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4.3
18 reviewsThe efcacy of chimeric antigen receptor (CAR) T cell therapy in solid tumours is limited by immunosuppression and antigen heterogeneity1–3. To overcome these barriers, ‘armoured’ CAR T cells, which secrete proinfammatory 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 identifed the NR4A2 and RGS16 promoters as promising candidates to support the delivery of cytokines such as IL-12 and IL-2 directly to the tumour site, leading to enhanced antitumour efcacy and long-term survival of mice in both syngeneic and xenogeneic models. This efect was concomitant with improved CAR T cell polyfunctionality, activation of endogenous antitumour immunity and a favourable safety profle, and was applicable in CAR T cells from patients.
