Applications and advances of CRISPR-Cas9 in cancer immunotherapy

Xia, Anliang; He, Qifeng; Wang, Jincheng; Zhu, Jing; Sha, Yeqin; Sun, Beicheng; Lu, Xiao‐Jie

doi:10.1136/jmedgenet-2018-105422

Cited by 42 publications

(27 citation statements)

References 78 publications

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“…Even though adverse events caused by neoreactivities linked to TCR mispairing have not been reported so far, it is an underlying issue that can be solved by disruption of the endogenous TCR using multiple techniques ( Figure 2 ), some of which have already been tested in the clinic with positive results [ 117 , 132 , 133 ]. In particular, the CRISPR-Cas9 system has revolutionized the way cells are genetically engineered for the treatment of cancer due to its simplicity, fidelity, and versatility [ 134 ]. Very recently, this method has been employed in refractory cancer patients to modify T cells with a cancer-specific TCR while suppressing the endogenous TCR chains and the negative immune checkpoint programmed cell death protein 1 (PD-1) genes in a multiplex system [ 132 ].…”

Section: Clinical Impact Of Tcr Affinity and Avidity In Cancer-spementioning

confidence: 99%

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

Campillo-Davò

Flumens

Lion

2020

Cells

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Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this approach, understanding the role that TCR affinity, avidity, and functional avidity play on how TCRs and T cells function in the context of tumor-associated antigen (TAA) recognition is vital to keep generating improved adoptive T-cell therapies. Aside from TCR-related parameters, other critical factors that govern T-cell activation are the effect of TCR co-receptors on TCR–peptide-major histocompatibility complex (pMHC) stabilization and TCR signaling, tumor epitope density, and TCR expression levels in TCR-engineered T cells. In this review, we describe the key aspects governing TCR specificity, T-cell activation, and how these concepts can be applied to cancer-specific TCR redirection of T cells.

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Section: Clinical Impact Of Tcr Affinity and Avidity In Cancer-spementioning

confidence: 99%

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

Campillo-Davò

Flumens

Lion

2020

Cells

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“…64 The CRISPR/Cas9 system has also be applied to eliminate other genes that encode inhibitory T-cell surface receptors, such as programmed cell death protein 1 (PD1), to improve the efficiency of T-cell-based immunotherapy. 65 To exploit CAR-T-cell therapy beyond the autologous setting, allogeneic universal T cells derived from healthy donors could be engineered by CRISPR/Cas9 upon disruption of TCR to prevent graft- versus -host disease, or beta-2-microglobulin, to eliminate major histocompatibility complex I (MHC I) expression, or by integrating a CAR precisely at the disrupted T-cell receptor α constant ( TRAC ) locus to improve safety and potency. 66–68 Thus, CRISPR/Cas9 technology holds enormous promise to advance the field of cancer immunotherapy and several clinical trials are running to assess the efficacy of CRISPR/Cas9-edited CAR-T cells (Table 6).…”

Section: Immunodeficienciesmentioning

confidence: 99%

CRISPR to fix bad blood: a new tool in basic and clinical hematology

et al. 2019

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A dvances in genome engineering in the last decade, particularly in the development of programmable nucleases, have made it possible to edit the genomes of most cell types precisely and efficiently. Chief among these advances, the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is a novel, versatile and easyto-use tool to edit genomes irrespective of their complexity, with multiple and broad applications in biomedicine. In this review, we focus on the use of CRISPR/Cas9 genome editing in the context of hematologic diseases and appraise the major achievements and challenges in this rapidly moving field to gain a clearer perspective on the potential of this technology to move from the laboratory to the clinic. Accordingly, we discuss data from studies editing hematopoietic cells to understand and model blood diseases, and to develop novel therapies for hematologic malignancies. We provide an overview of the applications of gene editing in experimental, preclinical and clinical hematology including interrogation of gene function, target identification and drug discovery and chimeric antigen receptor T-cell engineering. We also highlight current limitations of CRISPR/Cas9 and the possible strategies to overcome them. Finally, we consider what advances in CRISPR/Cas9 are needed to move the hematology field forward.

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“…The RNA-guided Cas9 nuclease has been developed into a powerful genome editing tool in recent years [1][2][3]. The Clustered Regularly Interspersed Short Palindromic Repeats CRISPR/Cas9 system is able to recognize and make double-strand breaks at target sequences based solely on a guide RNA [4,5]. More recently, the invention of deactivated Cas9 further expanded the scope of this technique, allowing the protein to specifically bind to designed DNA sequences without inducing strand breaks.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, the invention of deactivated Cas9 further expanded the scope of this technique, allowing the protein to specifically bind to designed DNA sequences without inducing strand breaks. A variety of functional components were fused to dCas9 to form molecular devices, which implemented novel biological functions aimed at the target DNA, such as transcriptional blockage, epigenetic modification and gene expression regulation [4][5][6]. For example, the ω group of RNA polymerase was fused to dCas9 to form a complex which was guided to promoter regions of E. coli genes to activate transcription initiation [6,7].…”

Section: Introductionmentioning

confidence: 99%

Manipulating the position of DNA expression cassettes using location tags fused to dCas9 (Cas9-Lag) to improve metabolic pathway efficiency

Xie

et al. 2020

Microb Cell Fact

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Background Deactivated Cas9 (dCas9) led to significant improvement of CRISPR/Cas9-based techniques because it can be fused with a variety of functional groups to form diverse molecular devices, which can manipulate or modify target DNA cassettes. One important metabolic engineering strategy is to localize the enzymes in proximity of their substrates for improved catalytic efficiency. In this work, we developed a novel molecular device to manipulate the cellular location of specific DNA cassettes either on plasmids or on the chromosome, by fusing location tags to dCas9 (Cas9-Lag), and applied the technique for synthetic biology applications. Carotenoids like β-carotene serve as common intermediates for the synthesis of derivative compounds, which are hydrophobic and usually accumulate in the membrane compartment. Results Carotenoids like β-carotene serve as common intermediates for the synthesis of derivative compounds, which are hydrophobic and usually accumulate in the membrane components. To improve the functional expression of membrane-bound enzymes and localize them in proximity to the substrates, Cas9-Lag was used to pull plasmids or chromosomal DNA expressing carotenoid enzymes onto the cell membrane. For this purpose, dCas9 was fused to the E. coli membrane docking tag GlpF, and gRNA was designed to direct this fusion protein to the DNA expression cassettes. With Cas9-Lag, the zeaxanthin and astaxanthin titer increased by 29.0% and 26.7% respectively. Due to experimental limitations, the electron microscopy images of cells expressing Cas9-Lag vaguely indicated that GlpF-Cas9 might have pulled the target DNA cassettes in close proximity to membrane. Similarly, protein mass spectrometry analysis of membrane proteins suggested an increased expression of carotenoid-converting enzymes in the membrane components. Conclusion This work therefore provides a novel molecular device, Cas9-Lag, which was proved to increase zeaxanthin and astaxanthin production and might be used to manipulate DNA cassette location.

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Applications and advances of CRISPR-Cas9 in cancer immunotherapy

Cited by 42 publications

References 78 publications

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

CRISPR to fix bad blood: a new tool in basic and clinical hematology

Manipulating the position of DNA expression cassettes using location tags fused to dCas9 (Cas9-Lag) to improve metabolic pathway efficiency

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