CD28 and neoplasm: Second- and third-generation CARs include one or two co-stimulatory domains (often CD28 and/or 4-1BB) to enhance T cell proliferation, cytotoxicity, and survival. Fourth generation CARs, also known as T-cells redirected for universal cytokine-mediated killing (TRUCKS), are based on second-generation constructs with the addition of an inducible transgenic protein, such as a cytokine interleukin-12 (IL-12), to enhance anti-tumor activity [7].