Narayan et al. focused on decreasing TGFβ in the TME to improve CAR T cell efficacy for treatment-refractory metastatic prostate cancer. In a phase 1 trial, 13 patients were treated with PSMA-targeted CAR T cells expressing a dominant-negative TGFβR, with or without lymphodepletion (LD). Both primary (safety and feasibility) and secondary (CAR T cell distribution, bioactivity, and disease response) endpoints were met, and 4 patients achieved a ≥30% PSA reduction. LD correlated with greater PSA reductions and enhanced CAR T cell proliferation and function, while CAR T cell loss was accompanied by increased inhibitory TME molecules.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine, University of Penns
Author Info: (1) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (6) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (8) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (10) Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (11) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (16) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (17) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (19) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (20) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (21) NanoString Technologies, Inc., Seattle, WA, USA. (22) NanoString Technologies, Inc., Seattle, WA, USA. (23) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (24) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (25) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (26) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (27) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (29) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (30) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (31) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (32) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (33) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (34) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (35) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (36) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (37) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (38) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu. (39) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jfrai@upenn.edu. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jfrai@upenn.edu. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jfrai@upenn.edu. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jfrai@upenn.edu. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. jfrai@upenn.edu. (40) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. naomi.haas@pennmedicine.upenn.edu. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. naomi.haas@pennmedicine.upenn.edu.
