Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37874-2 |
| _version_ | 1797845896694595584 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Vipul Bhatia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:46:24Z |
| format | Article |
| id | doaj.art-ba31d0647dda46c882a031a7d7f3aece |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T17:46:24Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ba31d0647dda46c882a031a7d7f3aece2023-04-16T11:19:27ZengNature PortfolioNature Communications2041-17232023-04-0114112310.1038/s41467-023-37874-2Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapyVipul Bhatia0Nikhil V. Kamat1Tiffany E. Pariva2Li-Ting Wu3Annabelle Tsao4Koichi Sasaki5Huiyun Sun6Gerardo Javier7Sam Nutt8Ilsa Coleman9Lauren Hitchcock10Ailin Zhang11Dmytro Rudoy12Roman Gulati13Radhika A. Patel14Martine P. Roudier15Lawrence D. True16Shivani Srivastava17Colm M. Morrissey18Michael C. Haffner19Peter S. Nelson20Saul J. Priceman21Jun Ishihara22John K. Lee23Human Biology Division, Fred Hutchinson Cancer CenterDivision of Medical Oncology, University of WashingtonHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterDepartment of Bioengineering, Imperial College LondonHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterPublic Health Sciences Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterDepartment of Urology, University of WashingtonDepartment of Pathology and Laboratory Medicine, University of WashingtonHuman Biology Division, Fred Hutchinson Cancer CenterDepartment of Urology, University of WashingtonHuman Biology Division, Fred Hutchinson Cancer CenterHuman Biology Division, Fred Hutchinson Cancer CenterDepartment of Hematology and Hematopoietic Cell Transplantation, City of HopeDepartment of Bioengineering, Imperial College LondonHuman Biology Division, Fred Hutchinson Cancer CenterAbstract 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.https://doi.org/10.1038/s41467-023-37874-2 |
| spellingShingle | 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 Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy Nature Communications |
| title | Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy |
| title_full | Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy |
| title_fullStr | Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy |
| title_full_unstemmed | Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy |
| title_short | Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy |
| title_sort | targeting advanced prostate cancer with steap1 chimeric antigen receptor t cell and tumor localized il 12 immunotherapy |
| url | https://doi.org/10.1038/s41467-023-37874-2 |
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