Details

Autor(en) / Beteiligte

• Frigault, Matthew J
• Lee, Jihyun
• Basil, Maria Ciocca
• Carpenito, Carmine
• Motohashi, Shinichiro
• Scholler, John
• Kawalekar, Omkar U
• Guedan, Sonia
• McGettigan, Shannon E
• Posey, Jr, Avery D
• Ang, Sonny
• Cooper, Laurence J N
• Platt, Jesse M
• Johnson, F Brad
• Paulos, Chrystal M
• Zhao, Yangbing
• Kalos, Michael
• Milone, Michael C
• June, Carl H

Titel

Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells

Ist Teil von

• Cancer immunology research, 2015-04, Vol.3 (4), p.356-367

Ort / Verlag

United States

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• This study compared second-generation chimeric antigen receptors (CAR) encoding signaling domains composed of CD28, ICOS, and 4-1BB (TNFRSF9). Here, we report that certain CARs endow T cells with the ability to undergo long-term autonomous proliferation. Transduction of primary human T cells with lentiviral vectors encoding some of the CARs resulted in sustained proliferation for up to 3 months following a single stimulation through the T-cell receptor (TCR). Sustained numeric expansion was independent of cognate antigen and did not require the addition of exogenous cytokines or feeder cells after a single stimulation of the TCR and CD28. Results from gene array and functional assays linked sustained cytokine secretion and expression of T-bet (TBX21), EOMES, and GATA-3 to the effect. Sustained expression of the endogenous IL2 locus has not been reported in primary T cells. Sustained proliferation was dependent on CAR structure and high expression, the latter of which was necessary but not sufficient. The mechanism involves constitutive signaling through NF-κB, AKT, ERK, and NFAT. The propagated CAR T cells retained a diverse TCR repertoire, and cellular transformation was not observed. The CARs with a constitutive growth phenotype displayed inferior antitumor effects and engraftment in vivo. Therefore, the design of CARs that have a nonconstitutive growth phenotype may be a strategy to improve efficacy and engraftment of CAR T cells. The identification of CARs that confer constitutive or nonconstitutive growth patterns may explain observations that CAR T cells have differential survival patterns in clinical trials.