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• W4308376687 abstract "<h3>Background</h3> Chimeric antigen receptor (CAR)-T cell therapy is a recent clinically successful approach to tackling cancer, in which T cells are genetically modified to allow specific recognition and efficient killing of cancer cells via tumor associated antigens.¹ Current CAR-based treatments require costly and time-consuming autologous cell transfer. Patients’ own cells are frequently of low quality and difficult to obtain, further supporting the advantage of an allogeneic transplantation. To prevent graft versus host reactions and avoid host-mediated rejection of healthy donor-derived allogeneic cells, these cells must be adjusted by eliminating the expression of endogenous recognition components, such as T cell receptor alpha constant (TRAC or TCR) and CD3, and of HLA class I molecules such as β-2 microglobulin (B2M).^2,3 In this study, we tested the feasibility of gene editing in allogeneic cells using our novel high-fidelity CRISPR-associated nuclease OMNIA4. OMNIA4 is a highly active nuclease with a unique non-NGG PAM recognition domain. The unique PAM allows gene-editing in exclusive genomic sequences that are not accessible by commonly used nucleases. Our strategy involves disrupting endogenous T cell recognition elements as well as checkpoint receptors and exhaustion genes that restrict anti-tumor T cell response. <h3>Methods</h3> RNA guides (gRNAs) were designed for several of such genes of interest and their editing via OMNIA4 nuclease was evaluated by NGS in HeLa cells. Ribonucleoproteins (RNPs), including OMNIA4 and gRNAs designed to target distinctive sites in either TRAC, CD3e or B2M genes, were applied to primary T cells. The resulting editing outcome was evaluated by measuring T cell receptor (TCR), CD3e or B2M surface expression by flow cytometry. In addition, an unbiased analysis was performed to identify ‘off-targets’ edited by the nuclease. <h3>Results</h3> Our gRNA screening yielded at least one (and up to five) active gRNA for each gene of interest, with editing level >70%. Flow cytometric analysis showed that editing in primary T cells resulted in about 94% TCR negative cells, about 85% CD3e negative cells and about 95% B2M negative cells. An unbiased assay revealed no off-targets for neither of the guides. <h3>Conclusions</h3> These findings demonstrate efficient, accurate and safe impairment of a self-presenting element and endogenous T cell recognition components. Our approach offers gene editing at unique targets as a tool to generate universal allogeneic T cells that could be employed in the development of ‘off-the-shelf’ ‘ready-to-use’ CAR-T therapeutic agents for large-scale clinical applications. <h3>References</h3> Labanieh, L., Majzner, R.G., and Mackall, C.L. (2018). Programming CAR-T cells to kill cancer. <i>Nat. Biomed. Eng</i>. <b>2</b>, 377–391. Liu, X., Zhang, Y., Cheng, C., Cheng, A.W., Zhang, X., Li, N., Xia, C., Wei, X., Liu, X., and Wang, H. (2017). CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. <i>Cell Res</i>. <b>27</b>, 154–157. Depil, S., Duchateau, P., Grupp, S.A., Mufti, G., and Poirot, L. (2020). ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. <i>Nat. Rev. Drug Discov</i>. <b>19</b>, 185–199" @default.
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• W4308376687 date "2022-11-01" @default.
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• W4308376687 title "200 A unique CRISPR-based nuclease with a non-NGG PAM efficiently targets multiple exclusive genomic sites for immuno-oncology based therapy" @default.
• W4308376687 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0200" @default.
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