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.
Nature communications. 2023 Apr 11*** epublish ***
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, John K Lee
Human Biology Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA., Division of Medical Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA., Department of Bioengineering, Imperial College London, 86 Wood Lane, London, W12 0BZ, UK., Public Health Sciences Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA., Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA., Department of Pathology and Laboratory Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA., Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA., Department of Bioengineering, Imperial College London, 86 Wood Lane, London, W12 0BZ, UK. ., Human Biology Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA. .