Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC)

Abstract

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has become a "game changer" in the treatment of advanced non-small cell lung cancer (NSCLC). Its most clinically important advantage over traditional chemotherapy using cytotoxic agents are its long-term survival benefits, and some advanced NSCLC patients treated with an antibody against programmed cell death 1 (PD-1) have survived for 5 years or longer. Immune checkpoint inhibitors (ICIs) are also potentially useful for earlier-stage NSCLC when used in combination with surgery or radiotherapy. A recent clinical trial has shown that consolidation treatment with an antibody against a ligand of PD-1 (PD-L1) following chemo-radiotherapy significantly improves progression-free survival for patients with locally advanced NSCLC. However, current single-agent treatment with an anti-PD-1/PD-L1 antibody may provide significant survival benefits only in a small subset of patients. PD-L1 expression status on tumor cells is an approved biomarker to predict response to ICIs, but is not enough for optimal patient selection. To improve the therapeutic outcomes, development of novel biomarkers other than PD-L1 expression status is essential. Combination treatment strategies based on blockade of PD-1/PD-L1 may also be promising, and a variety of combinations, such as ICIs plus chemotherapy, are being examined in ongoing clinical trials. Here we review and discuss the current status and future perspectives of immunotherapy with ICIs.

Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

“…Combination therapy with trastuzumab [136], with the insulin-like growth factor receptor 1 (IGF1R) TKI linsitinib [137] or with the anti-HER3 antibodies currently in development [138] can also prove beneficial to shut down compensatory signalling. Other new therapies instead reverse the immune tolerance towards cancer through the blockade of negative immune regulators such as PD-1/PD-1L and CTLA4 have enjoyed vast success in clinical trials of NSCLC and bypass the need of targeting EGFR specifically, providing an attractive therapeutic [139,140].…”

Prognostic impact of PD-L1 expression in correlation with neutrophil-to-lymphocyte ratio in squamous cell carcinoma of the lung

“…Accordingly, blockade of PD-1/PD-L1 axis can be a promising strategy to kill TCs with strong expression of PD-L1. In fact, tumoral PD-L1 expression status has been approved for clinical use as a biomarker to predict the efficacy of pembrolizumab, an anti-PD-1 antibody, in NSCLC [4][5][6][7] .…”

“…However, the prognostic significant of tumoral PD-L1 status remains controversial, as inconsistent results have been reported in several retrospective clinical studies 8,9 . One possible reason for such conflict results is that the prognostic impact of tumoral PD-L1 status can be influenced by the status of cancer immune activity and by several stimulatory and/ or inhibitory factors associated with cancer immunity other than PD-L1 5,7,9 . The neutrophil-to-lymphocyte ratio Prognostic impact of PD-L1 expression status in combination with NLR status.…”

Epigenetics, a key player of immunotherapy resistance

“…Anti-PD-1 and anti-PD-L1 immunotherapy protocols (such as nivolumab or pembrolizumad) have been developed and used to restore immune edition in cancers [ Figure 2]. This process is called immune checkpoint blockade (ICB) and, in the last few years, this new treatment has been tested and shown promising results in many different types of cancers such as: non-small cell lung carcinoma (NSCLC), melanoma, mesothelioma, renal cell carcinoma (RCC), bladder cancer, head and neck squamous cell carcinoma (HNSCC) [14][15][16][17][18][19] . Unfortunately, although some very interesting results were obtained in some patients, resistance to ICB are observed in a large percentage of cases.…”