Fig. 1

Chimeric Antigen Receptor (CAR) design across generations. First generation Chimeric Antigen Receptors (CARs) include an extracellular antigen-binding domain and an intracellular T cell activation domain, commonly CD3ζ or FcεRIγ. Second generation CARs built upon first generation constructs by including an intracellular costimulatory domain, commonly 4-1BB or CD28, incorporated into the FDA approved CAR T therapies tisagenlecleucel and axicabtagene ciloleucel, respectively. Costimulatory domains help enhance CAR T cell cytotoxicity and proliferation compared to first generation designs. Third generation CARs include multiple costimulatory domains, primarily to increase CAR T cell proliferation and persistence