Engineering Chimeric Antigen Receptor T Cells against Immune Checkpoint Inhibitors PD-1/PD-L1 for Treating Pancreatic Cancer
Journal
MOLECULAR THERAPY-ONCOLYTICS
Journal Volume
17
Pages
571
Date Issued
2020
Author(s)
Abstract
Yang et al. developed armed third-generation PD-L1-targeted ACR/CAR T cells utilizing a PD-1/PD-L1 immune checkpoint axis. Both engineered CAR T cells significantly improved tumor control and survival in models of PD-L1-expressed pancreatic cancers. ? 2020 The Author(s)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. ? 2020 The Author(s)
SDGs
Other Subjects
CD27 antigen; CD28 antigen; CD3 antigen; chimeric antigen receptor; cytotoxic T lymphocyte antigen 4; gamma interferon; hepatitis A virus cellular receptor 2; immune checkpoint inhibitor; immunological antineoplastic agent; Ki 67 antigen; L selectin; lentivirus vector; messenger RNA; platelet derived growth factor; platelet derived growth factor AA; programmed death 1 ligand 1; programmed death 1 receptor; single chain fragment variable antibody; tumor necrosis factor; tumor necrosis factor receptor superfamily member 9; unclassified drug; adoptive transfer; animal tissue; antineoplastic activity; Article; binding affinity; comparative study; controlled study; cytokine release; cytotoxicity; enzyme linked immunosorbent assay; expression vector; flow cytometry; human; immunohistochemistry; in vitro study; intracellular signaling; mouse; MTT assay; nonhuman; overall survival; pancreas cancer; priority journal; real time reverse transcription polymerase chain reaction; survival rate; T lymphocyte activation; tumor growth; tumor weight; Western blotting
Publisher
CELL PRESS
Type
journal article