Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy
Menée sur des lignées cellulaires de neuroblastome et un modèle murin de médulloblastome, cette étude met en évidence l'intérêt de lymphocytes NKT, manipulés pour exprimer un récepteur d'antigène chimérique contre le ganglioside GD2, pour réduire la toxicité associée à cette forme d'immunothérapie
Advances in the design of chimeric antigen receptors (CARs) have improved the antitumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. We proposed that CAR expression in Vα24-invariant NKT cells (NKTs) can build upon the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKTs were engineered to express a CAR against the GD2 ganglioside (CAR.GD2), which is highly expressed by neuroblastoma. We compared CAR.GD2 constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB co-stimulatory endodomains. CAR.GD2 expression rendered NKTs highly cytotoxic against neuroblastoma cells without affecting their CD1d-dependent reactivity. We observed a striking Th1-like polarization of NKTs by 4-1BB-containing CARs. Importantly, expression of both CD28 and 4-1BB endodomains in the CAR.GD2 enhanced in vivo persistence of NKTs. These CAR.GD2 NKTs effectively localized to the tumor site, had potent antitumor activity and repeat injections significantly improved the long-term survival of mice with metastatic neuroblastoma. Unlike T cells, CAR.GD2 NKTs did not induce graft-versus-host disease. These results establish the potential of NKTs to serve as a safe and effective platform for CAR-directed cancer immunotherapy.