Modular design of synthetic receptors for programmed gene regulation in cell therapies

Iowis Zhu; Raymond Liu; Julie M Garcia; Axel Hyrenius-Wittsten; Dan I Piraner; Josef Alavi; Divya V Israni; Bin Liu; Ahmad S Khalil; Kole T Roybal

doi:10.1016/j.cell.2022.03.023

Modular design of synthetic receptors for programmed gene regulation in cell therapies

Cell. 2022 Apr 14;185(8):1431-1443.e16. doi: 10.1016/j.cell.2022.03.023.

Authors

Affiliations

¹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA.
² Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund 221 84, Sweden.
³ Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215, USA.
⁴ Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA; Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94110, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁶ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Gladstone UCSF Institute for Genetic Immunology, San Francisco, CA 94107, USA; UCSF Cell Design Institute, San Francisco, CA 94158, USA. Electronic address: kole.roybal@ucsf.edu.

Abstract

Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.

Keywords: CAR-T cells; cancer immunotherapy; cell therapy; synNotch; synthetic biology.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Cell- and Tissue-Based Therapy*
Humans
Receptors, Antigen, T-Cell / genetics
Receptors, Artificial* / genetics
Synthetic Biology
T-Lymphocytes

Substances

Receptors, Antigen, T-Cell
Receptors, Artificial

Abstract

Publication types

MeSH terms

Substances

Grants and funding