Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials

Abstract

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells' responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.

Keywords: cancer; combination therapy; immune checkpoint inhibitors; ipilimumab; nivolumab.

Figure 1

The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in the activation of T cells. A: Antigen-presenting cells (APCs), including dendritic cells (DCs), macrophages, natural killer (NK) cells, and B cells, process tumor antigens and present them to specific T cells, leading to activation of the T cells and immune responses to the tumor. B: Upon T cell receptor activation, CTLA-4 is expressed on the T cell surface and interacts with the co-receptor CD28 that is expressed on APCs, leading to the end of the T cell responses. C: Anti-CTLA-4—specific monoclonal antibodies prevent the interaction between CTLA-4 and CD28 and contribute to inhibitory signals in T cells. The figure was produced using Servier Medical Art (http://smart.servier.com/).

Figure 2

Mechanism of CTLA-4 and PD-1 inhibition.