Engineering light-controllable CAR T cells for cancer immunotherapy

Huang, Zhongliang; Wu, Yiqian; Allen, Michael G.; Pan, Yijia; Kyriakakis, Phillip; Lu, Shaoying; Chang, Ya‐Ju; Wang, Xin; Chien, Shu; Wang, Yingxiao

doi:10.1126/sciadv.aay9209

Cited by 114 publications

(102 citation statements)

References 51 publications

(86 reference statements)

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“…CRY2/CIB1 and VVD have been fused to a variety of DBDs and effector domains to control both transcription [ 109 , 110 ] and translation [ 111 , 112 ] in mammalian cells, bacteria [ 113 ], and yeast [ 110 , 114 , 115 ]. They have been applied in various fields including the study of oscillating gene expression [ 116 ] and in cell-based immunotherapies [ 117 ]. Blue light-induced dimerisation of CRY2/CIB1, VVD, and ‘Magnets’, improved VVD mutants [ 118 ], have also been used to control gene expression by reconstituting split enzymes, such as Cre recombinases [ 110 , 119 , 120 ] and RNA polymerases [ 121 , 122 ] ( Figure 4A -ii).…”

Section: Light-controlled Gene Expression Using Proteinsmentioning

confidence: 99%

Controlling gene expression with light: a multidisciplinary endeavour

Hartmann

Smith

Mazzotti

et al. 2020

Biochemical Society Transactions

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The expression of a gene to a protein is one of the most vital biological processes. The use of light to control biology offers unparalleled spatiotemporal resolution from an external, orthogonal signal. A variety of methods have been developed that use light to control the steps of transcription and translation of specific genes into proteins, for cell-free to in vivo biotechnology applications. These methods employ techniques ranging from the modification of small molecules, nucleic acids and proteins with photocages, to the engineering of proteins involved in gene expression using naturally light-sensitive proteins. Although the majority of currently available technologies employ ultraviolet light, there has been a recent increase in the use of functionalities that work at longer wavelengths of light, to minimise cellular damage and increase tissue penetration. Here, we discuss the different chemical and biological methods employed to control gene expression, while also highlighting the central themes and the most exciting applications within this diverse field.

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Section: Light-controlled Gene Expression Using Proteinsmentioning

confidence: 99%

Controlling gene expression with light: a multidisciplinary endeavour

Hartmann

Smith

Mazzotti

et al. 2020

Biochemical Society Transactions

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“…Although these systems have only been tested for light-activated gene expression, they should be useful for controlling other cellular processes, for example, the spatiotemporal activation of chimeric antigen receptor T (CAR-T) cells. [37,38] Their use of the mammalian endogenous metabolite as chromophore and the compatibility of deep tissue penetration offer the unique potential to address clinical challenges such as CAR-T therapy targeting solid tumors. Figure 6.…”

Section: Resultsmentioning

confidence: 99%

Creating Red Light-Controlled Protein Dimerization Systems as Genetically Encoded Actuators with High Specificity

Huang¹,

Zhang²,

Dong³

et al. 2020

Preprint

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Protein dimerization systems that can be controlled by red light with increased tissue penetration depth are a highly needed optogenetic tool for clinical applications such as cell and gene therapies. However, existing red light-induced dimerization systems are all based on phytochrome photoreceptors and naturally occurring binding partners with complex structures and suboptimal in vivo performance, limiting mammalian applications. Here, we introduce an efficient, generalizable method (COMBINES-LID) for creating highly specific light-induced dimerization systems. Proof-of-principle was provided by creating nanobody-based, red light-induced dimerization (nanoReD) systems comprising a truncated bacterial phytochrome sensory module using a mammalian endogenous chromophore, biliverdin, and light-form specific nanobodies. Selected nanoReD systems were biochemically characterized and exhibited low dark activity and high induction specificity for in vivo activation of gene expression. Overall, COMBINES-LID opens new opportunities for creating genetically encoded actuators for the optical manipulation of biological processes.

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“…Other groups have developed reversible systems based on optogenetic activation of T cells for tumor recognition. In these systems, a pulse of blue light enables the antitumor function [ 24 , 25 ].…”

Section: Improving the Car For Increased Safety And Efficacymentioning

confidence: 99%

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

Chicaybam

Bonamino

Invitti

et al. 2020

Cancers

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Gene therapy is now surpassing 30 years of clinical experience and in that time a variety of approaches has been applied for the treatment of a wide range of pathologies. While the promise of gene therapy was over-stated in the 1990’s, the following decades were met with polar extremes between demonstrable success and devastating setbacks. Currently, the field of gene therapy is enjoying the rewards of overcoming the hurdles that come with turning new ideas into safe and reliable treatments, including for cancer. Among these modalities, the modification of T cells with chimeric antigen receptors (CAR-T cells) has met with clear success and holds great promise for the future treatment of cancer. We detail a series of considerations for the improvement of the CAR-T cell approach, including the design of the CAR, routes of gene transfer, introduction of CARs in natural killer and other cell types, combining the CAR approach with checkpoint blockade or oncolytic viruses, improving pre-clinical models as well as means for reducing cost and, thus, making this technology more widely available. While CAR-T cells serve as a prime example of translating novel ideas into effective treatments, certainly the lessons learned will serve to accelerate the current and future development of gene therapy drugs.

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Engineering light-controllable CAR T cells for cancer immunotherapy

Cited by 114 publications

References 51 publications

Controlling gene expression with light: a multidisciplinary endeavour

Controlling gene expression with light: a multidisciplinary endeavour

Creating Red Light-Controlled Protein Dimerization Systems as Genetically Encoded Actuators with High Specificity

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

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