Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies
Abstract Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Biomarker Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40364-023-00509-1 |
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| author | Hamed Dabiri Pooria Safarzadeh Kozani Mahdi Habibi Anbouhi Mohadeseh Mirzaee Godarzee Mohammad Hossein Haddadi Mohsen Basiri Vahab Ziaei Majid Sadeghizadeh Ensiyeh Hajizadeh Saffar |
| author_facet | Hamed Dabiri Pooria Safarzadeh Kozani Mahdi Habibi Anbouhi Mohadeseh Mirzaee Godarzee Mohammad Hossein Haddadi Mohsen Basiri Vahab Ziaei Majid Sadeghizadeh Ensiyeh Hajizadeh Saffar |
| author_sort | Hamed Dabiri |
| collection | DOAJ |
| description | Abstract Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical success in certain patients with leukemias and lymphomas and offered therapeutic benefits to those resistant to conventional therapies. The universal approach to stable CAR transgene delivery into the T/NK cells is the use of viral particles. Such approaches mediate semi-random transgene insertions spanning the entire genome with a high preference for integration into sites surrounding highly-expressed genes and active loci. Regardless of the variable CAR expression level based on the integration site of the CAR transgene, foreign integrated DNA fragments may affect the neighboring endogenous genes and chromatin structure and potentially change a transduced T/NK cell behavior and function or even favor cellular transformation. In contrast, site-specific integration of CAR constructs using recent genome-editing technologies could overcome the limitations and disadvantages of universal random gene integration. Herein, we explain random and site-specific integration of CAR transgenes in CAR-T/NK cell therapies. Also, we tend to summarize the methods for site-specific integration as well as the clinical outcomes of certain gene disruptions or enhancements due to CAR transgene integration. Also, the advantages and limitations of using site-specific integration methods are discussed in this review. Ultimately, we will introduce the genomic safe harbor (GSH) standards and suggest some appropriate safety prospects for CAR integration in CAR-T/NK cell therapies. |
| first_indexed | 2024-03-13T00:41:06Z |
| format | Article |
| id | doaj.art-e123e0ee3ccd44b0bac4eac716517241 |
| institution | Directory Open Access Journal |
| issn | 2050-7771 |
| language | English |
| last_indexed | 2024-03-13T00:41:06Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Biomarker Research |
| spelling | doaj.art-e123e0ee3ccd44b0bac4eac7165172412023-07-09T11:20:07ZengBMCBiomarker Research2050-77712023-07-0111112310.1186/s40364-023-00509-1Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapiesHamed Dabiri0Pooria Safarzadeh Kozani1Mahdi Habibi Anbouhi2Mohadeseh Mirzaee Godarzee3Mohammad Hossein Haddadi4Mohsen Basiri5Vahab Ziaei6Majid Sadeghizadeh7Ensiyeh Hajizadeh Saffar8Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares UniversityDepartment of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares UniversityNational Cell Bank of Iran, Pasteur Institute of IranDepartment of Genetics, Faculty of Biological Sciences, Tarbiat Modares UniversityClinical Microbiology Research Center, Ilam University of Medical SciencesDepartment of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRNational Cell Bank of Iran, Pasteur Institute of IranDepartment of Genetics, Faculty of Biological Sciences, Tarbiat Modares UniversityDepartment of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRAbstract Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical success in certain patients with leukemias and lymphomas and offered therapeutic benefits to those resistant to conventional therapies. The universal approach to stable CAR transgene delivery into the T/NK cells is the use of viral particles. Such approaches mediate semi-random transgene insertions spanning the entire genome with a high preference for integration into sites surrounding highly-expressed genes and active loci. Regardless of the variable CAR expression level based on the integration site of the CAR transgene, foreign integrated DNA fragments may affect the neighboring endogenous genes and chromatin structure and potentially change a transduced T/NK cell behavior and function or even favor cellular transformation. In contrast, site-specific integration of CAR constructs using recent genome-editing technologies could overcome the limitations and disadvantages of universal random gene integration. Herein, we explain random and site-specific integration of CAR transgenes in CAR-T/NK cell therapies. Also, we tend to summarize the methods for site-specific integration as well as the clinical outcomes of certain gene disruptions or enhancements due to CAR transgene integration. Also, the advantages and limitations of using site-specific integration methods are discussed in this review. Ultimately, we will introduce the genomic safe harbor (GSH) standards and suggest some appropriate safety prospects for CAR integration in CAR-T/NK cell therapies.https://doi.org/10.1186/s40364-023-00509-1Chimeric antigen receptorCancer immunotherapyGenome-editing technologiesRetroviral vectorsNatural killer cells |
| spellingShingle | Hamed Dabiri Pooria Safarzadeh Kozani Mahdi Habibi Anbouhi Mohadeseh Mirzaee Godarzee Mohammad Hossein Haddadi Mohsen Basiri Vahab Ziaei Majid Sadeghizadeh Ensiyeh Hajizadeh Saffar Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies Biomarker Research Chimeric antigen receptor Cancer immunotherapy Genome-editing technologies Retroviral vectors Natural killer cells |
| title | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies |
| title_full | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies |
| title_fullStr | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies |
| title_full_unstemmed | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies |
| title_short | Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies |
| title_sort | site specific transgene integration in chimeric antigen receptor car t cell therapies |
| topic | Chimeric antigen receptor Cancer immunotherapy Genome-editing technologies Retroviral vectors Natural killer cells |
| url | https://doi.org/10.1186/s40364-023-00509-1 |
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