Rewiring endogenous genes in CAR T cells for tumour-restricted payload delivery

Abstract

The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid tumours is limited by immunosuppression and antigen heterogeneity1, 2–3. To overcome these barriers, ‘armoured’ CAR T cells, which secrete proinflammatory cytokines, have been developed4. However, their clinical application has been limited because of toxicity related to peripheral expression of the armouring transgene5. Here, we have developed a CRISPR knock-in strategy that leverages the regulatory mechanisms of endogenous genes to drive transgene expression in a tumour-localized manner. By screening endogenous genes with tumour-restricted expression, we have identified the NR4A2 and RGS16 promoters as promising candid..