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Updated: Sep 29, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1
Vivek Narayan1,2, Julie S Barber-Rotenberg3, In-Young Jung2,3,4
1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
Insights
Chimeric antigen receptor (CAR) T-cell therapy for prostate cancer is feasible and safe, despite challenges from the tumor microenvironment. Future research should explore multi-pronged strategies to enhance CAR T-cell effectiveness.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR) T-cells show promise in hematologic cancers but face challenges in solid tumors due to the immunosuppressive tumor microenvironment (TME).
- Transforming growth factor (TGF)-β is a key inhibitory factor within the TME that can limit CAR T-cell efficacy.
Purpose of the Study:
- To evaluate the safety and feasibility of castration-resistant prostate cancer-directed CAR T-cells armored with a dominant-negative TGF-β receptor in a Phase 1 clinical trial.
- To assess CAR T-cell distribution, bioactivity, and disease response in patients with advanced prostate cancer.
Main Methods:
- Phase 1 clinical trial (NCT03089203) involving patients with castration-resistant prostate cancer.
- Administration of CAR T-cells engineered with a dominant-negative TGF-β receptor across four dose levels.
- Monitoring of safety endpoints, including cytokine release syndrome (CRS), and secondary objectives like CAR T-cell kinetics, bioactivity, and prostate-specific antigen (PSA) levels.
Main Results:
- The trial met its primary endpoints for safety and feasibility, with 13 patients receiving therapy.
- Five patients experienced grade ≥2 cytokine release syndrome (CRS), with one fatal event of grade 4 CRS and sepsis.
- Three patients achieved a PSA reduction of ≥30%, though CAR T-cell failure was observed with TME-localized inhibitory molecule upregulation. CAR T-cell expansion and tumor trafficking were noted.
Conclusions:
- Clinical application of TGF-β-resistant CAR T-cells is feasible and generally safe for treating prostate cancer.
- The immunosuppressive tumor microenvironment remains a significant barrier to CAR T-cell efficacy in solid tumors.
- Future studies necessitate advanced, multi-pronged strategies to overcome TME-mediated resistance and improve therapeutic outcomes.
