Original ResearchBasic and Translational—PancreasT Cells That Target Carcinoembryonic Antigen Eradicate Orthotopic Pancreatic Carcinomas Without Inducing Autoimmune Colitis in Mice
Section snippets
Cell Lines
293T cells are human embryonic kidney cells that express the SV40 large T antigen (ATCC CRL-11268). Panc02 is a tumorigenic murine pancreatic carcinoma line.9 The Panc02 CEA+cells were derived from Panc02 cells by transfection with plasmid-encoding human CEA (kindly provided by Dr David Gilham, University of Manchester, UK). The Panc02 CEA+ and the Panc02 CEA− cells coexpress green fluorescence protein and click beetle luciferase (CBLuc). MC38 is a murine fibrosarcoma line; C15A3 is a CEA+
CAR-Engineered T-Cells Target CEA+ Pancreas Carcinoma Cells
Mouse T cells were genetically engineered with the CEA-specific CAR that is entirely composed of murine domains and harbors the murine anti-CEA scFv Sca421 in the extracellular domain for targeting, and the CD28 and CD3ζ signaling endodomains for T-cell activation (Figure 1A). Both CD4+ and CD8+ T cells expressed the CAR on the cell surface (Figure 1B); both modified T-cell subsets were present in the therapeutic T-cell inoculums in same frequencies as in the peripheral blood of healthy mice.
Discussion
The study represents first strong evidence in a clinically relevant model that adoptive T-cell therapy targeting CEA is effective toward pancreas carcinoma and can be feasible without inducing severe autoimmune colitis. All mice treated with a single intravenous dose of the SCA431 CAR-engineered T cells showed profound regression of CEA+ pancreatic cancer; 6 of 8 mice were cured of pancreatic carcinoma in the long term. The anti-tumor response was specifically mediated by the engineered CAR
Acknowledgments
We thank Dr David Gilham and the Central Animal Facility, Patterson Institute for Cancer Research, Manchester, UK, for providing us with CEAtg mice.
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Conflict of interest The authors disclose no conflicts.
Funding Work was funded by the Deutsche Krebshilfe, Bonn, Germany, the Wilhelm Sander-Stiftung, München, and the Else Kröner-Fresenius Stiftung, Homburg v.d.H., Germany.