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Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells

2015; Cell Press; Volume: 28; Issue: 4 Linguagem: Inglês

10.1016/j.ccell.2015.09.004

1878-3686

Zeguo Zhao, Maud Condomines, Sjoukje J. C. van der Stegen, Fabiana Perna, Christopher C. Kloss, Gertrude Gunset, Jason Plotkin, Michel Sadelain,

Viral Infectious Diseases and Gene Expression in Insects

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 CD3ζ) 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/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.