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PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial.

Vivek NarayanJulie S Barber-RotenbergIn-Young JungSimon F LaceyAndrew J RechMegan M DavisWei-Ting HwangPriti LalErica L CarpenterShannon L MaudeGabriela PlesaNeha VapiwalaAnne ChewMichael MoniakRonnie A SebroMichael D FarwellAmy MarshallJoan GilmoreLester LledoKaren DengelSarah E ChurchTyler D HetherJun XuMercy GohilThomas H BuckinghamStephanie S YeeVanessa E GonzalezIrina KulikovskayaFang ChenLifeng TianKyle TienWhitney GladneyChristopher L NoblesHayley E Raymondnull nullElizabeth O HexnerDonald L SiegelFrederic D BushmanCarl H JuneJoseph A FraiettaNaomi B Haas
Published in: Nature medicine (2022)
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.
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