Highly Efficient Targeting of EGFR-Expressing Tumor Cells with UniCAR T Cells via Target Modules Based on Cetuximab®

Justyna Jureczek; Anja Feldmann; Ralf Bergmann; Claudia Arndt; Nicole Berndt; Stefanie Koristka; Liliana Rodrigues Loureiro; Nicola Mitwasi; Anja Hoffmann; Alexandra Kegler; Tabea Bartsch; Michael Bachmann

doi:10.2147/OTT.S245169

Highly Efficient Targeting of EGFR-Expressing Tumor Cells with UniCAR T Cells via Target Modules Based on Cetuximab^®

Onco Targets Ther. 2020 Jun 12:13:5515-5527. doi: 10.2147/OTT.S245169. eCollection 2020.

Authors

Justyna Jureczek^{1

2

3}, Anja Feldmann³, Ralf Bergmann^{3

4}, Claudia Arndt³, Nicole Berndt³, Stefanie Koristka³, Liliana Rodrigues Loureiro^{3

5}, Nicola Mitwasi³, Anja Hoffmann³, Alexandra Kegler^{1

2

3}, Tabea Bartsch³, Michael Bachmann^{1

2

3

5

6}

Affiliations

¹ German Cancer Consortium (DKTK), Dresden, Germany.
² German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
⁴ Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
⁵ National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
⁶ Tumor Immunology, University Cancer Center (UCC), University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.

Abstract

Introduction: Since epithelial growth factor receptor (EGFR) overexpression is linked to a variety of malignancies, it is an attractive target for immune therapy including chimeric antigen receptor (CAR)-engineered T cells. Unfortunately, CAR T cell therapy harbors the risk of severe, even life-threatening side effects. Adaptor CAR T cell platforms such as the previously described UniCAR system might be able to overcome these problems. In contrast to conventional CARs, UniCAR T cells are per se inert. Their redirection towards target cells occurs only in the presence of a tumor-specific target molecule (TM). TMs are bifunctional molecules being able to recognize a tumor-associated antigen and to cross-link the CAR T cell via a peptide epitope recognized by the UniCAR domain.

Materials and methods: Here, we compare αEGFR TMs: a nanobody (nb)-based αEGFR TM derived from the camelid αEGFR antibody 7C12 with a murine and humanized single-chain fragment variable (scFv) based on the clinically used antibody Cetuximab^®.

Results: In principle, both the nb- and scFv-based TM formats are able to redirect UniCAR T cells to eliminate EGFR-expressing tumor cells in an antigen-specific and TM-dependent manner. However, the scFv-based αEGFR TM was significantly superior to the nb-based TM especially with respect to lysis of tumor cells.

Discussion: Improved efficiency of the scFv-based TM allowed the redirection of UniCAR T cells towards tumor cells expressing high as well as low EGFR levels in comparison to nb-based αEGFR TMs.

Keywords: CAR T cells; EGFR; UniCAR; adaptor CARs; immunotherapy; solid tumors.