Phase 1 Trial: IL‑18–Armored STEAP1 CAR T Cells for Metastatic Castration‑Resistant Prostate Cancer

IL‑18–armored STEAP1 CAR T cells represent a biologically rational, early‑clinical strategy that combines a well‑validated prostate‑cancer target with next‑generation cytokine armoring designed to overcome the hostile tumour microenvironment and antigen heterogeneity that have limited earlier immunotherapy efforts.

STEAP1 (six‑transmembrane epithelial antigen of the prostate 1) was first identified in advanced prostate cancer and is now recognized as a cell‑surface protein overexpressed in the vast majority of lethal mCRPC specimens, with broad expression across bone, lymph‑node and visceral metastases and minimal presence in most normal tissues. This pattern makes STEAP1 attractive for targeted therapies, including antibody–drug conjugates and CAR T cells, because it offers relatively uniform antigen coverage in late‑stage disease compared with targets such as PSMA, which can be heterogeneous or downregulated under therapeutic pressure. A phase I trial of a STEAP1‑targeting antibody–drug conjugate in mCRPC already showed acceptable safety and signals of activity, including PSA declines ≥50% in a subset of patients and radiographic responses or stable disease in many evaluable cases, reinforcing the clinical relevance of STEAP1 as a therapeutic target.

Building on this foundation, preclinical work at Fred Hutchinson Cancer Center and collaborators developed second‑generation STEAP1 CAR T cells. In prostate cancer xenograft and disseminated models, these STEAP1 CAR T cells induced substantial tumour regression and survival benefit compared with control CAR T cells. The addition of cytokine armoring to the STEAP1 platform, with interleukin‑18 (IL‑18) selected for its ability to boost T‑cell activation, promotes Th1‑type inflammatory responses, and recruit innate immune effectors such as NK cells and macrophages.

IL‑18–armored STEAP1 CAR T cells (often referred to in industry materials as PRO CAR‑202) are engineered to constitutively secrete IL‑18, creating a pro‑inflammatory cytokine milieu concentrated at the tumour site. In Ewing sarcoma preclinical models, where STEAP1 is also highly expressed (~97% of primary tumours), IL‑18‑armored STEAP1 CAR T cells achieved complete responses in ~80% of mice at a five‑fold lower cell dose than unarmored CAR T cells, without overt toxicity, demonstrating that IL‑18 armoring can markedly increase potency and allow dose sparing. In aggressive, disseminated syngeneic prostate cancer models, the same IL‑18‑armored construct extended survival, suggesting that the mechanistic benefits seen in Ewing sarcoma translate to prostate cancer biology. Across multiple tumour types, IL‑18‑armored CAR T cells consistently show enhanced expansion and persistence, higher IFN‑γ and TNF‑α production, reduced exhaustion markers, and reprogramming of the tumour microenvironment toward a more inflammatory, antitumor state, including increased M1‑like macrophages and activated NK cells.

From a prostate‑cancer perspective, these properties directly address several limitations of earlier immunotherapy attempts in mCRPC. Checkpoint inhibitors have shown modest activity except in biomarker‑selected subgroups (MSI‑H/dMMR, TMB‑high), and earlier CAR T programs targeting PSMA and other antigens have struggled with antigen heterogeneity, limited persistence, and on‑target off‑tumour toxicities, with some trials reporting serious cytokine release syndrome and neurotoxicity and even patient deaths during dose escalation. By targeting STEAP1, which is broadly and uniformly expressed in lethal mCRPC, and by arming CAR T cells with IL‑18 to sustain activation and engage endogenous immunity, the IL‑18–STEAP1 approach aims to generate stronger and more durable tumour killing while mitigating antigen‑loss escape.

Clinical trial.