2. Academic Validation
  3. Rewiring endogenous genes in CAR T cells for tumour-restricted payload delivery

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

  • Nature. 2025 Aug;644(8075):241-251. doi: 10.1038/s41586-025-09212-7.
Amanda X Y Chen # 1 2,  Kah Min Yap # 3 4,  Joelle S Kim 5 6,  Kevin Sek 5 6,  Yu-Kuan Huang 5 6,  Phoebe A Dunbar 5 6,  Volker Wiebking 7,  Jesse D Armitage 8 9,  Isabelle Munoz 5 6,  Kirsten L Todd 5 6,  Emily B Derrick 5 6,  Dat Nguyen 5 6,  Junming Tong 5 6,  Cheok Weng Chan 5 6,  Thang X Hoang 5 6,  Katherine M Audsley 5 6,  Marit J van Elsas 5 6,  Jim Middelburg 5 6,  Joel N Lee 5 6,  Maria N de Menezes 5 6,  Thomas J Cole 5 6,  Jasmine Li 5 6,  Christina Scheffler 5 6,  Andrew M Scott 10 11,  Laura K Mackay 12,  Jason Waithman 8 9,  Jane Oliaro 5 6,  Simon J Harrison 6 13,  Ian A Parish 5 6,  Junyun Lai 5 6,  Matthew H Porteus 7,  Imran G House 5 6,  Phillip K Darcy 14 15 16,  Paul A Beavis 17 18
Affiliations

Affiliations

  • 1 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Amanda.chen@petermac.org.
  • 2 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Amanda.chen@petermac.org.
  • 3 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. kahmin.yap@petermac.org.
  • 4 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. kahmin.yap@petermac.org.
  • 5 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 6 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
  • 7 Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • 8 School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia.
  • 9 Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, Western Australia, Australia.
  • 10 Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
  • 11 Faculty of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
  • 12 Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia.
  • 13 Clinical Haematology and Centre of Excellence for Cellular Immunotherapies, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
  • 14 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Phil.darcy@petermac.org.
  • 15 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Phil.darcy@petermac.org.
  • 16 Department of Immunology, Monash University, Clayton, Australia. Phil.darcy@petermac.org.
  • 17 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Paul.beavis@petermac.org.
  • 18 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Paul.beavis@petermac.org.
  • # Contributed equally.
PMID: 40604285 DOI: 10.1038/s41586-025-09212-7
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.

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