Rewiring endogenous genes in CAR T cells for tumour-restricted payload delivery
- Author(s)
- Chen, AXY; Yap, KM; Kim, JS; Sek, K; Huang, YK; Dunbar, PA; Wiebking, V; Armitage, JD; Munoz, I; Todd, KL; Derrick, EB; Nguyen, D; Tong, J; Chan, CW; Hoang, TX; Audsley, KM; van Elsas, MJ; Middelburg, J; Lee, JN; de Menezes, MN; Cole, TJ; Li, J; Scheffler, C; Scott, AM; Mackay, LK; Waithman, J; Oliaro, J; Harrison, SJ; Parish, IA; Lai, J; Porteus, MH; House, IG; Darcy, PK; Beavis, PA;
- Journal Title
- Nature
- Publication Type
- Online publication before print
- Abstract
- The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid tumours is limited by immunosuppression and antigen heterogeneity(1-3). To overcome these barriers, 'armoured' CAR T cells, which secrete proinflammatory cytokines, have been developed(4). However, their clinical application has been limited because of toxicity related to peripheral expression of the armouring transgene(5). 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 candidates to support the delivery of cytokines such as IL-12 and IL-2 directly to the tumour site, leading to enhanced antitumour efficacy and long-term survival of mice in both syngeneic and xenogeneic models. This effect was concomitant with improved CAR T cell polyfunctionality, activation of endogenous antitumour immunity and a favourable safety profile, and was applicable in CAR T cells from patients.
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41586-025-09212-7
- Open Access at Publisher's Site
https://doi.org/10.1038/s41586-025-09212-7- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-07-22 03:31:08
Last Modified: 2025-07-22 03:31:16