High-performance multiplex drug-gated CAR circuits

Li, Huishan; Wong, Nicole M. L.; Tague, Elliot P.; Ngo, John T.; Khalil, Ahmad S.; Wong, Wilson

doi:10.1016/j.ccell.2022.08.008

Cited by 55 publications

(53 citation statements)

References 51 publications

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“…Irreversible elimination of CAR T cells using suicide switches prior to complete tumour eradication might limit clinical efficacy. An alternative could be designing reversible off/on-switches that permit temporal control of CAR T cell activation and preserve antitumour function [138][139][140] . Several designs have been proposed to date, many of which rely on the administration of small molecules 109,141,142 or antibodies 143 , among other methods [144][145][146] .…”

Section: Review Articlementioning

confidence: 99%

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

et al. 2022

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Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cellmediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR Review articlewe examine the implications of OTOT on the development of CAR T cell therapies targeting solid tumours, summarize OTOT evidence in preclinical and clinical studies, and discuss advances in CAR T cell engineering that might help to overcome OTOT in the clinic. Risks and mechanisms of OTOTOTOT stems from CAR T cell-mediated recognition and lysis of nonmalignant tissues expressing the target antigen, potentially causing severe adverse events 23,26 . Upon recognition of a target antigen, CAR T cell activation leads to the formation of an immune synapse between the CAR and the target cell 27 , triggering effector functions (Fig. 2). The release of perforin and granzymes 28 is assumed to be a principal mechanism of CAR T cell-mediated cytotoxicity. However, other mechanisms, such as upregulation of T cell-surface molecules to induce target apoptosis (such as FAS ligand) 29 or secretion of cytokines, including IFNγ and/or TNF, may also contribute to tissue destruction [29][30][31] (Fig. 2).To generate CAR T cells that are both safe and effective in patients with solid tumours, target antigen selection is crucial. Optimal antigen candidates, referred to as neoantigens, should be exclusively expressed on malignant cells and not on non-malignant cells. Such antigens could arise from tumour-specific non-synonymous mutations, insertions or deletions that alter the amino acid sequence of cell-surface proteins, aberrant expression of oncofetal antigens, or tumour-specific posttranslational modifications [32][33][34][35][36][37] . However, cell-surface neoantigens are rare, particularly in tumours with a low mutational burden 38 . EGFRvIII, found in 24-67% of glioblastomas, is one of the few identified examples 39,40 . Consequently, the majority of CAR T cell therapy targets for solid tumours are tumour-associated antigens (TAAs) that are also expressed on non-malignant tissues (Fig. 3).

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Section: Review Articlementioning

confidence: 99%

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

et al. 2022

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“…Authors have further exploited the SUPRA CAR and demonstrated broad applicability on adaptive and innate immune cells [48]. Li et al [49] developed a collection of versatile protease regulated (VIPER) CAR receptors using viral non-structural protein 3 (NS3) with proteolytic activity, and an exogenous control with clinically approved antiviral drugs (Figure 5b). To create a universal CAR receptor that could be switched ON and OFF on the demand, they applied the OFF VIPER CAR design to a SUPRA CAR technology.…”

Section: Car Receptor Designs With Coiled Coilsmentioning

confidence: 99%

Coiled Coils as Versatile Modules for Mammalian Cell Regulation

Merljak

Golob-Urbanc

Plaper

et al. 2023

Synthetic Biology and Engineering

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Synthetic biology is a rapidly growing field that allows us to better understand biological processes at the molecular level, and enables therapeutic interventions and biotechnological applications. One of the most powerful tools in synthetic biology is the small, customizable, and modular protein-protein interaction domains, which is used to regulate a wide variety of processes within mammalian cells. Here we review designed coiled coil dimers that represent a set of heterodimerization domains with many advantages. These dimers have been useful for directing the localization of selected proteins within cells, enhancing chemical or light-regulated transcription, creating fast proteolysis-based responsive systems and protein secretion, genome editing, and cell-cell interaction motifs. Additionally, we will discuss how these building blocks are used in diverse applications, such as CAR T cell regulation and genome editing. Finally, we will look at the potential for future advances in synthetic biology using these building modules.

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“…Due to the essential function of NS3 in viral replication, multiple approaches have been employed to develop NS3 inhibitor ligands, including genetically encodable ligands such as RNA aptamers and peptides 10,11 . Recent applications utilize NS3 and genetically encoded antiviral peptides to control various protein functions [12][13][14][15] . In this schema, NS3 protease serves as a high affinity binder to antiviral peptides, which can be conditionally displaced by small molecule drugs.…”

Section: Introductionmentioning

confidence: 99%

Controlled protein activities with viral proteases, antiviral peptides, and antiviral drugs

Tague

McMahan

Tague

et al. 2023

Preprint

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Chemical control of protein activity is a powerful tool for scientific study, synthetic biology, and cell therapy; however, for broad use, effective chemical inducer systems must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties. Accordingly, the drug-controllable proteolytic activity of hepatitis C cis-protease NS3 and its associated antiviral drugs have been used to regulate protein activity and gene modulation. These tools advantageously exploit non-eukaryotic/prokaryotic proteins and clinically approved inhibitors. Here we expand the toolkit by utilizing catalytically inactive NS3 protease as a high affinity binder to genetically encoded, antiviral peptides. Through our approach, we create NS3-peptide complexes that can be displaced by FDA-approved drugs to modulate transcription, cell signaling, split-protein complementation. With our developed system, we discover a new mechanism to allosterically regulate Cre recombinase. Allosteric Cre regulation with NS3 ligands enables orthogonal recombination tools in eukaryotic cells and functions in divergent organisms to control prokaryotic recombinase activity.

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High-performance multiplex drug-gated CAR circuits

Cited by 55 publications

References 51 publications

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

Coiled Coils as Versatile Modules for Mammalian Cell Regulation

Controlled protein activities with viral proteases, antiviral peptides, and antiviral drugs

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