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Adjuvant therapy of melanoma - from chemotherapy and cytokines/interferons, to vaccines of high specificity and immunogenicity

Kirkwood, J.M.

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doi: 10.1097/01.cmr.0000382770.98440.97
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Melanoma has eluded international explorations of systemic therapeutics for advanced disease, to date. The successful adjuvant therapy of melanoma with IFN alfa-2b at high dosages, has not been surpassed by any alternative regimens of agents, alone or in combination. This experience allows us to draw principles that pertain to active specific immunotherapy of melanoma—particularly that:

  • (1) The clinical benefits obtained in the adjuvant setting are multifold those obtained in advanced disease;
  • (2) Profiling of subject populations demonstrates subpopulations that are more and less responsive to this therapy;
  • (3) The benefits of IFN adjuvant therapy derive from immunomodulation, not from anti-angiogenic, antitumor cytotoxic or pro-apoptotic mechanisms posited for this pleiotropic agent.

Active specific immunotherapy for melanoma has progressed from studies of crude whole tumor cell vaccines to ganglioside vaccines, and the more recent multicenter cooperative group evaluation of lineage antigens that induce immunity in more than 1/3 of patients with advanced disease, where immune response is correlated with the survival outcome of stage IV disease. These same multi-epitope peptide vaccines have now also been tested in the adjuvant setting (Intergroup E4697). Separately, adenoviral vaccination has been shown to induce antitumor responses, and induction of immunity to nonvaccine epitopes (‘epitope spreading’) is associated with antitumor response. Cancer germline antigens appear to be most relevant to the immunotherapy of melanoma–and MAGE A3 is now being tested in the phase III DERMA trial. This adjuvant study has developed from the systematic exploration of MAGE A3 for immunotherapy of advanced melanoma, and represents the culmination of active specific adjuvant immunotherapy for high-risk melanoma. The foundations of the DERMA trial, the rationale for its exploration in melanoma as a lead indication, and the parallel pursuit of a signature of responsiveness in the tumor tissues of subjects enrolled in this trial will be discussed in the context of current immunological approaches to adjuvant therapy of melanoma. These build logically upon the past 25 years of adjuvant studies in melanoma, and are proceeding on target toward completion of the trial through an international community who are engaged in the immunotherapy for melanoma.

© 2010 Lippincott Williams & Wilkins, Inc.