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

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. Elsas, Jim Middelburg, Joel N. Lee, Maria N. 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 () and Paul A. Beavis ()
Additional contact information
Amanda X. Y. Chen: Peter MacCallum Cancer Centre
Kah Min Yap: Peter MacCallum Cancer Centre
Joelle S. Kim: Peter MacCallum Cancer Centre
Kevin Sek: Peter MacCallum Cancer Centre
Yu-Kuan Huang: Peter MacCallum Cancer Centre
Phoebe A. Dunbar: Peter MacCallum Cancer Centre
Volker Wiebking: Stanford University
Jesse D. Armitage: University of Western Australia
Isabelle Munoz: Peter MacCallum Cancer Centre
Kirsten L. Todd: Peter MacCallum Cancer Centre
Emily B. Derrick: Peter MacCallum Cancer Centre
Dat Nguyen: Peter MacCallum Cancer Centre
Junming Tong: Peter MacCallum Cancer Centre
Cheok Weng Chan: Peter MacCallum Cancer Centre
Thang X. Hoang: Peter MacCallum Cancer Centre
Katherine M. Audsley: Peter MacCallum Cancer Centre
Marit J. Elsas: Peter MacCallum Cancer Centre
Jim Middelburg: Peter MacCallum Cancer Centre
Joel N. Lee: Peter MacCallum Cancer Centre
Maria N. Menezes: Peter MacCallum Cancer Centre
Thomas J. Cole: Peter MacCallum Cancer Centre
Jasmine Li: Peter MacCallum Cancer Centre
Christina Scheffler: Peter MacCallum Cancer Centre
Andrew M. Scott: La Trobe University
Laura K. Mackay: The University of Melbourne
Jason Waithman: University of Western Australia
Jane Oliaro: Peter MacCallum Cancer Centre
Simon J. Harrison: The University of Melbourne
Ian A. Parish: Peter MacCallum Cancer Centre
Junyun Lai: Peter MacCallum Cancer Centre
Matthew H. Porteus: Stanford University
Imran G. House: Peter MacCallum Cancer Centre
Phillip K. Darcy: Peter MacCallum Cancer Centre
Paul A. Beavis: Peter MacCallum Cancer Centre

Nature, 2025, vol. 644, issue 8075, 241-251

Abstract: Abstract The efficacy 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 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.

Date: 2025
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DOI: 10.1038/s41586-025-09212-7

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