Novel Immunotherapies and Novel Combinations of Immunotherapy for Metastatic Melanoma

The introduction of immune checkpoint therapy has dramatically changed the treatment of metastatic melanoma. The characterization of immune checkpoints and the processes that mediate immune recognition of melanoma, as well as the ways in which melanoma escapes immune detection, have opened new areas of investigation in developmental therapeutics within the melanomafield. A central paradigm for drug development is the T-cell-inflamed versus non-inflamed tumor microenvironment. Thismodel characterizes therapies to overcome local mechanisms of immunosuppression to already recognized tumors versus therapies targeting the escape mechanisms that deny the initial infiltration of T cells into atumor. Multiple strategies have been developed to address mechanisms of resistance in T-cellinflamed versus non-T-cell-inflamed tumors. These include novel checkpoints and vaccines, novel antibody therapies, adoptive T-cell therapies, and direct intra-tumoral therapies. This chapter provides an overview of this paradigm in developmental therapies, as well as the multiple agents in development to overcome the multiple mechanisms of resistance in melanoma.