title: Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition.
abstract: Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z+ T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1+ or 19z1-CD80+ T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z+ T cells had 10-fold reduced tumor progression compared to those treated with 19z1+ or 19z1-CD80+ T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80+ T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z+ T cells. Our results establish that CTLA-4 down-regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function.
authors.affiliation: Center for Cell Engineering and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Maud
authors.initials: M
authors.lastname: Condomines
authors.affiliation: Center for Cell Engineering and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.affiliation: Center for Cell Engineering and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Reuben
authors.initials: R
authors.lastname: Benjamin
authors.affiliation: Center for Cell Engineering and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Gertrude
authors.initials: G
authors.lastname: Gunset
authors.affiliation: Center for Cell Engineering and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Plotkin
authors.affiliation: Center for Cell Engineering and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D018106:CD28 Antigens / Q000008:administration & dosage / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011946:Receptors, Antigen / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D011946:Receptors, Antigen