Abstract
Immunotherapy using chimeric antigen receptor (CAR)-engineered T-cells has achieved unprecedented efficacy in selected hematological cancers. However, solid tumors such as lung cancer impose several additional challenges to the attainment of clinical success using this emerging therapeutic modality. Lung cancer is the biggest cause of cancer-related mortality worldwide, accounting for approximately 1.8 million deaths worldwide each year. Obstacles to the development of CAR T-cell immunotherapy for lung cancer include the selection of safe tumor-selective targets, accounting for the large number of candidates that have been evaluated thus far. Tumor heterogeneity is also a key hurdle, meaning that single target-based approaches are susceptible to therapeutic failure through the emergence of antigen null cancers. There is also a need to enable CAR T-cells to traffic efficiently to sites of disease, to infiltrate tumor deposits and to operate within the hostile tumor microenvironment formed by solid tumors, resisting the onset of exhaustion. Multiple immune, metabolic, physical and chemical barriers operate at the core of malignant lesions, with potential for further heterogeneity and evolution in the face of selective therapeutic pressures. Although the extraordinarily adaptable nature of lung cancers has recently been unmasked, immunotherapy using immune checkpoint blockade can achieve long-term disease control in a small number of patients, establishing clinical proof of concept that immunotherapies can control advanced lung carcinomas. This review summarizes pre-clinical CAR T-cell research that is specifically focused on lung cancer in addition to published and ongoing clinical trial activity. A number of advanced engineering strategies are also described which are designed to bridge the gap to the attainment of meaningful efficacy using genetically engineered T-cells.