Miniaturized CAR knocked onto CD3ε extends TCR function with CAR specificity under control of endogenous TCR signaling cascade
Manske K, Dreßler L, Fräßle SP, Effenberger M, Tschulik C, Cletiu V, Benke E, Wagner M, Schober K, Müller TR, Stemberger C, Germeroth L, Busch DH, Poltorak MP (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 526
Article Number: 113617
DOI: 10.1016/j.jim.2024.113617
Abstract
Immunotherapy using TCR and especially CAR transgenic T cells is a rapidly advancing field with the potential to become standard of care for the treatment of multiple diseases. While all current FDA approved CAR T cell products are generated using lentiviral gene transfer, extensive work is put into CRISPR/Cas mediated gene delivery to develop the next generation of safer and more potent cell products. One limitation of all editing systems is the size restriction of the knock-in cargo. Targeted integration under control of an endogenous promotor and/or signaling cascades opens the possibility to reduce CAR gene size to absolute minimum. Here we demonstrate that a first-generation CAR payload can be reduced to its minimum component - the antigen-binding domain - by targeted integration under control of the CD3ε promoter generating a CAR-CD3ε fusion protein that exploits the endogenous TCR signaling cascade. Miniaturizing CAR payload in this way results in potent CAR activity while simultaneously retaining the primary antigen recognition function of the TCR. Introducing CAR-specificity using a CAR binder only while maintaining endogenous TCR function may be an appealing design for future autologous CAR T cell therapies.
Involved external institutions
United States (USA) (US)
Germany (DE)How to cite
APA:
Manske, K., Dreßler, L., Fräßle, S.P., Effenberger, M., Tschulik, C., Cletiu, V.,... Poltorak, M.P. (2024). Miniaturized CAR knocked onto CD3ε extends TCR function with CAR specificity under control of endogenous TCR signaling cascade. Journal of Immunological Methods, 526. https://doi.org/10.1016/j.jim.2024.113617
MLA:
Manske, Katrin, et al. "Miniaturized CAR knocked onto CD3ε extends TCR function with CAR specificity under control of endogenous TCR signaling cascade." Journal of Immunological Methods 526 (2024).
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