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Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor-Modified T Cells Engineered to Secrete Checkpoint Inhibitors.
Li, Si; Siriwon, Natnaree; Zhang, Xiaoyang; Yang, Shuai; Jin, Tao; He, Feng; Kim, Yu Jeong; Mac, John; Lu, Zhengfei; Wang, Sijie; Han, Xiaolu; Wang, Pin.
Affiliation
  • Li S; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California.
  • Siriwon N; Mork Family Department of Chemical Engineering and Materials Sciences, University of Southern California, Los Angeles, California.
  • Zhang X; Mork Family Department of Chemical Engineering and Materials Sciences, University of Southern California, Los Angeles, California.
  • Yang S; Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California.
  • Jin T; Technology Department, HRAIN Biotechnology Co., Ltd., Shanghai, China.
  • He F; Technology Department, HRAIN Biotechnology Co., Ltd., Shanghai, China.
  • Kim YJ; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California.
  • Mac J; Mork Family Department of Chemical Engineering and Materials Sciences, University of Southern California, Los Angeles, California.
  • Lu Z; Department of Pathology, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California.
  • Wang S; Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California.
  • Han X; Department of Biological Sciences, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California.
  • Wang P; Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California.
Clin Cancer Res ; 23(22): 6982-6992, 2017 Nov 15.
Article in En | MEDLINE | ID: mdl-28912137
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Recombinant Fusion Proteins / Receptors, Antigen, T-Cell / T-Lymphocytes / Neoplasms Limits: Animals / Female / Humans Language: En Journal: Clin Cancer Res Journal subject: NEOPLASIAS Year: 2017 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Recombinant Fusion Proteins / Receptors, Antigen, T-Cell / T-Lymphocytes / Neoplasms Limits: Animals / Female / Humans Language: En Journal: Clin Cancer Res Journal subject: NEOPLASIAS Year: 2017 Document type: Article Country of publication: United States