Immunotherapy in Lung Cancer
Immunotherapy in Lung Cancer
Immunotherapy has emerged in recent years as a promising therapeutic approach in lung cancer. Two approaches are of particular interest: immune checkpoint inhibition, which aims to counteract the physiologic mechanisms of immune tolerance co-opted by some tumors, and vaccine therapy, which enables enhanced exposure to tumor antigen. Immune checkpoint therapies include the monoclonal antibody blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) with ipilimumab, as well as antibody blockade of the programmed cell death-1 (PD-1) receptor and the PD-1 ligand. These immune checkpoint therapies have been evaluated in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with early evidence of activity. Vaccines include antigen specific therapies which induce specific antitumor immunity against relevant tumor-associated antigens. In lung cancer, these include the melanoma-associated antigen-A3 (MAGE-A3), membrane-associated glycoprotein (MUC-1), and the epidermal growth factor receptor (EGFR). Whole tumor vaccines have also been evaluated in lung cancer and influence the patient's immune system to allow recognition of the tumor as foreign creating de novo immunity. This review summarizes the evidence to date for the efficacy and safety of immunotherapies in lung cancer.
Lung cancer is the leading cause of cancer mortality in the United States and worldwide. An estimated 226,160 new cases of lung cancer will be diagnosed in 2012 in the United States alone, and 160,340 lung cancer deaths are estimated to occur. Broadly classified as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the five year survival for all lung cancer patients is a dismal 15%. NSCLC is the most common type of lung cancer, accounting for about 85% of all cases. In recent years, the recognition that NSCLC does not represent a single disease entity, but rather a collection of distinct molecularly-driven neoplasms has shifted the landscape of NSCLC therapy to a personalized approach based on the molecular alterations of a patient's tumor; a paradigm typified by targeted therapies in epidermal growth factor receptor (EGFR) mutant and ALK translocation driven adenocarcinomas of the lung. Despite these therapeutic advances, metastatic NSCLC in the absence of an EGFR mutation or ALK translocation is still associated with a disappointing median overall survival (OS) of about one year. The remaining 15% of lung cancer cases represent SCLC. SCLC is associated with an aggressive clinical course characterized by rapid growth and a tendency to metastasize early. While often initially highly sensitive to chemotherapy and radiation therapy, the majority of patients with SCLC will relapse and long-term survival is rare.
While the role of immunotherapy in the treatment of melanoma and renal cell carcinoma is well established, immunotherapies in lung cancer have historically been associated with disappointing results. Lung cancer's ability to evade the immune system is characterized by cytokine alterations, cellular immune dysfunction, and antigen presentation defects. Decrease in the function of the tumor suppressor cytokine TGFβ in lung cancer has been linked to the downregulation of the TGFβ type II receptor. Patients with advanced lung cancer have been shown to have both T- and B-cell peripheral blood lymphopenias, and T-cell subset alterations in lung cancer are characterized by decreased naïve T-cells and increased effector/memory CD4+ and CD8+ T-cell subsets. Studies in early stage disease have demonstrated an increased proportion of CD4+ regulatory T-cells (CD4+ Tregs) in NSCLC, which have a constitutive high level expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and mediate potent inhibition of autologous T-cell proliferation. This has important consequences as CD4+ Tregs suppress cytotoxic T-lymphocytes (CD8+ T-cells), which are responsible for tumor cell cytotoxicity, immunosurveillance and immune memory. Recently, there have been several novel immunotherapeutic strategies that have been evaluated in lung cancer with early evidence of activity. This review will highlight two approaches of particular interest: immune checkpoint inhibition, which aims to counteract the physiologic mechanisms of immune tolerance co-opted by some tumors, and vaccine therapy, which enables enhanced exposure to tumor antigen.
Abstract and Introduction
Abstract
Immunotherapy has emerged in recent years as a promising therapeutic approach in lung cancer. Two approaches are of particular interest: immune checkpoint inhibition, which aims to counteract the physiologic mechanisms of immune tolerance co-opted by some tumors, and vaccine therapy, which enables enhanced exposure to tumor antigen. Immune checkpoint therapies include the monoclonal antibody blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) with ipilimumab, as well as antibody blockade of the programmed cell death-1 (PD-1) receptor and the PD-1 ligand. These immune checkpoint therapies have been evaluated in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with early evidence of activity. Vaccines include antigen specific therapies which induce specific antitumor immunity against relevant tumor-associated antigens. In lung cancer, these include the melanoma-associated antigen-A3 (MAGE-A3), membrane-associated glycoprotein (MUC-1), and the epidermal growth factor receptor (EGFR). Whole tumor vaccines have also been evaluated in lung cancer and influence the patient's immune system to allow recognition of the tumor as foreign creating de novo immunity. This review summarizes the evidence to date for the efficacy and safety of immunotherapies in lung cancer.
Introduction
Lung cancer is the leading cause of cancer mortality in the United States and worldwide. An estimated 226,160 new cases of lung cancer will be diagnosed in 2012 in the United States alone, and 160,340 lung cancer deaths are estimated to occur. Broadly classified as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the five year survival for all lung cancer patients is a dismal 15%. NSCLC is the most common type of lung cancer, accounting for about 85% of all cases. In recent years, the recognition that NSCLC does not represent a single disease entity, but rather a collection of distinct molecularly-driven neoplasms has shifted the landscape of NSCLC therapy to a personalized approach based on the molecular alterations of a patient's tumor; a paradigm typified by targeted therapies in epidermal growth factor receptor (EGFR) mutant and ALK translocation driven adenocarcinomas of the lung. Despite these therapeutic advances, metastatic NSCLC in the absence of an EGFR mutation or ALK translocation is still associated with a disappointing median overall survival (OS) of about one year. The remaining 15% of lung cancer cases represent SCLC. SCLC is associated with an aggressive clinical course characterized by rapid growth and a tendency to metastasize early. While often initially highly sensitive to chemotherapy and radiation therapy, the majority of patients with SCLC will relapse and long-term survival is rare.
While the role of immunotherapy in the treatment of melanoma and renal cell carcinoma is well established, immunotherapies in lung cancer have historically been associated with disappointing results. Lung cancer's ability to evade the immune system is characterized by cytokine alterations, cellular immune dysfunction, and antigen presentation defects. Decrease in the function of the tumor suppressor cytokine TGFβ in lung cancer has been linked to the downregulation of the TGFβ type II receptor. Patients with advanced lung cancer have been shown to have both T- and B-cell peripheral blood lymphopenias, and T-cell subset alterations in lung cancer are characterized by decreased naïve T-cells and increased effector/memory CD4+ and CD8+ T-cell subsets. Studies in early stage disease have demonstrated an increased proportion of CD4+ regulatory T-cells (CD4+ Tregs) in NSCLC, which have a constitutive high level expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and mediate potent inhibition of autologous T-cell proliferation. This has important consequences as CD4+ Tregs suppress cytotoxic T-lymphocytes (CD8+ T-cells), which are responsible for tumor cell cytotoxicity, immunosurveillance and immune memory. Recently, there have been several novel immunotherapeutic strategies that have been evaluated in lung cancer with early evidence of activity. This review will highlight two approaches of particular interest: immune checkpoint inhibition, which aims to counteract the physiologic mechanisms of immune tolerance co-opted by some tumors, and vaccine therapy, which enables enhanced exposure to tumor antigen.
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