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

Sumin Jo, Shipra Das, Alan Williams, Anne-Sophie Chretien, Thomas Pagliardini, Aude Roy, Jorge Postigo Fernandez, Diane Clerre, Billal Jahangiri, Isabelle Chion-Sotinel, Sandra Rozlan, Emilie Dessez, Agnes Gouble, Mathilde Dusséaux, Roman Galetto, Aymeric Duclert, Emanuela Marcenaro, Raynier Devillier, Daniel Olive (), Philippe Duchateau, Laurent Poirot and Julien Valton ()
Additional contact information
Sumin Jo: Cellectis, Inc.
Shipra Das: Cellectis, Inc.
Alan Williams: Cellectis, Inc.
Anne-Sophie Chretien: Institut Paoli-Calmettes; Aix-Marseille Université UM105
Thomas Pagliardini: Institut Paoli-Calmettes; Aix-Marseille Université UM105
Aude Roy: Institut Paoli-Calmettes; Aix-Marseille Université UM105
Jorge Postigo Fernandez: Cellectis, Inc.
Diane Clerre: Cellectis, 8 rue de la Croix Jarry
Billal Jahangiri: Cellectis, Inc.
Isabelle Chion-Sotinel: Cellectis, 8 rue de la Croix Jarry
Sandra Rozlan: Cellectis, 8 rue de la Croix Jarry
Emilie Dessez: Cellectis, 8 rue de la Croix Jarry
Agnes Gouble: Cellectis, 8 rue de la Croix Jarry
Mathilde Dusséaux: Cellectis, 8 rue de la Croix Jarry
Roman Galetto: Cellectis, 8 rue de la Croix Jarry
Aymeric Duclert: Cellectis, 8 rue de la Croix Jarry
Emanuela Marcenaro: Department of Experimental Medicine, University of Genova
Raynier Devillier: Institut Paoli-Calmettes; Aix-Marseille Université UM105
Daniel Olive: Institut Paoli-Calmettes; Aix-Marseille Université UM105
Philippe Duchateau: Cellectis, 8 rue de la Croix Jarry
Laurent Poirot: Cellectis, Inc.
Julien Valton: Cellectis, Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30896-2

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DOI: 10.1038/s41467-022-30896-2

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