Chimeric antigen receptor

A chimeric antigen receptor (CAR) is a genetically engineered receptor that confers a new antigen specificity on an immune effector cell. CARs are synthetic membrane proteins assembled from antibody-derived and T-cell signaling elements. Unlike a conventional T-cell receptor (TCR), which recognizes peptide antigens presented by major histocompatibility complex molecules, a CAR generally binds a surface antigen directly through an antibody-derived recognition domain, commonly a single-chain variable fragment (scFv).

A typical CAR contains an extracellular antigen-binding domain, a hinge or spacer region, a transmembrane segment, and one or more intracellular signaling domains. Engagement of the target antigen brings signaling components together and can activate the engineered cell, promoting cytotoxicity, cytokine production, proliferation, and persistence. CARs are most extensively used in CAR-T cells, in which T-lymphocytes are genetically modified ex vivo and reinfused as a form of CAR-T cells. The approach has also been adapted to other immune cells, including natural-killer-cell-like systems and neutrophils.

CAR-based therapies are being investigated across hematological malignancies and solid tumors. Their potential advantages include antigen-directed recognition that is less dependent on peptide presentation and the ability to combine tumor specificity with selected intracellular activation and costimulatory signals. Important biological and clinical considerations include tumor heterogeneity, antigen loss, limited trafficking or persistence in solid tumors, and immune-mediated toxicities such as cytokine release syndrome. CAR designs and delivery systems are also being studied in combination with checkpoint inhibitors, bispecific engagers, and approaches intended to overcome an immunosuppressive microenvironment.