GITR domain inside CAR co-stimulates activity of CAR-T cells against cancer.
Front Biosci (Landmark Ed)
; 23(12): 2245-2254, 2018 06 01.
Article
de En
| MEDLINE
| ID: mdl-29772559
ABSTRACT
T cells expressing Chimeric antigen receptors or CAR-T cells are used as a novel treatment against hematological and solid cancers. In this report, we designed CAR with glucocorticoid-induced TNFR-related protein (GITR) co-stimulatory domain to study its ability to co-activate CAR-T cells. EGFR-GITR-CD3 CAR-T cells were cytotoxic against EGFR-positive pancreatic and ovarian cancer cells but not against EGFR-negative cancer cells. The cytotoxic activity of EGFR-GITR-CD3 CAR-T cells was comparable or better than EGFR-28-CD3 or EGFR-41BB-CD3 CAR-T cells. We designed also EGFR-CD3-GITR-CAR and EGFR-ΔGITR-CD3 with deleted 184-192 amino-acids of co-stimulatory GITR domain, and showed that EGFR-GITR-CD3 had significantly higher cytotoxic activity against EGFR-positive cells. The EGFR-GITR-CD3 cells secreted significantly higher levels of IFN-gamma than EGFR-CD3-GITR and EGFR-ΔGITR-CD3 cells. In addition, Mesothelin-GITR-CD3 CAR-T cells also killed mesothelin-positive ovarian cancer cell lines, and pancreatic cancer cells. Moreover, CD19-GITR-CD3 CAR-T cells had significant cytotoxic activity against CD19-positive cancer cells in vitro and in Raji xenograft tumors in vivo. Thus, our results clearly show that GITR co-stimulatory domain can be used as a novel co-stimulatory domain in CAR-T cells.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Lymphocytes T
/
Tests d'activité antitumorale sur modèle de xénogreffe
/
Cytotoxicité immunologique
/
Protéine associée au récepteur du TNF induit par les corticoïdes
/
Récepteurs chimériques pour l'antigène
/
Tumeurs
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Humans
/
Male
Langue:
En
Journal:
Front Biosci (Landmark Ed)
Année:
2018
Type de document:
Article
Pays de publication:
SG
/
SINGAPORE
/
SINGAPUR
/
SINGAPURA