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© Research
Publication : Nature communications

Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 30 Jun 2022

Jo S, Das S, Williams A, Chretien AS, Pagliardini T, Le Roy A, Fernandez JP, Le Clerre D, Jahangiri B, Chion-Sotinel I, Rozlan S, Dessez E, Gouble A, Dusséaux M, Galetto R, Duclert A, Marcenaro E, Devillier R, Olive D, Duchateau P, Poirot L, Valton J

Link to Pubmed [PMID] – 35773273

Link to DOI – 10.1038/s41467-022-30896-2

Nat Commun 2022 Jun; 13(1): 3453

Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive universal CAR T-cells scaffold using precise TALEN-mediated gene editing and DNA matrices vectorized by recombinant adeno-associated virus 6. We simultaneously disrupt and repurpose the endogenous TRAC and B2M loci to generate TCRαβ- and HLA-ABC-deficient T-cells expressing the CAR construct and the NK-inhibitor named HLA-E. This highly efficient gene editing process enables the engineered T-cells to evade NK cell and alloresponsive T-cell attacks and extend their persistence and antitumor activity in the presence of cytotoxic levels of NK cell in vivo and in vitro, respectively. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications.