دورية
Cytosine Base Editing Enables Quadruple-Edited Allogeneic CAR-T Cells for T-ALL
| العنوان: | Cytosine Base Editing Enables Quadruple-Edited Allogeneic CAR-T Cells for T-ALL |
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| المؤلفون: | Diorio, Caroline, Murray, Ryan, Naniong, Mark, Barrera, Luis, Camblin, Adam, Chukinas, John, Coholan, Lindsey, Edwards, Aaron, Fuller, Tori, Gonzales, Claudia, Grupp, Stephan A., Ladd, Alden, Le, Melissa, Messana, Angelica, Musenge, Faith, Newman, Haley, Poh, Yeh-Chuin, Poulin, Henry, Ryan, Theresa, Shraim, Rawan, Tasian, Sarah K., Vincent, Tiffaney, Young, Lauren, Zhang, Yingying, Ciaramella, Giuseppe, Gehrke, Jason, Teachey, David T. |
| المصدر: | Blood; 20220101, Issue: Preprints |
| مستخلص: | Allogeneic chimeric antigen receptor T cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CART have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells with between 90-99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared to CRISPR-Cas9. Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using four simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitroand in vivomodels. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells with high potential for clinical translation for relapsed and refractory T-ALL. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00064971 15280020 |
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| DOI: | 10.1182/blood.2022015825 |