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Oncotarget. 2018 May 22;9(39):25597-25616. doi: 10.18632/oncotarget.25390. eCollection 2018 May 22.

From mono- to bivalent: improving theranostic properties of target modules for redirection of UniCAR T cells against EGFR-expressing tumor cells in vitro and in vivo.

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UniversityCancerCenter (UCC) Dresden, Tumor Immunology, 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany.
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
German Cancer Consortium (DKTK), part\ner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Immunology, Medical Faculty, 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany.
Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Germany.


CAR-modified T cells show impressive results in clinical trials. However, cytokine release syndrome and "on-target, off-tumor" reactions represent most concerning side effects. To improve the safety of CAR-T cell therapy, we established a switchable CAR platform termed UniCAR system consisting of two components: UniCAR-modified T cells and tumor-specific target modules (TM). For treatment of EGFR+ epithelial tumors, we recently described a monovalent nanobody-based α-EGFR TM, either expressed in bacteria or eukaryotic cells. In spite of the identical primary sequence the eukaryotic TM showed a reduced killing capability and affinity. Here we describe a novel bivalent α-EGFR-EGFR TM. As expected, the avidity of the bivalent TM is higher than that of its monovalent counterpart. Binding of neither the monovalent α-EGFR TM nor the bivalent α-EGFR-EGFR TM to EGFR effected the EGF-mediated signaling. While the monovalent α-EGFR TM could only mediate the killing of tumor cells expressing high levels of EGFR, the bivalent α-EGFR-EGFR TM could redirect UniCAR T cells to tumor cells expressing low levels of EGFR. According to PET experiments in vivo, the increased avidity of the bivalent α-EGFR-EGFR TM improves the enrichment at the tumor site and its use for PET imaging.


CAR T cell immunotherapy; PET imaging; affinity; nanobody; solid epithelial tumor

Conflict of interest statement

CONFLICTS OF INTEREST MB has filed patent applications related to the UniCAR platform.

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