Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier

Abstract

Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60-70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.

Keywords: Combination therapy; Immune cells; Immune-checkpoint inhibitors (ICIs); Resistance; Tumor microenvironment (TME).

Fig. 1

The FDA-approved immune checkpoint inhibitors (ICIs). PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab, PD-L1 inhibitors atezolizumab, avelumab, and durvalumab, and also CTLA-4 inhibitor ipilimumab have been approved as most eminent ICIs to treat a myriad of cancers

Fig. 2

Human epidermal growth factor receptor 2 (HER2) signaling pathway. HER2 and other EGFR family members as RTK located on the cell membrane can responds to multiple ligands, which in turn, result in suppression of tumor cell apoptosis and conversely stimulation of tumor cells migration, proliferation and growth

Fig. 3

The pivotal role of vascular endothelium growth factor (VEGF) in tumor angiogenesis. The VEGF encourages angiogenesis in tumor cells by interface with responding receptor, VEGFR2, on tumor cells and afterward through activating several signaling axes