Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells
Menée in vitro et in vivo, cette étude met en évidence l'activité antitumorale d'une nouvelle génération de lymphocytes T modifiés pour exprimer un récepteur d'antigène chimérique (4-1BBL)
T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo ?stress test? to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3?) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFN? pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.
Cancer Cell , article en libre accès, 2014