CARs on a highway with roadblocks

On August 30th 2017, the US Food and Drug Administration (FDA) approved KYMRIAH？ (tisagenlecleucel, CTL019) for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse (source https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm).1–3 KYMRIAH？ consists of autologous cytotoxic T lymphocytes (CTLs) genetically engineered to express a CD19-specific chimeric antigen receptor (CAR), which are commonly referred to as CAR-T cells.4–6 CARs are fusion proteins that comprise (1) an extracellular single-chain variable fragment (scFV), which is responsible for antigen specificity; (2) a transmembrane domain; and (3) one or more intracellular domains with co-stimulatory functions, which are derived from CD247 (best known as CD3ζ) and - potentially - other receptors involved in T cell activation.5–7 Specifically, KYMRIAH？ harnesses the co-stimulatory domains of CD3ζ and TNF receptor superfamily member 9 (TNFRSF9, best known as 4-1BB or CD137).5,6,8 CAR expression endows CTLs with the ability to recognize and kill cells expressing a specific antigen independent of MHC Class I presentation.9,1