Narayan et al. focused on decreasing TGFβ in the TME to improve CAR T cell efficacy for treatment-refractory metastatic prostate cancer. In a phase 1 trial, 13 patients were treated with PSMA-targeted CAR T cells expressing a dominant-negative TGFβR, with or without lymphodepletion (LD). Both primary (safety and feasibility) and secondary (CAR T cell distribution, bioactivity, and disease response) endpoints were met, and 4 patients achieved a ≥30% PSA reduction. LD correlated with greater PSA reductions and enhanced CAR T cell proliferation and function, while CAR T cell loss was accompanied by increased inhibitory TME molecules.
Contributed by Katherine Turner
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.