title: Immunotherapy: Beyond Anti-PD-1 and Anti-PD-L1 Therapies.
abstract: Advanced-stage non-small cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a survival benefit, although it is small. We now know that anti-PD-1/PD-L1 has substantial clinical activity in both of these diseases, with an overall response rate (ORR) of 15%-20%. These responses are frequently rapid and durable, increase median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant results, many patients do not benefit from anti-PD-1/PD-L1. This is because of the potential for malignancies to co-opt myriad immunosuppressive mechanisms other than aberrant expression of PD-L1. Conceptually, these can be divided into three categories. First, for some patients there is likely a failure to generate sufficient functional tumor antigen-specific T cells. Second, for others, tumor antigen-specific T cells may be generated but fail to enter into the tumor parenchyma. Finally, there are a large number of immunosuppressive mechanisms that have the potential to be operational within the tumor microenvironment: surface membrane immune checkpoint proteins PD-1, CTLA-4, LAG3, TIM3, BTLA, and adenosine A2AR; soluble factors and metabolic alterations interleukin (IL)-10, transforming growth factor (TGF)-β, adenosine, IDO, and arginase; and inhibitory cells, cancer-associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages. In this article, we discuss three strategies to generate more tumor-reactive T cells for patients: anti-CTLA-4, therapeutic tumor vaccination, and adoptive cellular therapy, with T cells redirected to tumor antigens using T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene modification. We also review some of the various strategies in development to thwart tumor microenvironment immunosuppressive mechanisms. Strategies to drive more T cells into tumors remain a significant challenge.
authors.affiliation: From the Department of Thoracic Oncology Moffitt Cancer Center, Tampa, FL; Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium; Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Antonia
authors.affiliation: From the Department of Thoracic Oncology Moffitt Cancer Center, Tampa, FL; Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium; Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Johan F
authors.initials: JF
authors.lastname: Vansteenkiste
authors.affiliation: From the Department of Thoracic Oncology Moffitt Cancer Center, Tampa, FL; Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium; Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Edmund
authors.initials: E
authors.lastname: Moon
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000276:immunology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor