CRISPR/Cas9: A Powerful Strategy to Improve CAR-T Cell Persistence

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Aug 12

PMID 37569693

Authors

Wei Wei

Zhi-Nan Chen

Ke Wang

Affiliations

Soon will be listed here.

Abstract

As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has been markedly improved in the past decade. However, the clinical effect of CAR-T therapy is not so satisfying, especially in solid tumors. Even in hematologic malignancies, a proportion of patients eventually relapse after receiving CAR-T cell infusions, owing to the poor expansion and persistence of CAR-T cells. Recently, CRISPR/Cas9 technology has provided an effective approach to promoting the proliferation and persistence of CAR-T cells in the body. This technology has been utilized in CAR-T cells to generate a memory phenotype, reduce exhaustion, and screen new targets to improve the anti-tumor potential. In this review, we aim to describe the major causes limiting the persistence of CAR-T cells in patients and discuss the application of CRISPR/Cas9 in promoting CAR-T cell persistence and its anti-tumor function. Finally, we investigate clinical trials for CRISPR/Cas9-engineered CAR-T cells for the treatment of cancer.

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References

Xiang X, Niu Y, Wang Z, Ye L, Peng W, Zhou Q . Cancer-associated fibroblasts: Vital suppressors of the immune response in the tumor microenvironment. Cytokine Growth Factor Rev. 2022; 67:35-48. DOI: 10.1016/j.cytogfr.2022.07.006. View

Berdeja J, Madduri D, Usmani S, Jakubowiak A, Agha M, Cohen A . Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021; 398(10297):314-324. DOI: 10.1016/S0140-6736(21)00933-8. View

Long A, Haso W, Shern J, Wanhainen K, Murgai M, Ingaramo M . 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015; 21(6):581-90. PMC: 4458184. DOI: 10.1038/nm.3838. View

Martino M, Canale F, Alati C, Vincelli I, Moscato T, Porto G . CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma. Cancers (Basel). 2021; 13(11). PMC: 8197914. DOI: 10.3390/cancers13112639. View

Han J, Khatwani N, Searles T, Turk M, Angeles C . Memory CD8 T cell responses to cancer. Semin Immunol. 2020; 49:101435. PMC: 7738415. DOI: 10.1016/j.smim.2020.101435. View

Geiger R, Rieckmann J, Wolf T, Basso C, Feng Y, Fuhrer T . L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell. 2016; 167(3):829-842.e13. PMC: 5075284. DOI: 10.1016/j.cell.2016.09.031. View

Chen J, Lopez-Moyado I, Seo H, Lio C, Hempleman L, Sekiya T . NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019; 567(7749):530-534. PMC: 6546093. DOI: 10.1038/s41586-019-0985-x. View

Hsieh E, Scherer L, Rouce R . Replacing CAR-T cell resistance with persistence by changing a single residue. J Clin Invest. 2020; 130(6):2806-2808. PMC: 7260020. DOI: 10.1172/JCI136872. View

Dai H, Tong C, Shi D, Chen M, Guo Y, Chen D . Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial. Oncoimmunology. 2020; 9(1):1846926. PMC: 7714531. DOI: 10.1080/2162402X.2020.1846926. View

10.

Narayan V, Barber-Rotenberg J, Jung I, Lacey S, Rech A, Davis M . PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022; 28(4):724-734. PMC: 10308799. DOI: 10.1038/s41591-022-01726-1. View

11.

Jain N, Zhao Z, Feucht J, Koche R, Iyer A, Dobrin A . TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature. 2023; 615(7951):315-322. PMC: 10511001. DOI: 10.1038/s41586-022-05692-z. View

12.

Ghoneim H, Fan Y, Moustaki A, Abdelsamed H, Dash P, Dogra P . De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell. 2017; 170(1):142-157.e19. PMC: 5568784. DOI: 10.1016/j.cell.2017.06.007. View

13.

Melenhorst J, Chen G, Wang M, Porter D, Chen C, Collins M . Decade-long leukaemia remissions with persistence of CD4 CAR T cells. Nature. 2022; 602(7897):503-509. PMC: 9166916. DOI: 10.1038/s41586-021-04390-6. View

14.

Arcangeli S, Bove C, Mezzanotte C, Camisa B, Falcone L, Manfredi F . CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J Clin Invest. 2022; 132(12). PMC: 9197529. DOI: 10.1172/JCI150807. View

15.

Good C, Aznar M, Kuramitsu S, Samareh P, Agarwal S, Donahue G . An NK-like CAR T cell transition in CAR T cell dysfunction. Cell. 2021; 184(25):6081-6100.e26. PMC: 8827167. DOI: 10.1016/j.cell.2021.11.016. View

16.

Liu D, Zhao X, Tang A, Xu X, Liu S, Zha L . CRISPR screen in mechanism and target discovery for cancer immunotherapy. Biochim Biophys Acta Rev Cancer. 2020; 1874(1):188378. DOI: 10.1016/j.bbcan.2020.188378. View

17.

Crudele J, Chamberlain J . Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun. 2018; 9(1):3497. PMC: 6115392. DOI: 10.1038/s41467-018-05843-9. View

18.

Wiede F, Lu K, Du X, Zeissig M, Xu R, Goh P . PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity. Cancer Discov. 2021; 12(3):752-773. PMC: 8904293. DOI: 10.1158/2159-8290.CD-21-0694. View

19.

Shalem O, Sanjana N, Hartenian E, Shi X, Scott D, Mikkelson T . Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2013; 343(6166):84-87. PMC: 4089965. DOI: 10.1126/science.1247005. View

20.

Chen M, Mao A, Xu M, Weng Q, Mao J, Ji J . CRISPR-Cas9 for cancer therapy: Opportunities and challenges. Cancer Lett. 2019; 447:48-55. DOI: 10.1016/j.canlet.2019.01.017. View