期刊
MOLECULAR THERAPY
卷 24, 期 3, 页码 570-581出版社
CELL PRESS
DOI: 10.1038/mt.2015.197
关键词
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资金
- Children's Cancer Research Fund
- Lindahl Family & the Corrigan Family
- Masonic Cancer Center Cancer Experimental Therapeutics Initiative
- NIH [T32- HL007062]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000114]
- [R01 AR063070]
- [P01 CA065493]
- [8UL1TR000114-02]
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 anti host reactivity. To address these limitations, we assessed the ability of three different TCR-alpha-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.
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