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

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.

• Authors: Vivek Narayan, Julie S Barber-Rotenberg, In-Young Jung, Simon F Lacey, Andrew J Rech, Megan M Davis, Wei-Ting Hwang, Priti Lal, Erica L Carpenter, Shannon L Maude, Gabriela Plesa, Neha Vapiwala, Anne Chew, Michael Moniak, Ronnie A Sebro, Michael D Farwell, Amy Marshall, Joan Gilmore, Lester Lledo, Karen Dengel, Sarah E Church, Tyler D Hether, Jun Xu, Mercy Gohil, Thomas H Buckingham, Stephanie S Yee, Vanessa E Gonzalez, Irina Kulikovskaya, Fang Chen, Lifeng Tian, Kyle Tien, Whitney Gladney, Christopher L Nobles, Hayley E Raymond, Prostate Cancer Cellular Therapy Program Investigators, Elizabeth O Hexner, Donald L Siegel, Frederic D Bushman, Carl H June, Joseph A Fraietta, Naomi B Haas
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 4 Pg. 724-734 (04 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35314843 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Receptors, Chimeric Antigen
• Transforming Growth Factor beta
• Prostate-Specific Antigen

Topics

• Humans
• Immunotherapy, Adoptive (adverse effects, methods)
• Male
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms, Castration-Resistant (pathology)
• Receptors, Chimeric Antigen
• T-Lymphocytes
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment