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

• Published in: Nature medicine Vol. 28; no. 4; pp. 724 - 734
• Main Authors: Narayan, Vivek, Barber-Rotenberg, Julie S., Jung, In-Young, Lacey, Simon F., Rech, Andrew J., Davis, Megan M., Hwang, Wei-Ting, Lal, Priti, Carpenter, Erica L., Maude, Shannon L., Plesa, Gabriela, Vapiwala, Neha, Chew, Anne, Moniak, Michael, Sebro, Ronnie A., Farwell, Michael D., Marshall, Amy, Gilmore, Joan, Lledo, Lester, Dengel, Karen, Church, Sarah E., Hether, Tyler D., Xu, Jun, Gohil, Mercy, Buckingham, Thomas H., Yee, Stephanie S., Gonzalez, Vanessa E., Kulikovskaya, Irina, Chen, Fang, Tian, Lifeng, Tien, Kyle, Gladney, Whitney, Nobles, Christopher L., Raymond, Hayley E., Hexner, Elizabeth O., Siegel, Donald L., Bushman, Frederic D., June, Carl H., Fraietta, Joseph A., Haas, Naomi B.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2022; Nature Publishing Group
• Subjects: 631/250/1619/554; 631/67/580; 692/308/2779/109/1940; 692/699/67/1059/2325; 692/699/67/589/466; Anticancer properties; Antigens; Antitumor activity; Biocompatibility; Biological activity; Biomedical and Life Sciences; Biomedicine; Blood cancer; Cancer Research; Castration; Chimeric antigen receptors; Cytokines; Feasibility; Growth factors; Humans; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Infectious Diseases; Inflammation; Lymphocytes; Lymphocytes T; Male; Metabolic Diseases; Metastases; Metastasis; Molecular Medicine; Neurosciences; Patients; Prostate cancer; Prostate-specific antigen; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors; Receptors, Chimeric Antigen; Reduction; Sepsis; Solid tumors; T-Lymphocytes; Toxicity; Transforming Growth Factor beta - metabolism; Tumor Microenvironment
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-022-01726-1

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. CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer