Safety switch optimization enhances antibody-mediated elimination of CAR T cells

Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal grow...

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Bibliographic Details
Published in:	Frontiers in Molecular Medicine Vol. 2; p. 1026474
Main Authors:	Shabaneh, Tamer B, Moffett, Howell F, Stull, Sylvia M, Derezes, Thomas, Tait, Leah J, Park, Spencer, Riddell, Stan R, Lajoie, Marc J
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 11-10-2022
Subjects:	Molecular Medicine EGFRopt CAR T cell therapy safety switch antibody-dependent cellular cytotoxicity truncated EGFR-derived polypeptide
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Summary:	Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal growth factor receptor (EGFRt) is a promising safety switch that has been used in multiple clinical constructs and can be targeted by cetuximab, a clinically available monoclonal antibody. However, this approach requires high and persistent cell surface expression of EGFRt to ensure that antibody-mediated depletion of engineered cells is rapid and complete. Here we show that incorporating a short juxtamembrane sequence into the EGFRt polypeptide enhances its expression on the surface of T cells and their susceptibility to antibody-dependent cellular cytotoxicity (ADCC). Incorporating this optimized variant (EGFRopt) into bicistronic and tricistronic CAR designs results in more rapid elimination of CAR T cells and robust termination of their effector activity compared to EGFRt. These studies establish EGFRopt as a superior safety switch for the development of next-generation cell-based therapeutics.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Alice Turdo, University of Palermo, Italy Reviewed by: Pin Wang, University of Southern California, United States These authors have contributed equally to this work and share first authorship This article was submitted to Molecular Medicine and Cancer Treatment, a section of the journal Frontiers in Molecular Medicine Lucia Maria Vanrell, Universidad de la República, Uruguay
ISSN:	2674-0095 2674-0095
DOI:	10.3389/fmmed.2022.1026474