disseminated disease in patients with significant tumor burden and attendant tumor-induced immunosuppression, as opposed to the adjuvant setting. Phase III controlled clinical trials that have been designed with adequate power to determine efficacy for a vaccine in the adjuvant setting are quite rare.
In this review we will discuss the results that have been achieved in clinical trials of Melacine®, an allogeneic melanoma cell line lysate vaccine combined with a potent immunologic adjuvant (DETOX®) [14].
Section snippets
Phase I and II investigator-initiated clinical trials of Melacine®
In 1988, Malcolm Mitchell and his colleagues published their initial clinical experience with a mixture of mechanical lysates from two allogeneic melanoma cell lines co-administered with an immunologic adjuvant (DETOX®, “detoxified Freund’s adjuvant,” Corixa Corp, Seattle, WA) in 22 patients with advanced melanoma [15]. The trial involved a dose escalation of melanoma lysates with a constant amount of DETOX®. The combined mixture was administered subcutaneously on weeks 1, 2, 3, 4, and 6, in
Phase II and III trials of Melacine® under Ribi/Corixa IND
In 1988, Ribi Immunochem Research of Hamilton, MT (acquired in 1999 by Corixa Corp.) filed the IND for the combination of the two melanoma cell lysates and DETOX® under the trade name Melacine®. Under the Ribi IND, seven open-label phase II trials involving 139 patients with stage III/IV were conducted (see reference [16] and Investigator Brochure, FDA Briefing Document 2/2002). Of the 106 patients with measurable stage IV disease, there were two complete responses (CRs) and five partial
Trials of Melacine plus interferon in stage III and IV melanoma
In 1994, Mitchell reported on 18 patients whose disease had progressed after receiving a 6-week course of Melacine®, but then received interferon-alfa (IFNα) at 5–6 million units (MU)/m2 three times a week [18]. Eight of the 18 patients showed evidence for an objective clinical response to interferon, with a median response duration of 11 months. As a follow-up to this observation, Mitchell reported on 47 patients who enrolled onto a clinical trial of cyclophosphamide pretreatment followed by
SWOG-9035: phase III trial of Melacine in intermediate-thickness melanoma
Based largely on the documented evidence of objective responses in patients with stage IV melanoma using Melacine® alone or with cyclophosphamide, in 1992 the Southwest Oncology Group (SWOG) initiated a phase III observation-controlled trial of Melacine® in patients with intermediate thickness, 1.5–4.0 mm or level IV (if Breslow’s thickness not known or not measurable) and clinically negative regional lymph nodes (T3N0M0 melanoma, SWOG-9035). As suggested by preclinical animal models, it was
Impact of HLA class I expression and outcome after Melacine® vaccination
The concept that a polyvalent vaccine like Melacine® might have differential effects in different patient groups is not an outlandish one. In particular, one host factor clearly influences cytotoxic T cell-mediated responses to antigen and could affect any vaccine results: HLA class I antigen expression (haplotype). In 1992, Mitchell retrospectively evaluated the impact of HLA class I haplotype on the outcome of 70 patients with advanced melanoma treated with Melacine® on five different phase I
Proposed confirmatory trial of Melacine® in patients expressing HLA-A2 and/or HLA-C3
In an effort to confirm these highly promising and intriguing findings, SWOG has proposed an intergroup randomized, phase III trial, S0201. This trial will require nearly 1000 patients expressing either HLA-A2 or HLA-C3 or both. Eligible patients will have “intermediate risk” melanoma as defined by the current AJCC classification system [31], with surgically staged (sentinel node biopsy) node negative melanomas with primary tumors >2 mm in thickness or >1 mm in thickness if ulcerated
Summary
After more than 100 years of study, the optimal methodology for vaccinating patients against their established malignant tumors has not been defined. Indeed, few vaccine strategies have even been compared directly to determine their relative efficacy in the same patient population. Current dogma suggests that vaccines with limited but detectable efficacy in patients with advanced tumors and substantial tumor burden will prove more effective in the adjuvant therapy of minimal residual disease,
Acknowledgements
The authors wish to acknowledge Malcolm S. Mitchell, MD, for his foresight and persistence in the development and evaluation of Melacine®.
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