Strategies to overcome obstacles to successful immunotherapy of melanoma.

Summary The immunogenicity of Malignant Melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this review, we discuss recent data related to the ability of tumors to elude immune responses. In response, we discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression: including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered TCRs. These issues lead to the conclusion that successful immotherapy in malignant melanoma will require a combination of strategies aimed at both inducing immunostimulation and blocking immunosuppression.