Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment

Abstract

Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field.

Keywords: checkpoint inhibitors; immunotherapy; nivolumab; non-small-cell lung cancer; pembrolizumab; programmed death ligand-1; programmed death-1.

Figure 1

Image displays the different immune checkpoints between T-cells, APCs, and cancer cells that can be exploited in cancer therapeutics. Notes: T-cells are activated following the recognition of specific peptides presented by MHC1 at the surface of APCs to their TCR. T-cell activation and proliferation are further enhanced by the costimulatory signal deriving from CD28-CD80/86 interaction and are dampened by CTLA-4-CD80/86 interaction. Anti-CTLA-4 antibody, by releasing the inhibition exerted by CTLA-4-CD80/86 interaction, activates T-cells. Cytotoxic CD8 cells recognize and kill tumor cells after antigenic recognition. Immune checkpoint regulates the interaction among different cells of the immune system to ensure that the activation occurs at the appropriate time and minimizes the possibility of autoimmunity. Cancer cells take advantage of this mechanism to avoid the immune system. For instance, PD-L1 and PD-L2 on cancer cell surface bind to PD-1 on T-cell surface to deliver an inhibitory signal. PD-L1 can also interact with CD80 to exert an inhibitory signal on T-cells. Blockers of PD-L1 or PD-1 restore T-cell activity within the tumor microenvironment. Costimulatory checkpoints are depicted in red and inhibitory checkpoints are in blue. LAG-3 dampens T-cell differentiation and proliferation following interaction with MHC2, a mechanism that can be reversed with anti-LAG3 antibody. When 4-1BB binds to 4-1BBL or agonist antibodies, it stimulates T-cell activity. KIR expressed on NK cells suppresses their cytotoxic effect after binding to MHC1 found on normal as well as cancer tissues. Anti-KIR antibody can unleash NK cells against cancer cells. CD40 is another costimulatory receptor present on APCs and is required for their activation. It is activated by CD40L expressed on Th1 cells. Antibodies directed against CD40 are currently being tested in clinic. Abbreviations: APC, antigen-presenting cell; KIR, killer immunoglobulin like receptor; LAG-3, lymphocyte activation gene-3; PD-1, programmed death-1; PD-L1, programmed death ligand 1; MHC1, major histocompatibility complex 1; NK, natural killer; TCR, T-cell receptor; 4-1BB, CD137; 4-1BBL, 4-1BB ligand.