title: Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits.
abstract: T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual-receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo-sparing single antigen "bystander" tumors while efficiently clearing combinatorial antigen "disease" tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors. VIDEO ABSTRACT.
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Kole T
authors.initials: KT
authors.lastname: Roybal
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Rupp
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Morsut
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Whitney J
authors.initials: WJ
authors.lastname: Walker
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Krista A
authors.initials: KA
authors.lastname: McNally
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA. Electronic address: wendell.lim@ucsf.edu.
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology; D024201:Bystander Effect; D002450:Cell Communication; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D000090204:Mesothelin; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D051880:Receptors, Notch / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D018941:Antigens, CD19; D000954:Antigens, Surface; D058851:GPI-Linked Proteins; D051880:Receptors, Notch; D000090204:Mesothelin
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