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

• Published in: Cell Vol. 185; no. 8; pp. 1431 - 1443.e16
• Main Authors: Zhu, Iowis, Liu, Raymond, Garcia, Julie M., Hyrenius-Wittsten, Axel, Piraner, Dan I., Alavi, Josef, Israni, Divya V., Liu, Bin, Khalil, Ahmad S., Roybal, Kole T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.04.2022
• Subjects: Cancer and Oncology; cancer immunotherapy; Cancer och onkologi; CAR-T cells; cell therapy; Cell- and Tissue-Based Therapy; Clinical Medicine; Humans; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Receptors, Antigen, T-Cell - genetics; Receptors, Artificial - genetics; synNotch; Synthetic Biology; T-Lymphocytes; synthetic biology; synNotch; cell therapy; CAR-T cells; cancer immunotherapy
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2022.03.023

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. [Display omitted] •Synthetic intermembrane proteolysis receptors exhibit modularity•SNIPRs can be rationally optimized for sensitivity and strength of gene regulation•SNIPRs are compatible with a range of human and programmable transcription factors•Humanized SNIPR → CAR-T cells exhibit potent and precise anti-tumor activity in vivo The design framework for fully humanized transcriptional receptors for the programming of therapeutic cells.