Chimeric antigen receptors for the retargeting of cytotoxic effector cells

T lymphocytes recognize specific antigens through interaction of the T cell receptor (TCR) with short peptides presented by major histocompatibility c omplex (MHC) class I or II molecules. For initial activation and clonal exp ansion, naive T cells are dependent on professional antigen-presenting cell s (APCs) that provide additional co-stimulatory signals. TCR activation in the absence of co-stimulation can result in unresponsiveness and clonal ane rgy. To bypass immunization, different approaches for the derivation of cyt otoxic effector cells with grafted recognition specificity have been develo ped. Chimeric antigen receptors have been constructed that consist of bindi ng domains derived from natural ligands or antibodies specific for cell-sur face antigens, genetically fused to effector molecules such as the TCR alph a and beta chains, or components of the TCR-associated CD3 complex. Upon an tigen binding, such chimeric receptors link to endogenous signaling pathway s in the effector cell and generate activating signals similar to those ini tiated by the TCR complex. Since the first reports on chimeric antigen rece ptors, this concept has steadily been refined and the molecular design of c himeric receptors has been optimized. Aided by advances in recombinant anti body technology, chimeric antigen receptors targeted to a wide variety of a ntigens on the surface of cancer cells and of cells infected by human immun odeficiency virus (HIV) have been generated. In initial clinical studies, i nfusion of such cells into patients proved to be safe and transient therape utic effects have been observed.