CRISPR-edited CAR-T cells: Using CRISPR-Cas9 to Improve CAR-T Therapy
DOI:
https://doi.org/10.54097/hset.v14i.1846Keywords:
CAR-T Therapy, CRISPR-Cas9, T Cell Exhaustion, Toxicity, Allogenic CAR-T Cells.Abstract
One of the cornerstones of cancer immunotherapy, chimeric antigen receptor T cell (CAR-T) immunotherapy is a treatment comprising of T cells transfected with artificial receptors that target a specific tumor antigen, potentiating tumor destruction. Despite the effectiveness of this technique in treating hematopoietic malignancies, efficacy against other cancers leaves much to be desired. CAR-T therapy's anti-tumor effectiveness, safety, and accessibility are hampered by issues such T cell exhaustion, toxicity, and ineffective production techniques. With the advent of CRISPR-Cas9 technology, allowing ease of genome editing, it is now possible to address these challenges. By introducing a double-strand break at a particular genomic location, this gene editing technology can be utilized to target inhibitors of T lymphocyte function, directed to specific loci to produce a less toxic product, and engineer allogeneic CAR-T cells. However, CRISPR-Cas9 confers its own limitations, including off-target editing. This review introduces the applications of CRISPR technology to CAR-T therapy and evaluates how the technology can optimize the effectiveness, safety, and product availability of this cancer immunotherapy. This paper also addresses some of the potential drawbacks of CRISPR-edited CAR-T cells.
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Ferlay J L M, Ervik M, Lam F, et al. Global cancer observatory: cancer today [EB/OL]. Lyon, France: international agency for research on cancer, 2021-03-31. [2022-07-03] https://gco.iarc.fr/today.
Cancer Facts & Figures 2022 [EB/OL]. American Cancer Society. [2022-07-03] https://www.cancer.org/latest-news/facts-and-figures-2022.html
Razeghian E, Nasution M K M, Rahman H S, et al. A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies [J]. Stem Cell Research & Therapy, 2021, 12(1): 428.
Gennert D G, Lynn R C, Granja J M, et al. Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [J]. Proceedings of the National Academy of Sciences, 2021, 118(30): e2104758118.
Lynn R C, Weber E W, Gennert D, et al. Engineering AP1 to combat CAR T cell exhaustion [C]. Cancer Research, 2018, 78(13 Supplement): LB-112.
Chiarella A M, Butler K V, Gryder B E, et al. Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery [J]. Nature Biotechnology, 2020, 38(1): 50-55.
Yi Y, Chai X, Zheng L, et al. CRISPR-edited CART with GM-CSF knockout and auto secretion of IL6 and IL1 blockers in patients with hematologic malignancy [J]. Cell Discovery, 2021, 7(1): 27.
ODÉ Z, CONDORI J, PETERSON N, et al. CRISPR-Mediated Non-Viral Site-Specific Gene Integration and Expression in T Cells: Protocol and Application for T-Cell Therapy [J]. Cancers, 2020, 12(6): 1704.
Sterner R M, Sakemura R, Cox M J, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts [J]. Blood, 2019, 133(7): 697-709.
Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection [J]. Nature, 2017, 543(7643): 113-117.
Kagoya Y, Guo T, Yeung B, et al. Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy [J]. Cancer Immunol Res, 2020, 8(7): 926-936.
Rodríguez T C, Dadafarin S, Pratt H E, et al. Genome-wide detection and analysis of CRISPR-Cas off-targets [J]. Progress in Molecular Biology and Translational Science, 2021, 181: 31-43.
Ferdosi S R, Ewaisha R, Moghadam F, et al. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes [J]. Nature Communication, 2019, 10(1): 1842.
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