Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors

SIMPLE SUMMARY: The lung cancer treatment paradigm has been completely changed by immunotherapy; however, less than half of the treated patients obtain a response, and an even smaller proportion achieve a long survival. Primary and acquired resistance mechanisms and the immune-related adverse events limit the use of available immune checkpoint inhibitors (ICIs), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death protein 1/ligand 1 (PD-1/PD-L1). Several predictive biomarkers of ICI response have been evaluated so far, but only PD-L1 expression was approved for clinical use. In the last few years, new immune targets have been identified, and both inhibitory and stimulatory treatments have been developed. These molecules have shown to be safe and effective mostly in combination with anti CTLA-4 and PD-1/PD-L1. Preliminary data indicate their activity in non-small- and small-cell lung cancer, thus allowing the scheduling of further studies to improve the still poor prognosis of these patients. ABSTRACT: Immunotherapy is an ever-expanding field in lung cancer treatment research. Over the past two decades, there has been significant progress in identifying immunotherapy targets and creating specific therapeutic agents, leading to a major paradigm shift in lung cancer treatment. However, despite the great success achieved with programmed death protein 1/ligand 1 (PD-1/PD-L1) monoclonal antibodies and with anti-PD-1/PD-L1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), only a minority of lung cancer patients respond to treatment, and of these many subsequently experience disease progression. In addition, immune-related adverse events sometimes can be life-threatening, especially when anti-CTLA-4 and anti-PD-1 are used in combination. All of this prompted researchers to identify novel immune checkpoints targets to overcome these limitations. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are promising molecules now under investigation. This review aims to outline the current role of immunotherapy in lung cancer and to examine efficacy and future applications of the new immune regulating molecules.