TY - JOUR
T1 - Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells
AU - Frigault, Matthew J.
AU - Lee, Jihyun
AU - Basil, Maria Ciocca
AU - Carpenito, Carmine
AU - Motohashi, Shinichiro
AU - Scholler, John
AU - Kawalekar, Omkar U.
AU - Guedan, Sonia
AU - McGettigan, Shannon E.
AU - Posey, Avery D.
AU - Ang, Sonny
AU - Cooper, Laurence J.N.
AU - Platt, Jesse M.
AU - Johnson, F. Brad
AU - Paulos, Chrystal M.
AU - Zhao, Yangbing
AU - Kalos, Michael
AU - Milone, Michael C.
AU - June, Carl H.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/4
Y1 - 2015/4
N2 - 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 inprimary 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-kB, 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 non-constitutive 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.
AB - 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 inprimary 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-kB, 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 non-constitutive 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.
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U2 - 10.1158/2326-6066.CIR-14-0186
DO - 10.1158/2326-6066.CIR-14-0186
M3 - Article
C2 - 25600436
AN - SCOPUS:84962213143
SN - 2326-6066
VL - 3
SP - 356
EP - 367
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 4
ER -