Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells.
Mol Ther
; 32(10): 3485-3503, 2024 Oct 02.
Article
de En
| MEDLINE
| ID: mdl-39222637
ABSTRACT
Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1AKO 19CAR-T cells maintained potent in vitro functional profiles and controlled in vivo tumor progression similarly to untreated 19CAR-T cells. Moreover, immunosuppressant treatment averted in vivo allorejection permitting FKBP1AKO 19CAR-T cell-driven B cell aplasia. Thus, we demonstrate that genome engineering enables immunosuppressant treatment to improve the therapeutic potential of universal donor-derived CAR-T cells.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Immunothérapie adoptive
/
Protéine 1A de liaison au tacrolimus
/
Récepteurs chimériques pour l'antigène
/
Immunosuppresseurs
Limites:
Animals
/
Humans
Langue:
En
Journal:
Mol Ther
/
Mol. ther
/
Molecular therapy
Sujet du journal:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Année:
2024
Type de document:
Article
Pays de publication:
États-Unis d'Amérique