Addition of the C‐terminus of CD6 to a chimeric antigen receptor enhances cytotoxicity and does not compromise expression

T cells expressing chimeric antigen receptors (CARs) are a promising new cancer immunotherapy that has now reached the clinic. CARs are synthetic receptors that redirect T cells towards a tumour‐associated antigen and activate them through various fused signalling regions, for example derived from CD3ζ, 4‐1BB or CD28. Analysis of the optimal combination of CAR components including signalling domains is not yet comprehensive and may vary with the particular application. The C‐terminus of the T‐cell surface receptor CD6 is critical for its co‐stimulatory effects and signals through two phospho‐tyrosine motifs that bind to the intracellular adaptor proteins GADS and SLP‐76. Addition of the C terminus of CD6 did not compromise CAR expression, showing it was a stable moiety that can be used independently of the native receptor. A third‐generation CAR containing 4‐1BB, CD3ζ and the C terminus of CD6 (4‐1BBz‐CD6) enhanced interferon‐γ release and cytotoxicity when compared with the second‐generation 4‐1BB CD3ζ (4‐1BBz) CAR. The CD6 C terminus is a valuable addition to potential components for modular design of CARs to improve effector function, particularly cytotoxicity.