T cell targeting of TAG72+ tumor cells by a chimeric receptor with antibody-like specificity for a carbohydrate epitope

Background & Aims: Chimeric receptors with specificity for defined tumor antigens are valuable tools for targeting cytolytic T cells specifically to tumor cells, The aim of this study, for the situation of gastrointestinal cancer, was to investigate the generation of a chimeric T cell receptor that specifically binds the tumor antigen TAG72 (CA72-4) and transmits a signal for cellular activation, Methods: A single-chain antibody (scFv) was derived from the monoclonal anti-TAG72 antibody B72.3 by phage display techniques (B72.3-scFv) and fused to the signaling unit of the Fc epsilon-RI receptor gamma chain, resulting in a chimeric signaling receptor, B72.3-scFv-gamma, Results: The B72.3-scFv and the chimeric B72.3-scFv-gamma receptor bound specifically to the TAG72 antigen, After transfection, T cells expressing the chimeric B72.3-scFv-gamma specifically recognized TAG72 positive cells, Cross-linking of the chimeric receptor with antigen resulted in interleukin 2 release and cytolytic activity against TAG72 positive tumor cells in vitro. Conclusions: T cells equipped with the chimeric anti-TAG72 receptor can be specifically activated to target and lyse TAG72 positive gastrointestinal tumor cells.