Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies

Biomarker Research

Review

Mohammad Hossein Haddadi¹  Majid Sadeghizadeh²  Mohadeseh Mirzaee Godarzee³  Hamed Dabiri³  Pooria Safarzadeh Kozani⁴  Ensiyeh Hajizadeh Saffar⁵  Mohsen Basiri⁶  Mahdi Habibi Anbouhi⁷  Vahab Ziaei⁷ 

[1] Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran;Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran;Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran;Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran;Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran;

关键词: Chimeric antigen receptor;    Cancer immunotherapy;    Genome-editing technologies;    Retroviral vectors;    Natural killer cells;   

DOI  :  10.1186/s40364-023-00509-1

 received in 2023-03-07, accepted in 2023-06-09,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023

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