期刊
NATURE MEDICINE
卷 28, 期 4, 页码 724-734出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01726-1
关键词
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资金
- University of Pennsylvania
- Prostate Cancer Foundation Challenge Award
- Tmunity Therapeutics, Inc.
- George Weiss Funding Group
- Alliance for Cancer Gene Therapy Investigator Award in Cell and Gene Therapy for Cancer
- Prostate Cancer Foundation Young Investigator Award
- ACC P30 Core Grant [P30 CA016520-42]
- [U54 CA244711-01]
- [R01 CA241762-03]
CAR T cells show promising efficacy in hematologic malignancies, but face challenges in solid tumors due to the immunosuppressive tumor microenvironment. This study reports results from a phase 1 trial using engineered CAR T cells resistant to TGF-beta signaling in castration-resistant prostate cancer patients, showing both efficacy and dose-dependent toxicity. Future studies should explore multipronged approaches to improve outcomes in this setting.
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)-beta. 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-beta 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-beta-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes. CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGF beta signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer
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