Armoring STEAP1 CAR T cells with IL-18 potentiates antitumor activity in Ewing sarcoma

Abstract

Ewing sarcoma (EwS) is an aggressive malignancy of children, adolescents, and young adults driven by the EWS::FLI1 fusion oncoprotein with few effective treatment options in the relapsed or refractory setting. We validate six transmembrane epithelial antigen of the prostate 1 (STEAP1) as a fusion-regulated and clinically actionable surface antigen with broad expression across a series of primary EwS tumors. Analysis of EWS::FLI1 perturbation in EwS models demonstrated regulation of STEAP1 transcript and protein expression by oncogenic EWS::FLI1. Second-generation STEAP1 CAR T cells induced complete tumor regression in orthotopic models and exhibited dose-dependent activity in disseminated disease without evidence of antigen escape. Armoring STEAP1 CAR T cells with IL-18 further potentiated antitumor efficacy, achieving complete responses without overt toxicity in approximately 80% of mice at a five-fold lower cell dose where unarmored STEAP1 CAR T cells were ineffective. Notably, adoptive transfer of autologous STEAP1 CAR T cells is currently being evaluated in a first-in-human phase I/II clinical trial in metastatic castration-resistant prostate cancer (NCT06236139) and the compelling preclinical data presented here support clinical translation to relapsed/refractory EwS.