Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children

  • 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.
Metadaten
Author:Michael Merker, Verena Pfirrmann, Sarah Oelsner, Simone FuldaORCiDGND, Thomas KlingebielORCiDGND, Winfried S. Wels, Peter Bader, Eva Rettinger
URN:urn:nbn:de:hebis:30:3-439157
DOI:https://doi.org/10.18632/oncotarget.19821
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29029499
Parent Title (German):Oncotarget
Publisher:Impact Journals LLC
Place of publication:[s. l.]
Document Type:Article
Language:English
Date of Publication (online):2017/11/07
Date of first Publication:2017/08/02
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2017/11/07
Tag:cell therapy; chimeric antigen receptor; cytokine-induced killer cells; pediatric cancer; soft tissue sarcoma
Volume:8
Issue:39
Page Number:17
First Page:66137
Last Page:66153
Note:
Copyright: Merker et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS-PPN:425034054
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0