Beyond Conventional Chimeric Antigen Receptors: Expanding the Targetable Antigen Landscape in Chimeric Antigen Receptor-T Cell Therapy.

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a central pillar of immunotherapy, with astonishing achievements in the treatment of CD19-positive B cell malignancies and multiple myeloma. In recent years, substantial efforts have been made to translate CAR-T cell therapy into other hematologic malignancies, solid tumors, and also non-malignant disorders, such as autoimmune diseases. Nonetheless, several challenges constrain the broader application of CAR-T cell therapy. Conventional CARs can only recognize extracellular protein antigens, which severely limits the range of targetable antigens. Moreover, extracellular disease-associated proteins are often shared with healthy cells, increasing the risk of on-target, off-tumor toxicities. Consequently, expanding the targetable antigen repertoire in parallel with reducing off-tumor toxicities has become a focus of current research. This review aims to provide a comprehensive overview of recent advances in the design of innovative CAR architectures to expand the targetable antigen landscape. In this regard, we discuss innovative CARs in four main categories: (1) peptide-major histocompatibility complex-targeting CARs capable of recognizing intracellular proteins; (2) ultra-precision CARs capable of recognizing pathogenic cells while sparing healthy counterparts; (3) ligand/receptor-based CARs; (4) non-protein antigen-targeting CARs.