Rationale for New Checkpoint Inhibitor Combinations in Melanoma Therapy
The use of monoclonal antibodies that block immunologic checkpoints, which mediate adaptive immune resistance, has revolutionized the treatment of metastatic melanoma patients. Specifically, targeting single immune suppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or programmed cell death protein 1 (PD-1) expressed on T cells or its primary ligand, programmed cell death ligand 1 (PD-L1), resulted in pronounced clinical benefit for a subset of melanoma patients. Although single-agent immune checkpoint inhibitor therapy has demonstrated promising clinical activity in metastatic melanoma patients, there is still a significant proportion of patients who show primary resistance to these therapies. Increased clinical efficacy was reported in phase II and III randomized studies by co-targeting CTLA-4 and PD-1 in the treatment of advanced melanoma, indicating the existence of multiple non-redundant immunosuppressive pathways in the tumor microenvironment. Nevertheless, only 50% of patients responded to combined anti-CTLA-4 and anti-PD-1 treatment. Additionally, the combination regimen was associated with severe toxicity in >50–60% of patients. In this review we summarize the rationale for new checkpoint inhibitor combinations in melanoma therapy and discuss how biologic-driven stratification enables the design of optimal combination therapies tailored to target different tumor microenvironments.
Compliance with Ethical Standards
This work was supported by Fondazione Oncologica Bergamasca (MM); Ministero dell’Istruzione, dell’Università e della Ricerca, Rome (MiUR) (PRIN 2015HAJH8E) (DM), and Fondazione Ente Cassa di Risparmio di Firenze (DM).
Conflict of interest
Dr. Mandala has received honoraria from Novartis, GSK, BMS, MSD, and Roche; personal fees for speakers bureau participation from Novartis, GSK, Roche, and BMS; personal fees for advisory board participation from Novartis, Amgen, MSD, and BMS; and research funding from Roche. Dr. Massi has received personal fees for speakers bureau participation from Novartis, GSK, Roche, Menarini Diagnostics, and BMS; and personal fees for advisory board participation from MSD. Dr. Tondini and Dr. Merelli declare no conflicts of interest.
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