1区 · 综合性期刊
ArticleOA
作者: Rudoy, Dmytro ; Wu, Li-Ting ; Zhang, Ailin ; Haffner, Michael C ; Tsao, Annabelle ; Nutt, Sam ; Ishihara, Jun ; Lee, John K ; Pariva, Tiffany E ; Patel, Radhika A ; True, Lawrence D ; Roudier, Martine P ; Nelson, Peter S ; Priceman, Saul J ; Kamat, Nikhil V ; Morrissey, Colm M ; Gulati, Roman ; Bhatia, Vipul ; Coleman, Ilsa ; Sasaki, Koichi ; Sun, Huiyun ; Hitchcock, Lauren ; Srivastava, Shivani ; Javier, Gerardo
AbstractSix 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.
