title: Remote control of therapeutic T cells through a small molecule-gated chimeric receptor.
abstract: There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA. The Cell Propulsion Lab, an NIH Nanomedicine Development Center, University of California, San Francisco, CA 94158, USA.
authors.forename: Chia-Yung
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA. The Cell Propulsion Lab, an NIH Nanomedicine Development Center, University of California, San Francisco, CA 94158, USA.
authors.forename: Kole T
authors.initials: KT
authors.lastname: Roybal
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Elias M
authors.initials: EM
authors.lastname: Puchner
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA. The Cell Propulsion Lab, an NIH Nanomedicine Development Center, University of California, San Francisco, CA 94158, USA. jamesonuffer@gmail.com wendell.lim@ucsf.edu.
authors.forename: James
authors.initials: J
authors.lastname: Onuffer
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA. The Cell Propulsion Lab, an NIH Nanomedicine Development Center, University of California, San Francisco, CA 94158, USA. Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. jamesonuffer@gmail.com wendell.lim@ucsf.edu.
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D060846:Cell Engineering; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000941:Antigens; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries