A Deep Insight Into Crispr/Cas9 Application in Car-T Cell-Based Tumor Immunotherapies Publisher Pubmed



Razeghian E¹ ; Nasution MKM² ; Rahman HS^{3, 4} ; Gardanova ZR⁵ ; Abdelbasset WK^{6, 7} ; Aravindhan S⁸ ; Bokov DO^{9, 10} ; Suksatan W¹¹ ; Nakhaei P¹² ; Shariatzadeh S¹³ ; Marofi F¹⁴ ; Yazdanifar M¹⁵ ; Shamlou S¹⁶ ; Motavalli R¹⁷ Show All Authors Show Affiliations
Source: Stem Cell Research and Therapy Published:2021

Abstract

To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish “off-the-shelf” CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also β-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. Indeed, the ablation of β2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology. © 2021, The Author(s).