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

Zhu, Iowis ; Liu, Raymond ; Garcia, Julie M. ; Hyrenius-Wittsten, Axel LU ; Piraner, Dan I. ; Alavi, Josef ; Israni, Divya V. ; Liu, Bin ; Khalil, Ahmad S. and Roybal, Kole T. (2022) In Cell 185(8). p.16-1443
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cancer immunotherapy, CAR-T cells, cell therapy, synNotch, synthetic biology
in
Cell
volume
185
issue
8
pages
16 - 1443
publisher
Cell Press
external identifiers
  • scopus:85127922599
  • pmid:35427499
ISSN
0092-8674
DOI
10.1016/j.cell.2022.03.023
language
English
LU publication?
yes
id
06fea773-593d-43aa-9c87-6820eb1bc97f
date added to LUP
2022-06-09 14:13:06
date last changed
2024-06-27 17:12:18
@article{06fea773-593d-43aa-9c87-6820eb1bc97f,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhu, Iowis and Liu, Raymond and Garcia, Julie M. and Hyrenius-Wittsten, Axel and Piraner, Dan I. and Alavi, Josef and Israni, Divya V. and Liu, Bin and Khalil, Ahmad S. and Roybal, Kole T.}},
  issn         = {{0092-8674}},
  keywords     = {{cancer immunotherapy; CAR-T cells; cell therapy; synNotch; synthetic biology}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{16--1443}},
  publisher    = {{Cell Press}},
  series       = {{Cell}},
  title        = {{Modular design of synthetic receptors for programmed gene regulation in cell therapies}},
  url          = {{http://dx.doi.org/10.1016/j.cell.2022.03.023}},
  doi          = {{10.1016/j.cell.2022.03.023}},
  volume       = {{185}},
  year         = {{2022}},
}