T cells are potent mediators of anti-leukemic effects and are routinely being genetically programmed using viral vectors to express chimeric antigen receptors (CAR) against B cell cancers in particular. Most therapies use T cells collected from a patient’s own blood, but it is also now possible to further engineer cells to overcome issues with matching that allow cells form healthy donors to be used. Clinical trials of gene edited universal CAR T cells generated with TALENs, homing endonucleases and CRISPR/Cas9 are underway for ‘off the shelf’ approached. In order to generate T cells against T cell cancers, the issue of ‘Blue-on-Blue’ fire and resultant ‘fratricide’ has to be addressed. Here we apply base-editing for targeted C>>U>T conversions which to introduce stop codons, or disrupt splice sites, in order to disrupt multiple genes in T cells simultaneously. The technique has an advantage over existing Cas9 nucleases with reduced levels of translocations from sites of DNA breakage. Strategies combining anti-CD3 and anti-CD7 CARs are tested, including in a humanised mouse model of T cell malignancy. The approach is scalable and adaptable for compliant manufacturing, including semi-automated cell production for proposed phase 1 trials patients undergoing bone marrow transplant for T-ALL
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