Simultaneous Deletion of Endogenous TCRαβ for TCR Gene Therapy Creates an Improved and Safe Cellular Therapeutic

Morton, Laura T.; Reijmers, Rogier M.; Wouters, Anne K.; Kweekel, Christiaan; Remst, Dennis F. G.; Pothast, Cilia R.; Falkenburg, J.H. Frederik; Heemskerk, Mirjam H.M.

doi:10.1016/j.ymthe.2019.10.001

Cited by 59 publications

(73 citation statements)

References 36 publications

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“…Recently, CRISPR-driven knockout of both TRAC and TRBC, to disrupt exogenous α and ß chains, respectively, for construction of transgenic TCR T-cell was evaluated. This double knockout led to the enhancement of both expression and function of recombinant TCR T-cells and hence increased their potential in antigen-sensing and control of tumor growth in multiple myeloma models compared to homologous single-locus-(TRAC or TRBC)-depleted TCR T-cells [ 95 ].…”

Section: The Deluxe Zone Of Cancer Therapy Where Crispr Meets Immunomentioning

confidence: 99%

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

et al. 2020

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Cancer immunotherapy has been emerged as a promising strategy for treatment of a broad spectrum of malignancies ranging from hematological to solid tumors. One of the principal approaches of cancer immunotherapy is transfer of natural or engineered tumor-specific T-cells into patients, a so called “adoptive cell transfer”, or ACT, process. Construction of allogeneic T-cells is dependent on the employment of a gene-editing tool to modify donor-extracted T-cells and prepare them to specifically act against tumor cells with enhanced function and durability and least side-effects. In this context, CRISPR technology can be used to produce universal T-cells, equipped with recombinant T cell receptor (TCR) or chimeric antigen receptor (CAR), through multiplex genome engineering using Cas nucleases. The robust potential of CRISPR-Cas in preparing the building blocks of ACT immunotherapy has broaden the application of such therapies and some of them have gotten FDA approvals. Here, we have collected the last investigations in the field of immuno-oncology conducted in partnership with CRISPR technology. In addition, studies that have addressed the challenges in the path of CRISPR-mediated cancer immunotherapy, as well as pre-treatment applications of CRISPR-Cas have been mentioned in detail.

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Section: The Deluxe Zone Of Cancer Therapy Where Crispr Meets Immunomentioning

confidence: 99%

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

et al. 2020

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“…The two main hurdles in allogeneic CAR-T therapy are graft-versus-host disease and graft rejection, both of which can be prevented by deletion of the TCR α and β chains and B2M in donor T cells ( 44 ). Further, the disruption of endogenous TCR α and β genes can be used to prevent mispairing with exogenous TCR, potentially enhancing the function and safety of TCR-T therapy ( 45 ).…”

Section: Crispr/cas9-based Genome Editing For Therapeutic T-cell Engimentioning

confidence: 99%

Genome editing of immune cells using CRISPR/Cas9

et al. 2021

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The ability to read, write, and edit genomic information in living organisms can have a profound impact on research, health, economic, and environmental issues. The CRISPR/Cas system, recently discovered as an adaptive immune system in prokaryotes, has revolutionized the ease and throughput of genome editing in mammalian cells and has proved itself indispensable to the engineering of immune cells and identification of novel immune mechanisms. In this review, we summarize the CRISPR/Cas9 system and the history of its discovery and optimization. We then focus on engineering T cells and other types of immune cells, with emphasis on therapeutic applications. Last, we describe the different modifications of Cas9 and their recent applications in the genome-wide screening of immune cells.

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“…As recently summarized by Zhang et al, the use of CRISPR/Cas9 technology in primary T cells increased the success rate of gene editing compared to ZFN and TALENs [42] and has, in some cases, reached up to 90% of target gene deletion [43]. With these techniques, gene editing multiple genes at the same time (multiplexing) is feasible; for example, CRISPR/Cas9 multiple guide RNAs (gRNAs) can be delivered simultaneously [43][44][45][46]. In 2017, a pioneer clinical administration of CAR19 T cells, gene edited with TALEN to simultaneously deplete eTCR and CD52, a target of the serotherapeutic molecule alemtuzumab, showed the successful induction of molecular tumor remission ahead of allogeneic stem cell transplantation in two pediatric B-ALL patients.…”

Section: Genetic Elimination Of Endogenous Tcr To Improve Efficacy Anmentioning

confidence: 99%

Gene Augmentation and Editing to Improve TCR Engineered T Cell Therapy against Solid Tumors

et al. 2020

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Recent developments in gene engineering technologies have drastically improved the therapeutic treatment options for cancer patients. The use of effective chimeric antigen receptor T (CAR-T) cells and recombinant T cell receptor engineered T (rTCR-T) cells has entered the clinic for treatment of hematological malignancies with promising results. However, further fine-tuning, to improve functionality and safety, is necessary to apply these strategies for the treatment of solid tumors. The immunosuppressive microenvironment, the surrounding stroma, and the tumor heterogeneity often results in poor T cell reactivity, functionality, and a diminished infiltration rates, hampering the efficacy of the treatment. The focus of this review is on recent advances in rTCR-T cell therapy, to improve both functionality and safety, for potential treatment of solid tumors and provides an overview of ongoing clinical trials. Besides selection of the appropriate tumor associated antigen, efficient delivery of an optimized recombinant TCR transgene into the T cells, in combination with gene editing techniques eliminating the endogenous TCR expression and disrupting specific inhibitory pathways could improve adoptively transferred T cells. Armoring the rTCR-T cells with specific cytokines and/or chemokines and their receptors, or targeting the tumor stroma, can increase the infiltration rate of the immune cells within the solid tumors. On the other hand, clinical “off-tumor/on-target” toxicities are still a major potential risk and can lead to severe adverse events. Incorporation of safety switches in rTCR-T cells can guarantee additional safety. Recent clinical trials provide encouraging data and emphasize the relevance of gene therapy and gene editing tools for potential treatment of solid tumors.

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Simultaneous Deletion of Endogenous TCRαβ for TCR Gene Therapy Creates an Improved and Safe Cellular Therapeutic

Cited by 59 publications

References 36 publications

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

CRISPR-Cas, a robust gene-editing technology in the era of modern cancer immunotherapy

Genome editing of immune cells using CRISPR/Cas9

Gene Augmentation and Editing to Improve TCR Engineered T Cell Therapy against Solid Tumors

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