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Cancer Cell. 2015 Oct 12;28(4):415-428. doi: 10.1016/j.ccell.2015.09.004.

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

Author information

1
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
2
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA. Electronic address: m-sadelain@ski.mskcc.org.

Abstract

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.

PMID:
26461090
PMCID:
PMC5003056
DOI:
10.1016/j.ccell.2015.09.004
[Indexed for MEDLINE]
Free PMC Article

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