Truncated epidermal growth factor receptor (EGFRt) (EGFRt)

The truncated epidermal growth factor receptor (EGFRt) is an engineered, non-functional cell surface marker widely utilized in adoptive T-cell therapies, particularly chimeric antigen receptor (CAR) T-cell treatments (Wang et al., 2011, Blood). It consists of the human EGFR extracellular domains III and IV and the transmembrane domain, but lacks the intracellular signaling domains and the ligand-binding domains I and II, rendering it incapable of signal transduction or activation by endogenous epidermal growth factor (Paszkiewicz et al., 2016, Journal of Clinical Investigation). EGFRt serves as a versatile tool for the clinical management of engineered cells, functioning as a selection marker for enriching modified cells during manufacturing and as a tracking marker for monitoring T-cell persistence in patients. Most importantly, it acts as a safety switch; the administration of the monoclonal antibody Cetuximab, which specifically recognizes the Domain III epitope of EGFRt, can trigger antibody-dependent cellular cytotoxicity (ADCC) to eliminate the engineered T cells (Gargett et al., 2019, Molecular Therapy). This mechanism allows clinicians to rapidly deplete the T-cell population in the event of severe, life-threatening toxicities such as cytokine release syndrome or neurotoxicity. While highly effective, challenges include the potential for Cetuximab to cause off-target skin toxicity by binding to endogenous EGFR in healthy tissues and the requirement for robust host ADCC activity for complete cell clearance.

Other names

EGFRttEGFRTruncated human epidermal growth factor receptorHuman epidermal growth factor receptor truncationNon-signaling EGFR

Cetuximab binds to the extracellular Domain III of the truncated EGFR, facilitating the elimination of engineered T cells through antibody-dependent cellular cytotoxicity (ADCC) (Wang et al., 2011).