American Journal of Clinical Dermatology

, Volume 18, Issue 5, pp 597–611 | Cite as

Rationale for New Checkpoint Inhibitor Combinations in Melanoma Therapy

  • Mario Mandalà
  • Carlo Tondini
  • Barbara Merelli
  • Daniela Massi
Current Opinion

Abstract

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.

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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Mario Mandalà
    • 1
  • Carlo Tondini
    • 1
  • Barbara Merelli
    • 1
  • Daniela Massi
    • 2
  1. 1.Unit of Medical Oncology, Department of Oncology and HaematologyPapa Giovanni XXIII Cancer Center HospitalBergamoItaly
  2. 2.Division of Pathological Anatomy, Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly

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