Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models
Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimaeric antigen receptor (CAR)-T cell therapies applied to solid tumours. Previously, CAR-T cells were armoured with immunostimulatory molecules, such as interleukin 12 (IL-12), to overcome this issue, but faced high toxicity. Here we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of prostate 1 (STEAP1) is retained within murine prostate tumours. This leads to high intratumoural interferon-γ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumour antigens after CBD-IL-12-armoured CAR-T cell treatment. A combination of CBD-IL-12-armoured CAR-T cells and immune checkpoint inhibitors eradicated large tumours in an established prostate cancer mouse model. In addition, human CBD-IL-12-armoured CAR-T cells showed potent anti-tumour efficacy in a 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armoured CAR-T cells. CBD fusion to potent payloads for CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumours.
Authors
- Vipul Bhatia (ORCID: https://orcid.org/0000-0002-4091-8866)
- Yuta Asano (ORCID: https://orcid.org/0000-0002-4720-2238)
- Po-Chuan Chiu
- Olivier Dubois
- Ioanna Panagi
- Saul J. Priceman (ORCID: https://orcid.org/0000-0002-8136-2112)
- Aude G. Chapuis (ORCID: https://orcid.org/0000-0002-9574-5448)
- Pooja Kaur (ORCID: https://orcid.org/0000-0001-7446-8667)
- Donny Gun
- Laurine Noblecourt (ORCID: https://orcid.org/0009-0002-8710-6846)
- Tsung Wen Chong (ORCID: https://orcid.org/0000-0002-6790-902X)
- Koichi Sasaki (ORCID: https://orcid.org/0000-0001-9966-957X)
- Maria Nikolaidi (ORCID: https://orcid.org/0000-0001-7196-2707)
- John K. Lee (ORCID: https://orcid.org/0000-0002-6570-2180)
- Chuyi Wang (ORCID: https://orcid.org/0009-0005-9273-9906)
- Gerardo Javier
- Jun Ishihara (ORCID: https://orcid.org/0000-0002-9083-9859)
- Charanjit Singh (ORCID: https://orcid.org/0000-0002-3596-3013)
- Jakob Bakhtiari
- T. Matsuo
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- University of California, Los Angeles (US)
- University of Washington Medical Center (US)
- Fred Hutch Cancer Center (US)
- Laboratory of Molecular Genetics (PL)
- Parker Institute for Cancer Immunotherapy (US)
- City of Hope (US)
- Chiba Cancer Center (JP)
- Beckman Research Institute
- Imperial College London (GB)
Publication Details
- Journal
- Nature Biomedical Engineering
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1038/s41551-025-01508-3
- Citations
- 8
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 8.36
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Fred Hutchinson Cancer Research Center
- National Institute for Health and Care Research
- Prostate Cancer UK
- Japan Society for the Promotion of Science
- NIHR Imperial Biomedical Research Centre
- DOD Prostate Cancer Research Program