Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy
Using a TALEN-mediated gene-editing approach, we have previously described a process for the large-scale manufacturing of “off-the-shelf” CAR T cells from third-party donor T cells by disrupting the gene encoding TCRα constant chain (TRAC). Taking advantage of a previously described strategy to cont...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117302664 |
| _version_ | 1828238611154206720 |
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| author | Anne-Sophie Gautron Alexandre Juillerat Valérie Guyot Jean-Marie Filhol Emilie Dessez Aymeric Duclert Philippe Duchateau Laurent Poirot |
| author_facet | Anne-Sophie Gautron Alexandre Juillerat Valérie Guyot Jean-Marie Filhol Emilie Dessez Aymeric Duclert Philippe Duchateau Laurent Poirot |
| author_sort | Anne-Sophie Gautron |
| collection | DOAJ |
| description | Using a TALEN-mediated gene-editing approach, we have previously described a process for the large-scale manufacturing of “off-the-shelf” CAR T cells from third-party donor T cells by disrupting the gene encoding TCRα constant chain (TRAC). Taking advantage of a previously described strategy to control TALEN targeting based on the exclusion capacities of non-conventional RVDs, we have developed highly efficient and specific nucleases targeting a key T cell immune checkpoint, PD-1, to improve engineered CAR T cells’ functionalities. Here, we demonstrate that this approach allows combined TRAC and PDCD1 TALEN processing at the desired locus while eliminating low-frequency off-site processing. Thus, by replacing few RVDs, we provide here an easy and rapid redesign of optimal TALEN combinations. We anticipate that this method can greatly benefit multiplex editing, which is of key importance especially for therapeutic applications where high editing efficiencies need to be associated with maximal specificity and safety. |
| first_indexed | 2024-04-12T21:07:11Z |
| format | Article |
| id | doaj.art-64994fa029a0484386e24c93061ea7fd |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-12T21:07:11Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-64994fa029a0484386e24c93061ea7fd2022-12-22T03:16:40ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-12-019C31232110.1016/j.omtn.2017.10.005Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive ImmunotherapyAnne-Sophie Gautron0Alexandre Juillerat1Valérie Guyot2Jean-Marie Filhol3Emilie Dessez4Aymeric Duclert5Philippe Duchateau6Laurent Poirot7Cellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceCellectis Inc., 430E 29th Street, New York, NY 10016, USACellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceCellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceCellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceCellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceCellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceCellectis SA, 8 Rue de la Croix Jarry, 75013 Paris, FranceUsing a TALEN-mediated gene-editing approach, we have previously described a process for the large-scale manufacturing of “off-the-shelf” CAR T cells from third-party donor T cells by disrupting the gene encoding TCRα constant chain (TRAC). Taking advantage of a previously described strategy to control TALEN targeting based on the exclusion capacities of non-conventional RVDs, we have developed highly efficient and specific nucleases targeting a key T cell immune checkpoint, PD-1, to improve engineered CAR T cells’ functionalities. Here, we demonstrate that this approach allows combined TRAC and PDCD1 TALEN processing at the desired locus while eliminating low-frequency off-site processing. Thus, by replacing few RVDs, we provide here an easy and rapid redesign of optimal TALEN combinations. We anticipate that this method can greatly benefit multiplex editing, which is of key importance especially for therapeutic applications where high editing efficiencies need to be associated with maximal specificity and safety.http://www.sciencedirect.com/science/article/pii/S2162253117302664multiplex gene editinggenotoxicityTALENimmunotherapychimeric antigen receptorscheckpoint inhibitors |
| spellingShingle | Anne-Sophie Gautron Alexandre Juillerat Valérie Guyot Jean-Marie Filhol Emilie Dessez Aymeric Duclert Philippe Duchateau Laurent Poirot Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy Molecular Therapy: Nucleic Acids multiplex gene editing genotoxicity TALEN immunotherapy chimeric antigen receptors checkpoint inhibitors |
| title | Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy |
| title_full | Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy |
| title_fullStr | Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy |
| title_full_unstemmed | Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy |
| title_short | Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy |
| title_sort | fine and predictable tuning of talen gene editing targeting for improved t cell adoptive immunotherapy |
| topic | multiplex gene editing genotoxicity TALEN immunotherapy chimeric antigen receptors checkpoint inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117302664 |
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