RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells.

Fiche publication


Date publication

mai 2023

Journal

Gene therapy

Auteurs

Membres identifiés du Cancéropôle Est :
Dr FERRAND Christophe, Dr DESCHAMPS Marina


Tous les auteurs :
Bouquet L, Bôle-Richard E, Warda W, Neto Da Rocha M, Trad R, Nicod C, Haderbache R, Genin D, Ferrand C, Deschamps M

Résumé

Even if adoptive cell transfer (ACT) has already shown great clinical efficiency in different types of disease, such as cancer, some adverse events consistently occur, and suicide genes are an interesting system to manage these events. Our team developed a new medical drug candidate, a chimeric antigen receptor (CAR) targeting interleukin-1 receptor accessory protein (IL-1RAP), which needs to be evaluated in clinical trials with a clinically applicable suicide gene system. To prevent side effects and ensure the safety of our candidate, we devised two constructs carrying an inducible suicide gene, RapaCasp9-G or RapaCasp9-A, containing a single-nucleotide polymorphism (rs1052576) affecting the efficiency of endogenous caspase 9. These suicide genes are activated by rapamycin and based on the fusion of human caspase 9 with a modified human FK-binding protein, allowing conditional dimerization. RapaCasp9-G- and RapaCasp9-A-expressing gene-modified T cells (GMTCs) were produced from healthy donors (HDs) and acute myeloid leukemia (AML) donors. The RapaCasp9-G suicide gene demonstrated better efficiency, and we showed its in vitro functionality in different clinically relevant culture conditions. Moreover, as rapamycin is not pharmacologically inert, we also demonstrated its safe use as part of our therapy.

Référence

Gene Ther. 2023 05 12;: