Figure 2.

Four generations of CAR-T cells. First generation CARs comprise of single chain variable fragment (scFv) antibody (orange) fused to transmembrane domain (purple) to TCR signaling component of CD3ζ (green) at the cytoplasmic tail. Second generation CARs have a CD28 co-stimulatory signaling domain (red) which enhances proliferation and cytotoxicity. Third generation CARs contain an additional co-stimulatory domain, 4-1BB (blue) to the second generation CARs which enhances proliferation, minimizes T cell exhaustion and improves CAR-T cells persistence. Fourth generation CARs also called “T cell directed for universal cytokine-mediated killing” (TRUCKs) are engineered to secrete cytokines (gray) to attract immune cells (NK and macrophages).