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Published on: February 21, 2025
Development of STEAP1 targeting chimeric antigen receptor for adoptive cell therapy against cancer
Yixin Jin1, Kristina Berg Lorvik1, Yang Jin2
1Department of Cancer Immunology, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Mail Box 4950 Nydalen, 0424 Oslo, Norway.
Abstract:
Chimeric antigen receptors (CARs) that retarget T cells against CD19 show clinical efficacy against B cell malignancies. Here, we describe the development of a CAR against the six-transmembrane epithelial antigen of prostate-1 (STEAP1), which is expressed in ∼90% of prostate cancers, and subgroups of other malignancies. STEAP1 is an attractive target, as it is associated with tumor invasiveness and progression and only expressed at low levels in normal tissues, apart from the non-vital prostate gland. We identified the antibody coding sequences from a hybridoma and designed a CAR that is efficiently expressed in primary T cells. The T cells acquired the desired anti-STEAP1 specificity, with a polyfunctional response including production of multiple cytokines, proliferation, and the killing of cancer cells. The response was observed for both CD4+ and CD8+ T cells, and against all STEAP1+ target cell lines tested. We evaluated the in vivo CAR T activity in both subcutaneous and metastatic xenograft mouse models of prostate cancer. Here, the CAR T cells infiltrated tumors and significantly inhibited tumor growth and extended survival in a STEAP1-dependent manner. We conclude that the STEAP1 CAR exhibits potent in vitro and in vivo functionality and can be further developed toward potential clinical use.
Insights
Researchers developed a novel chimeric antigen receptor (CAR) targeting STEAP1 for prostate cancer. This CAR T-cell therapy demonstrated significant anti-tumor activity in preclinical models, offering a promising new avenue for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptors (CARs) retarget T-cells for cancer therapy, with CD19-targeted CARs effective against B cell malignancies.
- The six-transmembrane epithelial antigen of prostate-1 (STEAP1) is highly expressed in prostate cancer and associated with tumor progression.
- STEAP1 is a promising target due to its tumor-specific expression and limited presence in normal tissues.
Purpose of the Study:
- To develop and characterize a novel CAR targeting STEAP1 for prostate cancer treatment.
- To evaluate the in vitro and in vivo efficacy of STEAP1-targeted CAR T-cells.
Main Methods:
- Identified antibody coding sequences from a hybridoma targeting STEAP1.
- Designed and engineered a CAR construct for efficient expression in primary T-cells.
- Assessed CAR T-cell specificity, polyfunctionality (cytokine production, proliferation, cytotoxicity), and in vivo efficacy in prostate cancer xenograft models.
Main Results:
- STEAP1 CAR was efficiently expressed in primary T-cells, conferring anti-STEAP1 specificity.
- CAR T-cells exhibited polyfunctional responses, including cytokine release, proliferation, and cancer cell killing.
- In vivo studies showed significant tumor growth inhibition and extended survival in a STEAP1-dependent manner.
Conclusions:
- The developed STEAP1 CAR demonstrates potent in vitro and in vivo anti-tumor activity against prostate cancer.
- STEAP1 CAR T-cell therapy shows potential for clinical development in treating prostate cancer and other STEAP1-expressing malignancies.
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