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Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Mol+Ther 2016 ; 24 (3): 570-81 Nephropedia Template TP
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Evaluation of TCR Gene Editing Achieved by TALENs, CRISPR/Cas9, and megaTAL Nucleases #MMPMID26502778
Osborn MJ; Webber BR; Knipping F; Lonetree Cl; Tennis N; DeFeo AP; McElroy AN; Starker CG; Lee C; Merkel S; Lund TC; Kelly-Spratt KS; Jensen MC; Voytas DF; von Kalle C; Schmidt M; Gabriel R; Hippen KL; Miller JS; Scharenberg AM; Tolar J; Blazar BR
Mol Ther 2016[Mar]; 24 (3): 570-81 PMID26502778show ga
Present adoptive immunotherapy strategies are based on the re-targeting of autologous T-cells to recognize tumor antigens. As T-cell properties may vary significantly between patients, this approach can result in significant variability in cell potency that may affect therapeutic outcome. More consistent results could be achieved by generating allogeneic cells from healthy donors. An impediment to such an approach is the endogenous T-cell receptors present on T-cells, which have the potential to direct dangerous off-tumor antihost reactivity. To address these limitations, we assessed the ability of three different TCR-?-targeted nucleases to disrupt T-cell receptor expression in primary human T-cells. We optimized the conditions for the delivery of each reagent and assessed off-target cleavage. The megaTAL and CRISPR/Cas9 reagents exhibited the highest disruption efficiency combined with low levels of toxicity and off-target cleavage, and we used them for a translatable manufacturing process to produce safe cellular substrates for next-generation immunotherapies.