Chimeric antigen receptors. The external domain in the upper portion of the figure is composed of a single chain monoclonal antibody of the desired specificity. Signaling is achieved by an internal domain (ζ) taken from the T-cell receptor. Second generation CARs are modified to include portions of other signaling molecules designed to provide costimulatory signals upon engagement of the CAR by the target antigen. CD28 is a costimulatory molecule expressed on T-cells and lck is a protein kinase associated with the T-cell receptor. Reprinted from Rossig and Brenner¹⁰⁶  with permission.