Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy

Vipul Bhatia, Nikhil V. Kamat, Tiffany E. Pariva, Li-Ting Wu, Annabelle Tsao, Koichi Sasaki, Huiyun Sun, Gerardo Javier, Sam Nutt, Ilsa Coleman, Lauren Hitchcock, Ailin Zhang, Dmytro Rudoy, Roman Gulati, Radhika A. Patel, Martine P. Roudier, Lawrence D. True, Shivani Srivastava, Colm M. Morrissey, Michael C. Haffner, Peter S. Nelson, Saul J. Priceman, Jun Ishihara () and John K. Lee ()
Additional contact information
Vipul Bhatia: Fred Hutchinson Cancer Center
Nikhil V. Kamat: University of Washington
Tiffany E. Pariva: Fred Hutchinson Cancer Center
Li-Ting Wu: Fred Hutchinson Cancer Center
Annabelle Tsao: Fred Hutchinson Cancer Center
Koichi Sasaki: Imperial College London
Huiyun Sun: Fred Hutchinson Cancer Center
Gerardo Javier: Fred Hutchinson Cancer Center
Sam Nutt: Fred Hutchinson Cancer Center
Ilsa Coleman: Fred Hutchinson Cancer Center
Lauren Hitchcock: Fred Hutchinson Cancer Center
Ailin Zhang: Fred Hutchinson Cancer Center
Dmytro Rudoy: Fred Hutchinson Cancer Center
Roman Gulati: Fred Hutchinson Cancer Center
Radhika A. Patel: Fred Hutchinson Cancer Center
Martine P. Roudier: University of Washington
Lawrence D. True: University of Washington
Shivani Srivastava: Fred Hutchinson Cancer Center
Colm M. Morrissey: University of Washington
Michael C. Haffner: Fred Hutchinson Cancer Center
Peter S. Nelson: Fred Hutchinson Cancer Center
Saul J. Priceman: City of Hope
Jun Ishihara: Imperial College London
John K. Lee: Fred Hutchinson Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Date: 2023
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DOI: 10.1038/s41467-023-37874-2

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