CAR-T cell therapy for triple-negative breast cancer and other solid tumors: preclinical and clinical progress

Most breast cancer-related deaths arise from triple-negative breast cancer (TNBC). Molecular heterogeneity, aggressiveness and the lack of effective therapies are major hurdles to therapeutic progress. Chimeric antigen receptor (CAR)-T cells have emerged as a promising immunotherapeutic strategy in TNBC. This approach combines the antigen specificity of an antibody with the effector function of T cells.This review examines the opportunities provided by CAR-T cell therapies in solid tumors. Emerging targets, ongoing clinical trials, and prospective clinical implications in TNBC are considered later. An emphasis is placed on the key challenges and possible solutions for this therapeutic approach.A challenge for CAR-T cell therapy is the selection of the optimal targets to minimize on-target/off-tumor toxicity. Tumor escape via antigen loss and intrinsic heterogeneity is a further hurdle. TROP2, GD2, ROR1, MUC1 and EpCAM are promising targets. Persistence and trafficking to tumor cells may be enhanced by the implementation of CARs with a chemokine receptor and/or constitutively activated interleukin receptors. Fourth-generation CARs (TRUCKs) may redirect T-cells for universal cytokine-mediated killing. Combinatorial approaches and the application of CARs to other immune cells could revert the suppressive immune environment that characterizes solid neoplasms.