Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors.
Redirecting T cells to attack cancer using engineered chimeric receptors provides powerful new therapeutic capabilities. However, the effectiveness of therapeutic T cells is constrained by the endogenous T cell response: certain facets of natural response programs can be toxic, whereas other responses, such as the ability to overcome tumor immunosuppression, are absent. Thus, the efficacy and safety of therapeutic cells could be improved if we could custom sculpt immune cell responses. Synthetic Notch (synNotch) receptors induce transcriptional activation in response to recognition of user-specified antigens. We show that synNotch receptors can be used to sculpt custom response programs in primary T cells: they can drive a la carte cytokine secretion profiles, biased T cell differentiation, and local delivery of non-native therapeutic payloads, such as antibodies, in response to antigen. SynNotch T cells can thus be used as a general platform to recognize and remodel local microenvironments associated with diverse diseases.
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Kole T
KT
Roybal
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Jasper Z
JZ
Williams
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Leonardo
L
Morsut
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Levi J
LJ
Rupp
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Isabel
I
Kolinko
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Joseph H
JH
Choe
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Whitney J
WJ
Walker
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Krista A
KA
McNally
Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA. Electronic address: wendell.lim@ucsf.edu.
Wendell A
WA
Lim
D000906:Antibodies / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060846:Cell Engineering; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000628:therapy*; D062165:Receptors, Artificial / Q000235:genetics / Q000276:immunology*; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014158:Transcription, Genetic; D059016:Tumor Microenvironment
D000906:Antibodies; D016207:Cytokines; D062165:Receptors, Artificial; D051880:Receptors, Notch; D053221:TNF-Related Apoptosis-Inducing Ligand
CARs; T cells; cancer; cellular engineering; immunotherapy; synthetic Notch; synthetic biology
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