TY - JOUR
T1 - ICOS-based chimeric antigen receptors program bipolar TH17/ TH1 cells
AU - Guedan, Sonia
AU - Chen, Xi
AU - Madar, Aviv
AU - Carpenito, Carmine
AU - McGettigan, Shannon E.
AU - Frigault, Matthew J.
AU - Lee, Jihyun
AU - Posey, Avery D.
AU - Scholler, John
AU - Scholler, Nathalie
AU - Bonneau, Richard
AU - June, Carl H.
PY - 2014/8/14
Y1 - 2014/8/14
N2 - With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of T H17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARsmediated efficient antitumor responses and showedenhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies.
AB - With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of T H17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARsmediated efficient antitumor responses and showedenhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies.
UR - http://www.scopus.com/inward/record.url?scp=84905996839&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905996839&partnerID=8YFLogxK
U2 - 10.1182/blood-2013-10-535245
DO - 10.1182/blood-2013-10-535245
M3 - Article
C2 - 24986688
AN - SCOPUS:84905996839
VL - 124
SP - 1070
EP - 1080
JO - Blood
JF - Blood
SN - 0006-4971
IS - 7
ER -