Co-opting signalling molecules enables logic-gated control of CAR T cells.

ABSTRACT: 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^1,2. Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity^3-5; however, a truly safe and effective logic-gated CAR has remained elusive⁶. Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules. We show that certain proximal signalling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumours in vivo while bypassing upstream signalling proteins, including CD3ζ.

SUBMITTER: Tousley AM 

PROVIDER: S-EPMC10564584 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature