Brief intro:
- Author: Amanda X. Y. Chen, Kah Min Yap, Joelle S. Kim, Kevin Sek, Yu-Kuan Huang, Phoebe A. Dunbar, Volker Wiebking, Jesse D. Armitage, Isabelle Munoz, Kirsten L. Todd, Emily B. Derrick, Dat Nguyen, Junming Tong, Cheok Weng Chan, Thang X. Hoang, Katherine M. Audsley, Marit J. van Elsas, Jim Middelburg, Joel N. Lee, Maria N. de Menezes, Thomas J. Cole, Jasmine Li, Christina Scheffler, Andrew M. Scott, Laura K. Mackay, Jason Waithman, Jane Oliaro, Simon J. Harrison, Ian A. Parish, Junyun Lai, Matthew H. Porteus, Imran G. House, Phillip K. Darcy & Paul A. Beavis
- Journal: Nature
- Doi: https://www.doi.org/10.1038/s41586-025-09212-7
- Publication Date: 2025/7/2
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 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.
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