ABSTRACT
The treatment landscape for patients with advanced melanoma has dramatically improved over the past decade, leading to unprecedented survival. Despite the robust activity of single-agent immune-checkpoint blockade with anti-CTLA-4 or anti-PD-1 agents, and the efficacy of targeted therapies capable of interrupting aberrant signaling resulting from BRAF mutations, the benefit from these therapies is not universal. Advanced understanding of immune and molecular processes underlying melanoma tumorigenesis has demonstrated the promise of combined, multidrug regimens. We discuss the currently available evidence that supports using combinatorial approaches in advanced melanoma treatment and provide insights into promising new combination strategies under investigation.
Subject(s)
Drug Therapy, Combination/methods , Melanoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Drug Resistance, Neoplasm/genetics , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy , Melanoma/genetics , Melanoma/pathology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitorsABSTRACT
The development of new treatment options has dramatically improved the landscape for patients with advanced melanoma. Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell-mediated responses termed "immune checkpoints." Indeed, blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients. Targeting a distinct checkpoint, the PD-1 yielded improved outcomes and reduced toxicity compared with CTLA-4 blockade and, in separate studies, chemotherapy. More recently, combined CTLA-4/PD-1 blockade was shown to result in higher response rates, while accompanied by increased toxicity. In this article, we review the clinical development of anti-PD-1 monotherapy and combinations that may expand the benefit of immunotherapy for patients with advanced melanoma.
Subject(s)
Melanoma/metabolism , Programmed Cell Death 1 Receptor/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , CTLA-4 Antigen/metabolism , Humans , Immunotherapy/methods , Melanoma/drug therapy , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
The term "antitumor immunity" refers to innate and adaptive immune responses which lead to tumor control. Turning the immune system into a destructive force against tumors has been achieved in a broad range of human cancers with the use of non-specific immunotherapies, vaccines, adoptive-cell therapy, and, more recently with significant success, through blockade of immune checkpoints. Nevertheless, the efficacy of these approaches is not universal, and tools to identify long-term responders and primarily refractory patients are warranted. In this article, we review recent advances in understanding the complex mechanisms of antitumor immunity and how these developments can be used to address open questions in a setting of growing clinical indications for the use of immunotherapy.
