CAR-T for lung cancers: challenges and innovations

Lung cancer (LC) is the leading cause of cancer mortality worldwide. Despite current therapies, including surgery, radiotherapy, targeted therapies, and immunotherapy, most patients experience relapse. Immune checkpoint inhibitors (ICIs) have revolutionized LC treatment, but only a subset of patients benefit from them. Chimeric antigen receptor (CAR) T cell therapy emerges as an innovative and promising strategy in oncology. CAR T cells are genetically modified T lymphocytes that express a chimeric receptor specific for a tumor antigen. Very promising in hematology, CAR T has so far struggled to be transferred into the clinic for solid tumors, including LC. CAR T strategy against LC presents challenges in the selection of the optimal antigen to avoid off-target effects, for the known antigen heterogeneity and immunosuppressive environment of LC and the relatively short persistence of CAR T that may encounter disseminated diseases. Despite these limitations, here we describe growing preclinical and clinical studies that are exploring various LC antigens for CAR T within a variety of novel approaches and combinatorial strategies to overcome the barriers. Considering this emerging critical mass and despite the limits, we expect this endeavour to translate a fraction CAR T into clinical practice with efficacy against the still deadly LCs.