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Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition
Open accessPublished version of a preprint
Abstract
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.
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“CRISPR-Cas9 genetic ablation of checkpoint targets such as PD-1 in adoptive T cell therapies has also shown increased functionality in certain models and is being persued clinically (Ren et al., 2017; Rupp et al., 2017; Stadtmauer et al., 2020; Su et al., 2016).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Ren et al., 2017
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Metadata
- Authors
- Ren, J., Liu, X., Fang, C., Jiang, S., June, C. H., & Zhao, Y.
- Affiliations
- Abramson Cancer Center (US)
- Corresponding author
- June, Carl H.
- Zhao, Yangbing
- Venue
- Clinical Cancer Research
- Published
- 2017-04-30
- Volume
- 23
- Issue
- 9
- Pages
- 2255-2266
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5413401
- OpenAlex
- W2548694234
- Cited by
- 942
- References
- 42
- Citations by year
- 2026: 58 · 2025: 87 · 2024: 104 · 2023: 98 · 2022: 104 · 2021: 125 · 2020: 116 · 2019: 113 · 2018: 74 · 2017: 59
- FWCI
- 44.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA120409, P30CA016520)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- universal CAR-T cells, allogeneic CAR T cells, multiplex genome editing, CRISPR/Cas9, anti-PD-1 resistance, HLA class I deficiency, beta2-microglobulin, lentiviral gene delivery, graft-versus-host disease, alloreactivity, anticancer activity, immune checkpoint blockade
- MeSH terms
- Gene Editing, Graft vs Host Disease, Humans, Lymphocyte Activation, Neoplasms, Receptors, Antigen, T-Cell, T-Lymphocytes, Immunotherapy, Adoptive, Severe Combined Immunodeficiency, Programmed Cell Death 1 Receptor, CRISPR-Cas Systems
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