Review of checkpoint immunotherapy for the management of non-small cell lung cancer

Abstract

Checkpoint immunotherapy uses highly selective humanized monoclonal antibodies against checkpoint signals such as programmed cell death receptor (PD-1) and programmed cell death ligand (PD-L1). By blocking these receptors and signals, the immune system can be reactivated to fight the tumor. Immunotherapy for advanced non-small cell lung cancer (NSCLC) has resulted in a new paradigm of treatment options resulting in improved survival and response rates and has a less severe yet unique toxicity profile when compared to chemotherapy. PD-1 inhibitors, nivolumab and pembrolizumab, and PD-L1 inhibitor, atezolizumab, are currently approved by regulatory authorities for the treatment of advanced NSCLC. This article provides a detailed review of these newer agents, their mechanism of action, side-effect profile, therapeutic indications and current evidence supporting their use in the management of NSCLC.

Keywords: PD-1 inhibitors; PD-L1 inhibitors; atezolizumab; nivolumab; non-small cell lung cancer; pembrolizumab.

Figure 1

PD-1 in T-cell activation, exhaustion and effector function. Notes: (A) T-cells are activated via (1) binding of MHC plus peptide on an APC to the TCR and then (2) binding of APC CD80/86 to T-cell CD28. In patients with cancer, tumor cells can also serve as APCs. Upon T-cell activation, PD-1 expression is induced. (B) In situations of chronic infection or persistent stimulation, PD-L1 signals through T-cell PD-1 to “turn off” T-cells in order to minimize damage to healthy tissue. Tumor cells can upregulate PD-L1 in order to “turn off” T-cells that might destroy them. (C) Blocking the PD-1/PD-L1 signaling pathway allows T-cells to maintain their effector functions. In patients with cancer, activated tumor-specific T-cells can kill tumor cells and secrete cytokines that activate/recruit other immune cells to participate in the antitumor response. Reproduced under Creative Commons Attribution License (CC BY), from McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013;2(5):662–673. © 2013 The Authors. Cancer Medicine published by John Wiley. Abbreviations: APC, antigen-presenting cell; IFN-γ, interferon gamma; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, PD ligand 1; TCR, T-cell receptor.