title: Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells.
abstract: T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Zeguo
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Maud
authors.initials: M
authors.lastname: Condomines
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Sjoukje J C
authors.initials: SJC
authors.lastname: van der Stegen
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Kloss
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Gertrude
authors.initials: G
authors.lastname: Gunset
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Plotkin
authors.affiliation: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA. Electronic address: m-sadelain@ski.mskcc.org.
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D016219:Immunotherapy, Adoptive; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
chemical_list: D018941:Antigens, CD19; D018106:CD28 Antigens; D050839:Interferon Regulatory Factor-7; D011946:Receptors, Antigen; D011994:Recombinant Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma