Journal
CANCER CELL
Volume 28, Issue 4, Pages 415-428Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.09.004
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Funding
- MSKCC Center for Cell Engineering
- MSKCC Experimental Therapeutics Center
- Cancer Research Institute
- Mallah fund
- Lake Road Foundation
- Mr. William H. and Mrs. Alice Goodwin
- Commonwealth Foundation for Cancer Research
- Stand Up To Cancer/American Association for Cancer Research
- MSK Cancer Center [P30 CA008748]
- Association pour la Recherche contre le Cancer
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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 zeta) 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 beta pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.
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