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Review
. 2022 Nov 16;13(11):864-873.
doi: 10.1016/j.cels.2022.09.006.

Recent progress of gene circuit designs in immune cell therapies

Seunghee Lee  1 , Ahmad S Khalil  2 , Wilson W Wong  3
Affiliations
Review

Recent progress of gene circuit designs in immune cell therapies

Seunghee Lee et al. Cell Syst. .

Abstract

The success of chimeric antigen receptor (CAR) T cell therapy against hematological cancers has convincingly demonstrated the potential of using genetically engineered cells as therapeutic agents. Although much progress has been achieved in cell therapy, more beneficial capabilities have yet to be fully explored. One of the unique advantages afforded by cell therapies is the possibility to implement genetic control circuits, which enables diverse signal sensing and logical processing for optimal response in the complex tumor microenvironment. In this perspective, we will first outline design considerations for cell therapy control circuits that address clinical demands. We will compare and contrast key design features in some of the latest control circuits developments and conclude by discussing potential future directions.

Keywords: CAR; gene circuits; immune cell therapy; synthetic biology.

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Conflict of interest statement

Declaration of interests W.W.W. is a co-founder and shareholder of Senti Biosciences. A.S.K. is a shareholder of Senti Bioscience and Chroma Medicine. S.L. is a current employee of Sanofi.

Figures

Figure 1.
Figure 1.. Comparison between cell-autonomous and exogenous control.
Autonomous control of engineered immune cells can sense and respond to the environment or internal signals, whereas exogenous control enables user intervention of the engineered cells through various types of inputs.
Figure 2.
Figure 2.. Schematics of chimeric antigen receptors and receptor logic circuits.
A. Chimeric antigen receptors are derived from native receptors, exchanging their intracellular domains with extracellular domains to rewire their targeting specificity. B. SUPRA CAR consists of zipFv and zipCAR. Swapping the zipFv allows targeting various antigens by the same zipCAR. C. SynNotch receptor can induce gene expression in response to the desired antigen. Once the antigen is bound to the scFv domain, membrane-bound transcription factor (txn factor) will be released to induce the gene expression. D. Co-LOCKR system consists of a CAR and two adaptor proteins; Cage and Key. Only when Cage and Key are bound on the same target cell, the Cage domain can be exposed to activate the CAR.
Figure 3.
Figure 3.. System designs for cell state-based control.
A. CAR with an oxygen-dependent degradation domain (ODD), for which its stability is dependent on hypoxia. The ODD will be degraded under normal oxygen concentration, resulting in the degradation of the CAR. B. A CAR design that can be activated only under the presence of tumor-specific protease. The scFv is masked by a cleavable linker and a masking peptide, and the protease can cleave off the linker to expose the scFv so that the CAR can be activated against the target antigen. C. Activation status of the immune cell can be utilized to control further cytokine generation. Once the T cell is activated, the NFAT can be phosphorylated and translocated into the nuclease to induce the target cytokine transcription.
Figure 4.
Figure 4.. Exogeneous cell control with ON- and OFF- switches.
A. Representative ON-switch incorporating an NS3 protease to control the CAR activity. CAR will be stabilized only under the presence of a drug that can inhibit the protease activity to induce the T cell activation. B. Representative OFF-switch using the zinc finger degron motif and a synthetic ubiquitin ligase. A drug that can induce the dimerization between the degron and the ligase will degrade the CAR, so the T cells cannot be activated under the presence of the drug.
Figure 5.
Figure 5.. Exogenous cell control with light and ultrasound inputs.
A. Photoactivable CAR activation system is designed with two light-inducible dimerization fused to a transcription factor. Upon light induction, the CAR will be expressed and activate the T cells. B. Ultrasound-inducible CAR system utilizes the heat-shock protein (Hsp) mediated gene expression. Hsp translocation will induce Cre expression, and the Cre will mediate the CAR expression on the T cell.
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