The evolutionary legacy of immune checkpoint inhibitors

Abstract

Immune check point inhibitors (ICIs) have marked their existence in the field of cancer immunotherapy. Their existence dates to 2011 when the first anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) got its FDA approval for the management of metastatic melanoma. The class of ICIs now also include antibodies against programmed cell death-1 (PD-1) and its ligand (PD-L1) which immediately gained FDA approval for use against multiple cancer types because of their effect on patient survival. These discoveries were followed by a significant rise in the identification of novel ICIs with potential anti-tumor response. Researchers have identified various novel checkpoint inhibitors which are currently under clinical trials. Despite the success of ICIs, only a small subset of patients with specific tumor types achieves a promising response. Not only efficient therapeutic response but also development of resistance, recurrence and other immune-related adverse effects limit the applicability of immune checkpoint inhibitors. These challenges can only be addressed when a directed approach is implemented at both basic and translational level. In this review, we have briefly discussed the history of ICIs, the next generation of inhibitors which are currently under clinical trial and mechanisms of resistance that can lead to treatment failure. Ultimately, by combining these insights researchers might be able to achieve a more durable and effective response in cancer patients.

Keywords: Antigen presenting cells; CTLA-4; PD-1/PD-L1; Tumor microenvironment.