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

• 成果类型: Article
• 署名作者: Chen, Amanda X. Y.; Yap, Kah Min; Kim, Joelle S.; Sek, Kevin; Huang, Yu-Kuan; Dunbar, Phoebe A.; Wiebking, Volker; Armitage, Jesse D.; Munoz, Isabelle; Todd, Kirsten L.; Derrick, Emily B.; Nguyen, Dat; Tong, Junming; Chan, Cheok Weng; Hoang, Thang X.; Audsley, Katherine M.; van Elsas, Marit J.; Middelburg, Jim; Lee, Joel N.; de Menezes, Maria N.; Cole, Thomas J.; Li, Jasmine; Scheffler, Christina; Scott, Andrew M.; Mackay, Laura K.; Waithman, Jason; Oliaro, Jane; Harrison, Simon J.; Parish, Ian A.; Lai, Junyun; Porteus, Matthew H.; House, Imran G.; Darcy, Phillip K.; Beavis, Paul A.
• 署名单位: Peter Maccallum Cancer Center; University of Melbourne; Peter Maccallum Cancer Center; Stanford University; University of Western Australia; University of Western Australia; The Kids Research Institute Australia; La Trobe University; Olivia Newton-John Cancer Research Institute; La Trobe University; University of Melbourne; University of Melbourne; Peter Doherty Institute; Peter Maccallum Cancer Center; Peter Maccallum Cancer Center; Melbourne Health; Royal Melbourne Hospital; Monash University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2060
• DOI: 10.1038/s41586-025-09212-7
• 发表日期: 2025-08-07
• 关键词: differential expression analysis; antigen; therapy; efficacy; immunotherapy; activation; mice

摘要

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.