Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children
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Michael Merker1, Verena Pfirrmann1, Sarah Oelsner1,2, Simone Fulda3,4,5, Thomas Klingebiel1, Winfried S. Wels2, Peter Bader1 and Eva Rettinger1
1Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
2Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
3Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany
4German Cancer Consortium (DKTK), Heidelberg, Germany
5German Cancer Research Center (DKFZ), Heidelberg, Germany
Michael Merker, email: [email protected]
Keywords: soft tissue sarcoma, cell therapy, cytokine-induced killer cells, chimeric antigen receptor, pediatric cancer
Received: April 04, 2017 Accepted: June 29, 2017 Published: August 02, 2017
Pediatric patients with recurrent, refractory or advanced soft tissue sarcoma (STS) who are simultaneously showing signs of cumulative treatment toxicity are in need of novel therapies. In this preclinical analysis, we identified ErbB2 as a targetable antigen on STS cells and used cytokine-induced killer (CIK) cells transduced with the lentiviral 2nd-generation chimeric antigen receptor (CAR) vector pS-5.28.z-IEW to target ErbB2-positive tumors. Solely CIK cell subsets with the CD3+ T cell phenotype showed up to 85% cell surface expression of the respective CAR. A comparison of wildtype (WT), mock-vector and ErbB2-CAR-CIK cells showed, that engineered cells exhibited diminished in vitro expansion, retained WT CIK cell phenotype with higher percentages of differentiated effector memory/effector cells. Activating natural killer (NK) cell receptor NKG2D-restricted target cell recognition and killing of WT and ErbB2-CAR-CIK cells was maintained against ErbB2-negative tumors, while ErbB2-CAR-CIK cells demonstrated significantly increased cytotoxicity against ErbB2-positive targets, including primary tumors. ErbB2-CAR- but not WT CIK cells proliferated, infiltrated and efficiently lysed tumor cell monolayers as well as 3D tumor spheroids.
Here, we demonstrate a potential cell therapeutic approach using ErbB2-CAR-CIK cells for the recognition and elimination of tumor cells expressing ErbB2, which we identified as a targetable antigen on high-risk STS cells.
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