Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells. Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity; however, a truly safe and effective logic-gated CAR has remained elusive. Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules.
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