Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of 9%. Major obstacles to successful treatment of pancreatic cancer are the immunosuppressive tumor microenvironment (TME) and antigenic complexity or heterogeneity. Programmed death-ligand 1 (PD-L1) is expr...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Molecular Therapy: Oncolytics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770520300723 |
| _version_ | 1818133866870734848 |
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| author | Ching-Yao Yang Ming Huei Fan Carol H. Miao Yi Jen Liao Ray-Hwang Yuan Chao Lien Liu |
| author_facet | Ching-Yao Yang Ming Huei Fan Carol H. Miao Yi Jen Liao Ray-Hwang Yuan Chao Lien Liu |
| author_sort | Ching-Yao Yang |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of 9%. Major obstacles to successful treatment of pancreatic cancer are the immunosuppressive tumor microenvironment (TME) and antigenic complexity or heterogeneity. Programmed death-ligand 1 (PD-L1) is expressed on PDAC and immunosuppressed cells within the TME, providing suitable immunotherapy targets. We applied a chimeric antigen receptor (CAR) strategy to target immune checkpoint programmed death-1 (PD-1)/PD-L1 interactions. Lentiviral vectors were used to express the extracellular domain of human PD-1 (PD-1-CD28-4-1BB activating chimeric receptor [PD1ACR]) or the single-chain variable fragment (scFv) region of anti-PD-L1 (PDL1CAR) that binds to PD-L1, and each was fused to intracellular signaling domains containing CD3 zeta, CD28, and 4-1BB (CD137). Both engineered CAR T cells recognized and eliminated PD-L1-overexpressing CFPAC1 cells efficiently at approximately 80% in vitro. Adoptive transfer of both CAR T cells enhanced T cell persistence and induced specific regression of established CFPAC1 cancer by >80% in both xenograft and orthotopic models. Ki67 expression in tumors decreased, whereas proinflammatory cytokines/chemokines increased in CAR T cell-treated mouse sera. PD1ACR and PDL1CAR obtained a similar therapeutic efficacy. Thus, these armed third-generation PD-L1-targeted CAR T cells confer antitumor activity and the ability to combat T cell exhaustion, providing a potentially new and innovative CAR T cell immunotherapy against pancreatic cancers. |
| first_indexed | 2024-12-11T08:59:32Z |
| format | Article |
| id | doaj.art-3eb61f68d3cd4091bfbc24084b804085 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-11T08:59:32Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-3eb61f68d3cd4091bfbc24084b8040852022-12-22T01:13:48ZengElsevierMolecular Therapy: Oncolytics2372-77052020-06-0117571585Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic CancerChing-Yao Yang0Ming Huei Fan1Carol H. Miao2Yi Jen Liao3Ray-Hwang Yuan4Chao Lien Liu5Department of Surgery, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 100, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; PhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanCenter for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, WA 98101, USASchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; PhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanDepartment of Surgery, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Surgery, National Taiwan University Hospital Biomedical Park Hospital, Hsinchu County 30261, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; PhD Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Corresponding author: Chao Lien Liu, School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of 9%. Major obstacles to successful treatment of pancreatic cancer are the immunosuppressive tumor microenvironment (TME) and antigenic complexity or heterogeneity. Programmed death-ligand 1 (PD-L1) is expressed on PDAC and immunosuppressed cells within the TME, providing suitable immunotherapy targets. We applied a chimeric antigen receptor (CAR) strategy to target immune checkpoint programmed death-1 (PD-1)/PD-L1 interactions. Lentiviral vectors were used to express the extracellular domain of human PD-1 (PD-1-CD28-4-1BB activating chimeric receptor [PD1ACR]) or the single-chain variable fragment (scFv) region of anti-PD-L1 (PDL1CAR) that binds to PD-L1, and each was fused to intracellular signaling domains containing CD3 zeta, CD28, and 4-1BB (CD137). Both engineered CAR T cells recognized and eliminated PD-L1-overexpressing CFPAC1 cells efficiently at approximately 80% in vitro. Adoptive transfer of both CAR T cells enhanced T cell persistence and induced specific regression of established CFPAC1 cancer by >80% in both xenograft and orthotopic models. Ki67 expression in tumors decreased, whereas proinflammatory cytokines/chemokines increased in CAR T cell-treated mouse sera. PD1ACR and PDL1CAR obtained a similar therapeutic efficacy. Thus, these armed third-generation PD-L1-targeted CAR T cells confer antitumor activity and the ability to combat T cell exhaustion, providing a potentially new and innovative CAR T cell immunotherapy against pancreatic cancers.http://www.sciencedirect.com/science/article/pii/S2372770520300723PD-1PD-L1ACRCARPDAC |
| spellingShingle | Ching-Yao Yang Ming Huei Fan Carol H. Miao Yi Jen Liao Ray-Hwang Yuan Chao Lien Liu Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer Molecular Therapy: Oncolytics PD-1 PD-L1 ACR CAR PDAC |
| title | Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer |
| title_full | Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer |
| title_fullStr | Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer |
| title_full_unstemmed | Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer |
| title_short | Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer |
| title_sort | engineering chimeric antigen receptor t cells against immune checkpoint inhibitors pd 1 pd l1 for treating pancreatic cancer |
| topic | PD-1 PD-L1 ACR CAR PDAC |
| url | http://www.sciencedirect.com/science/article/pii/S2372770520300723 |
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