TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells

Menger, Laurie; Gouble, Agnès; Marzolini, Maria A V; Pachnio, Annette; Bergerhoff, Katharina; Henry, Jake Y.; Smith, Julianne; Pulé, Martin; Moss, Paul; Riddell, Stanley R.; Quezada, Sergio A.; Peggs, Karl S.

doi:10.1182/blood-2015-08-664755

Cited by 56 publications

(42 citation statements)

References 59 publications

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“…S1). Three days after transfection, locus-specific PCRs were performed on genomic DNA (Supplementary Table S1), mutations were assessed by mismatches digestion (T7) and Miseq analysis (20).…”

Section: Talen Construction and Validationmentioning

confidence: 99%

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TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors

et al. 2016

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Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern. To overcome PD-L1-mediated immunosuppression and reduce CPI-associated toxicities, we used TALEN technology to render tumor-reactive T cells resistant to PD-1 signaling. Here, we demonstrate that inactivation of the PD-1 gene in melanoma-reactive CD8 þ T cells and in fibrosarcoma-reactive polyclonal T cells enhanced the persistence of PD-1 gene-modified T cells at the tumor site and increased tumor control. These results illustrate the feasibility and potency of approaches incorporating advanced gene-editing technologies into ACT protocols to silence immune checkpoints as a strategy to overcome locally active immune escape pathways.

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Section: Talen Construction and Validationmentioning

confidence: 99%

“…Efficient and rapid inactivation of genes in primary antigenspecific T cells is achievable using the transient expression of transcription activator-like effector nucleases (TALEN) mRNA, which offers several safety advantages for clinical applications (20) …”

Section: Introductionmentioning

confidence: 99%

TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors

et al. 2016

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“…Additionally, TALENs have demonstrated a higher genome-editing activity [29] while imposing less nuclease-associated toxicity, presumably owed to the lower off-target cleavage affects [30]. TALENs have been substantially utilized in T cell therapies against HIV [31], and virus-specific T cells with resistance to the immunosuppressive effects of corticosteroids have been developed through glucocorticoid receptor knockout [32]. The first clinical application of T cells modified by TALENs has seen successful remission of leukemia in an 11-month-old infant [33••].…”

Section: Toolsmentioning

confidence: 99%

Genome-Edited T Cell Therapies

Delhove

Qasim

2017

Curr Stem Cell Rep

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Purpose of ReviewAlternative approaches to conventional drug-based cancer treatments have seen T cell therapies deployed more widely over the last decade. This is largely due to their ability to target and kill specific cell types based on receptor recognition. Introduction of recombinant T cell receptors (TCRs) using viral vectors and HLA-independent T cell therapies using chimeric antigen receptors (CARs) are discussed. This article reviews the tools used for genome editing, with particular emphasis on the applications of site-specific DNA nuclease mediated editing for T cell therapies.Recent FindingsGenetic engineering of T cells using TCRs and CARs with redirected antigen-targeting specificity has resulted in clinical success of several immunotherapies. In conjunction, the application of genome editing technologies has resulted in the generation of HLA-independent universal T cells for allogeneic transplantation, improved T cell sustainability through knockout of the checkpoint inhibitor, programmed cell death protein-1 (PD-1), and has shown efficacy as an antiviral therapy through direct targeting of viral genomic sequences and entry receptors.SummaryThe combined use of engineered antigen-targeting moieties and innovative genome editing technologies have recently shown success in a small number of clinical trials targeting HIV and hematological malignancies and are now being incorporated into existing strategies for other immunotherapies.

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“…TALENs-mediated gene correction has been demonstrated in fibroblasts derived from epidermolysis bullosa patients [63]. Additionally, numerous studies have used TALENs on human pluripotent stem cells for development of targeted gene therapy [64][65][66][67].…”

Section: Zinc Finger Nucleasesmentioning

confidence: 99%

To Crispr And Beyond: The Evolution Of Genome Editing In Stem Cells

Chen

Knoepfler

2016

Regen. Med.

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The goal of editing the genomes of stem cells to generate model organisms and cell lines for genetic and biological studies has been pursued for decades. There is also exciting potential for future clinical impact in humans. While recent, rapid advances in targeted nuclease technologies have led to unprecedented accessibility and ease of gene editing, biology has benefited from past directed gene modification via homologous recombination, gene traps and other transgenic methodologies. Here we review the history of genome editing in stem cells (including via zinc finger nucleases, transcription activator-like effector nucleases and CRISPR–Cas9), discuss recent developments leading to the implementation of stem cell gene therapies in clinical trials and consider the prospects for future advances in this rapidly evolving field.

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TALEN-mediated genetic inactivation of the glucocorticoid receptor in cytomegalovirus-specific T cells

Abstract: Key Points The GR gene can be inactivated in Streptamer-selected CMV-specific CD8+ T cells using TALEN. The GR gene inactivation endows T cells with resistance to the immunosuppressive effects of corticosteroids in vitro and in vivo.

Cited by 56 publications

References 59 publications

TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors

TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors

Genome-Edited T Cell Therapies

To Crispr And Beyond: The Evolution Of Genome Editing In Stem Cells

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