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Jang Hwan Cho1,2,9, Atsushi Okuma1,2,9, Katri Sofjan1,2, Seunghee Lee1,2, James J. Collins3,4,5,6,7,8 & Wilson W. Wong1,2,*
1Department of Biomedical Engineering, Boston University, Boston, MA, USA. 2Biological Design Center, Boston University, Boston, MA, USA. 3Synthetic Biology Center, MIT, Cambridge, MA, USA. 4Institute for Medical Engineering and Science, MIT, Cambridge, MA, USA. 5Department of Biological Engineering, MIT, Cambridge, MA, USA. 6Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA. 7Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA, USA. 8Wyss Institute for Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, MA, USA.
9These authors contributed equally: Jang Hwan Cho, Atsushi Okuma.
*Corresponding author
Abstract
The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.
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