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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

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.

Details

Original languageEnglish
Pages (from-to)25597-25616
Number of pages20
JournalOncotarget
Volume9
Issue number39
Publication statusPublished - 22 May 2018
Peer-reviewedYes

External IDs

PubMed 29876011

Keywords

ASJC Scopus subject areas

Keywords

  • Affinity, CAR T cell immunotherapy, Nanobody, PET imaging, Solid epithelial tumor

Library keywords