Targeting Advanced Prostate Cancer with STEAP1 Chimeric Antigen Receptor T Cell and Tumor-localized IL-12 Immunotherapy

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Summary

Metastatic castration-resistant prostate cancer (mCRPC) is the late stage of prostate cancer. Researchers found that STEAP1, a six transmembrane epithelial antigen of the prostate 1, is highly expressed on prostate tumor cells and presents a more frequent and homogeneous expression in advanced prostate tumors. An anti-STEAP1 CAR-T cell is developed and shows specific killing with metastatic prostate cancer cells and prolonged survival of STEAP1+mice after adoptive transfer. Combined with collagen binding domain (CBD)-IL-12 therapy, STEAP1 CAR-T is promising to eradicate tumor cells with enhanced antigen presentation.

STEAP1-- A Promising Target for CAR-T Treatment of mCRPC

Metastatic castration-resistant prostate cancer (mCRPC) is a late-stage prostate cancer with high malignant, incurable, and short median survival time. Due to the resistance to approved ablation of androgen receptor (AR) signaling pathway-based therapies, current clinical treatments can only prolong patients' life for some months. Scientists have developed PSMA-targeted CAR-T cells for prostate cancer, which are safe and responsive, but the therapeutic efficacy is limited for the heterogeneous expression in mCRPC.

Previously, researchers from this article found that STEAP1, a six transmembrane epithelial antigen of the prostate 1, is highly expressed on prostate cancer cells using transcriptomic and proteomic techniques. Recently, they analyzed the expression landscape of STEAP1 in over 120 metastatic tumor tissues from forty-four mCRPC patients and demonstrated that STEAP1 presents a more frequent and more homogeneous expression in advanced prostate tumors.

Fig.1 Characterization of STEAP1 and PSMA expression profile in mCRPC patients using immunohistochemistry.¹

Broad expression in cancer and limited presentation in normal tissue makes STEAP1 an attractive antigen for targeted immunotherapy. Anti-STEAP1 CAR-T cells are generated using a lentiviral vector that contains a specific scFv, a CD28 transmembrane domain, and a 4-1BB co-stimulatory domain. These CAR-T cells specifically recognize human STEAP1 protein and do not cross-react with mouse Steap1 and other proteins in the human STEAP family. STEAP1-CAR also showed strong antitumor effects in the STEAP1 knock-in mouse model. To increase the therapeutic results of STEAP1 CAR-T treatment of mCRCS, collagen-binding domain IL-12 (CBD-IL-12) is injected simultaneously to remodel tumor immunosuppressive microenvironment and improved antigen processing and presentation.

Fig.2 Anti-STEAP1 CAR-T generated by lentiviral transfection and showed antigen-specific cytotoxicity.¹

Fig.3 STEAP1 CAR-T cells displayed significant anti-tumor function in mouse models.¹

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STEP1-Targeted Product Category

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Reference

Bhatia, V.; et al. Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nature communications. 2023, 14(1): 2041.