The Role of Immune Checkpoint Inhibitors in Cancer Therapy

Abstract

Over the years, immune checkpoint inhibitors (CPIs) have become a powerful treatment strategy in the field of cancer immunotherapy. In the last decade, the number of FDA-approved CPIs has been increasing prominently, opening new horizons for the treatment of a wide range of tumor types. Pointedly, three immune checkpoint molecules have been under extensive research, which include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand-1 (PD-L1). Despite remarkable success, not all patients respond positively to therapy, which highlights the complexity of the tumor microenvironment (TME) and immune system. This has led to the identification of molecular biomarkers to predict response and toxicity. In addition, there has been an emerging focus on developing new delivery and targeting approaches for better drug efficacy and potency. In this review, we highlight the mechanism of action of major CPIs, their clinical impact, variation in effectiveness, response prediction, updated clinical indications, current challenges and limitations, promising novel approaches, and future directions.

Keywords: CTLA-4; PD-1; PD-L1; cancer; checkpoint inhibitors; immunotherapy.

Figure 1

FDA-approved classes of immune checkpoint inhibitors (CPIs). CTLA-4 (through the interaction with its ligands B7-1/CD80 and B7-2/CD86) or PD-1 (via binding to its ligand PD-L1) trigger inhibitory signals to attenuate T-cell immune response. These T-cell receptor targets provide rationale for the use of CPIs such as anti-CTLA-4, PD-1, and PD-L1, which are illustrated with dotted-border boxes to increase immune response and kill tumor cells. CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; PD-1/PD-L1: Programmed cell death protein-1 and its ligand-1, respectively; APC: Antigen-presenting cell; Ag: Antigen; TCR: T-cell receptor; MHC: Major histocompatibility complex. (Figure was designed with BioRender.com, https://help.biorender.com/en/articles/3619405-how-do-i-cite-biorender, accessed on 7 November 2022).