Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy, yielding significant antitumor responses across multiple cancer types. Combination ICI therapy with anti-CTLA-4 and anti-PD-1 antibodies outperforms either antibody alone in terms of clinical efficacy. As a consequence, the U.S. Food and Drug Administration (FDA) approved ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) as the first-ever approved therapies for combined ICI in patients with metastatic melanoma. Despite the success of ICIs, treatment with checkpoint inhibitor combinations poses significant clinical challenges, such as increased rates of immune-related adverse events (irAEs) and drug resistance. Thus, identifying optimal prognostic biomarkers could help to monitor the safety and efficacy of ICIs and identify patients who may benefit the most from these treatments. In this review, we will first go over the fundamentals of the CTLA-4 and PD-1 pathways, as well as the mechanisms of ICI resistance. The results of clinical findings that evaluated the combination of ipilimumab and nivolumab are then summarized to support future research in the field of combination therapy. Finally, the irAEs associated with combined ICI therapy, as well as the underlying biomarkers involved in their management, are discussed.
Keywords: Biomarkers; Combination therapy; Immune-related adverse events; Ipilimumab; Nivolumab; Resistance.
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