Are entirely virus-free CAR T cells as good as lentiviral transduced universal cells?

Chimeric Antigen Receptor (CAR) T cells are commonly generated using gamma-retroviral or lentiviral vectors given their efficiency and stable integration, but vector supply constraints have created bottlenecks to wider access. Using a combination of lentiviral transduction and genome editing, 'universal' donor CAR-T cells devoid of endogenous TCRαβ and suitable for multiple recipients are also under investigation as 'off-the-shelf' therapies. In addition, nuclease mediated insertion by homology-directed repair (HDR) of CAR genes delivered by Adeno Associated Virus into the TRAC locus has been reported to mediate superior tumour clearance. We investigated alternative entirely virus-free procedures to insert synthetic DNA encoding CAR genes at either TRAC or CD3ζ loci in direct comparison to lentiviral generated universal 41BB-CD3ζ-CAR T cells. While non-viral manufacture was successful and in vitro cytotoxic function was comparable, in vivo inhibition of human leukemia in xenograft murine models was not superior to lentiviral products. Non-viral approaches offer attractive prospects for sophisticated editing and precise CAR insertion and may offer valuable therapeutic options, but careful preclinical evaluation and well-designed clinical trials benchmarked against existing lentiviral approaches are recommended.

Abstract from PubMed (PMID 42995495). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.