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

• DOI: 10.1038/s41591-022-01726-1
• Publication Date: 2022-03-21T17:02:59Z
• Authors: Vivek Narayan; Julie S. Barber-R...; 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. No...; Hayley E. Raymond; ; Diane Frazee; Mary Truran; Elizabeth Veloso; Holly McConville; Jonathan Aguedelo; Samantha Hower; Sophia Ngo; Julie Jadlowsky; J. Joseph Melenhorst; Aoife Roche; John Everett; Minnal Gupta; Farzana Nazimuddin; Chelsie Bartoszek; Natalka Koterba; Rachael Reynolds; Farris Ellington; Christopher C. Kloss; Jihyun Lee; Yangbing Zhao; John Scholler; James L. Riley; Christina Bailey; Andrew White; Briana Hudson; Pearl Chang; Marcela V. Maus; Bruce L. Levine; Elizabeth O. Hexner; Donald L. Siegel; Frederic D. Bushman; Carl H. June; Joseph A. Fraietta; Naomi B. Haas
• Keywords: Male; 0301 basic medicine; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; Receptors, Chimeric Antigen; Transforming Growth Factor beta; T-Lymphocytes; Tumor Microenvironment; Humans; Prostate-Specific Antigen; Immunotherapy, Adoptive

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.