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Data from Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor–Modified T Cells Engineered to Secrete Checkpoint Inhibitors
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Data from Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor–Modified T Cells Engineered to Secrete Checkpoint Inhibitors
Data from Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor–Modified T Cells Engineered to Secrete Checkpoint Inhibitors
SL
Si Li
Si Li
NS
Natnaree Siriwon
Natnaree Siriwon
XZ
Xiaoyang Zhang
Xiaoyang Zhang
SY
Shuai Yang
Shuai Yang
TJ
Tao Jin
Tao Jin
FH
Feng He
Feng He
YK
Yu Jeong Kim
Yu Jeong Kim
JM
John Mac
John Mac
ZL
Zhengfei Lu
Zhengfei Lu
SW
Sijie Wang
Sijie Wang
XH
Xiaolu Han
Xiaolu Han
PW
Pin Wang
Pin Wang
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31 March 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/1078-0432.c.6525213
Abstract
Purpose: Despite favorable responses of chimeric antigen receptor (CAR)-engineered T-cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR T cells secreting checkpoint inhibitors (CPI) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model.Experimental Design: To evaluate the effector function and expansion capacity of CAR.αPD1-T cells in vitro, we measured the production of IFNγ and T-cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.αPD1-T cells, CAR T cells, and CAR T cells combined with anti–PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism was investigated by analyzing the expansion and functional capacity of TILs.Results: Human anti–PD-1 CPIs secreted by CAR.αPD1-T cells efficiently bound to PD-1 and reversed the inhibitory effect of PD-1/PD-L1 interaction on T-cell function. PD-1 blockade by continuously secreted anti–PD-1 attenuated the inhibitory T-cell signaling and enhanced T-cell expansion and effector function both in vitro and in vivo. In the xenograft mouse model, we demonstrated that the secretion of anti–PD-1 enhanced the antitumor activity of CAR T cells and prolonged overall survival.Conclusions: With constitutive anti–PD-1 secretion, CAR.αPD1-T cells are more functional and expandable, and more efficient at tumor eradication than parental CAR T cells. Collectively, our study presents an important and novel strategy that enables CAR T cells to achieve better antitumor immunity, especially in the treatment of solid tumors. Clin Cancer Res; 23(22); 6982–92. ©2017 AACR.
Keywords
ANTIGEN
SECRETION
EFFECTOR FUNCTION
EFFICIENT
CPIS
TREATMENT OF SOLID
ENGINEERED
EFFICACY
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Open Access