Journal
CELLS
Volume 9, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/cells9061367
Keywords
TCR engineering; CRISPR; Cas9; orthotopic TCR replacement; OTR; gene editing; adoptive cell therapy; immunotherapy; T-cell therapy; gene therapy
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Funding
- German Centre for Infection Research (DZIF) [TTU 07.836]
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Natural adaptive immunity co-evolved with pathogens over millions of years, and adoptive transfer of non-engineered T cells to fight infections or cancer so far exhibits an exceptionally safe and functional therapeutic profile in clinical trials. However, the personalized nature of therapies using virus-specific T cells, donor lymphocyte infusion, or tumor-infiltrating lymphocytes makes implementation in routine clinical care difficult. In principle, genetic engineering can be used to make T-cell therapies more broadly applicable, but so far it significantly alters the physiology of cells. We recently demonstrated that orthotopic T-cell receptor (TCR) replacement (OTR) by clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9) can be used to generate engineered T cells with preservation of near-physiological function. In this review, we present the current status of OTR technology development and discuss its potential for TCR-based therapies. By providing the means to combine the therapeutic efficacy and safety profile of physiological T cells with the versatility of cell engineering, OTR can serve as an enabler for TCR-based therapies.
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