Advances in Immunotherapy for the Treatment of Non-Small Cell Lung Cancer
Published Online: Friday, April 25, 2014
AbstractDespite recent developments in targeted therapies, the overall survival for metastatic NSCLC remains poor. The need for novel therapeutic options has led to the development of various new immunotherapeutic agents including anti-PD-1 and anti-PD-L1 antibodies, which appear to have a promising role in the treatment of the disease. Additionally, other immunotherapy options including CTLA-4 inhibitors and various vaccines are also currently being investigated as potential treatment options.
Lung cancer continues to be the leading cause of cancer related deaths worldwide. Approximately 80% of lung cancers are diagnosed as non-small cell lung cancer (NSCLC), which is further classified into three main histologies: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The treatment decisions for NSCLC are primarily dependent on the patient’s performance status, extent of disease, and histological subtype. Significant developments in the area of targeted therapies have changed the treatment paradigm for NSCLC. New drugs targeting EGFR, EML4-ALK, and ROS-1 mutations have provided considerable benefit and new therapeutic options for patients. Despite these advancements, the overall survival (OS) in patients with metastatic disease continues to be poor, and the majority of NSCLC patients are not candidates for these therapies.
There is significant need for novel and alternative therapeutic agents. With this in mind, various immunotherapeutic options have recently garnered significant attention and appear to hold a promising role in the treatment of NSCLC.
The importance of an intact immune system in controlling the growth of cancer cells has been recognized since the beginning of the 20th century.1 Various studies have highlighted the role of the immune system in surveillance for elimination of preclinical cancers and the role of tumor-infiltrating lymphocytes as a prognostic tool.2-4
Immunotherapy has had limited success in the treatment of solid tumors except in the treatment of melanoma and renal cell cancers.5-8 This limitation has been thought to be the result of many factors including secretion of immunosuppressive cytokines and loss of major histocompatibility complex antigen expression.9-11 Recent improvements in our understanding of the functioning of the immune system and its relation to tumor evasion have led to the development of novel agents that have promising results in the treatment of NSCLC. These agents include immune checkpoint inhibitors such as anti-PD-1 antibody, anti-PD-L1 antibody, and CTLA-4 inhibitors, as well as vaccines. This review will discuss these therapeutic options and the emerging data to support their role in the management of patients with lung cancer.
Checkpoint InhibitorsTumors have various mechanisms by which they evade destruction by the immune system. One of these mechanisms is via the immune checkpoint pathway, which plays a key role in regulating T-cell responses. Under normal circumstances, the immune checkpoints are important in maintenance of self-tolerance by preventing autoimmunity and protecting the tissue from damage when the immune system is activated.12 The expression of immune-checkpoint proteins can be manipulated by the tumor cells to develop resistance mechanisms. The two major inhibitory pathways involve the PD-1/ PD-L1 pathway and the CTLA-4 pathway.
Anti-PD-1 AntibodyProgrammed cell death-1(PD-1) is one of the pathways that inhibits tumor-specific T cells. PD-1 is a member of the B7-CD28 superfamily, and is a cell surface receptor with two known ligands: PD-L1(B7-H1) and PD-L2(B7-DC).13 It is an inhibitory receptor, and mediates immunosuppression.14 PD-1 is expressed on activated CD4+ and CD8+ T cells, natural killer T cells, B cells, activated monocytes, and activated dendritic cells.13,15,16
Binding of the PD-1 receptor with its PD-L1 ligand causes T-cell inhibition and downregulation of T-cell response.17 PD-1 overexpression has been observed in patients with NSCLC,18 and an increase in PD-L1 positive tumor cells have been noted in tumor tissue as compared to normal lung parenchyma.19
Blocking the binding of PD-1 to its PD-L1 ligand can potentially restore the function of chronically exhausted tumor-specific T cells and augment the T-cell response.20
A phase I dose-escalation trial of a fully human IgG4-blocking monoclonal antibody against PD-1, nivolumab, administered once every 2 weeks, evaluated its efficacy in patients with previously treated solid tumors including NSCLC.14 Patients with melanoma, NSCLC, renal cell cancer, castrationresistant prostate cancer, or colorectal cancer were enrolled.
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