Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition

By Jiangtao Ren, Xiaojun Liu, C. Fang, Shuguang Jiang, C. June, Yangbing Zhao. Clinical Cancer Research, 2016

832 citations recorded by the source corpus.

Purpose: Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative and potentially improves current chimeric antigen receptor (CAR) T-cell therapy against cancers and infectious diseases. Experimental Design: The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining lentiviral delivery of CAR and electro-transfer of Cas9 mRNA and gRNAs targeting endogenous TCR, β-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1. Results: The CRISPR gene–edited CAR T cells showed potent antitumor activities, both in vitro and in animal models and were as potent as non-gene–edited CAR T cells. In addition, the TCR and HLA class I double deficient T cells had reduced alloreactivity and did not cause graft-versus-host disease. Finally, simultaneous triple genome editing by adding the disruption of PD1 led to enhanced in vivo antitumor activity of the gene-disrupted CAR T cells. Conclusions: Gene-disrupted allogeneic CAR and TCR T cells could provide an alternative as a universal donor to autologous T cells, which carry difficulties and high production costs. Gene-disrupted CAR and TCR T cells with disabled checkpoint molecules may be potent effector cells against cancers and infectious diseases. Clin Cancer Res; 23(9); 2255–66. ©2016 AACR.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/25922b27ff32bcc342bfc9c311bef27eb65d65aa

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Citations in the corpus

CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Trials are also in development to genetically remove PD-1 fromCART cells (302) to altogether avoid the negative regulation by this checkpoint in the exhaustion-promoting tumor microenvironment.”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, methodology): “Alternatively, the CRISPR–Cas9 platform has been used to prevent the expression of the TCR α chain 234,235 or a combination of the TCR α and β chains, β2M and PD-1 (reFs 231,236 ) in CAR T cells.”
CRISPR-engineered T cells in patients with refractory cancer (2020, result): “Our large-scale product manufacturing process resulted in gene-editing efficiencies similar to those in our preclinical studies (24).”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Finally, several recent efforts have been made to use CRISPR genome editing to remove the PD-1 receptor from T cells, rendering them non-responsive to PD-L1-mediated suppression (Ren et al., 2016; Schumann et al., 2015).”