Human epidermal growth factor receptor 2-specific T-cell receptor (HER2-specific TCR)

HER2-specific CD8+ T-cell receptors (TCRs) that recognize the GP2 peptide (residues 654–662) presented by MHC class I molecules, specifically HLA-A*02:01, are pivotal in the development of targeted immunotherapies for HER2-positive malignancies. HER2 (Human Epidermal Growth Factor Receptor 2) is a member of the epidermal growth factor receptor family and is frequently overexpressed in cancers such as breast, ovarian, and gastric carcinomas, where it promotes cell proliferation and survival (UniProt P04626). The GP2 peptide is a hydrophobic epitope derived from the transmembrane domain of the HER2 protein; although it has a lower binding affinity for HLA-A2 compared to other epitopes like E75, it is highly effective at inducing a potent cytotoxic T-lymphocyte (CTL) response (Mittendorf et al., 2014, Cancer). These TCRs are utilized in TCR-engineered T-cell (TCR-T) therapies, where a patient's T cells are modified to express the specific TCR, enabling them to recognize and eliminate HER2-expressing tumor cells. Additionally, GP2 peptide vaccines (e.g., GLSI-100) aim to stimulate and expand the endogenous population of T cells bearing these specific TCRs to prevent disease recurrence (Sahasrabudhe et al., 2012, Journal of Clinical Oncology). A significant therapeutic challenge involves the potential for on-target, off-tumor toxicity, as HER2 is expressed at low levels in normal tissues such as the heart and lungs, necessitating careful selection of TCR affinity to ensure safety (Morgan et al., 2010, Molecular Therapy).

Other names

GP2-specific T-cell receptorHER2(654-662)-specific TCRHLA-A*02:01-restricted HER2-specific TCRGP2-MHC-specific TCRERBB2-specific T-cell receptor

Recognition of the HER2-derived GP2 peptide (IISAVVGIL) presented by HLA-A*02:01 on the surface of tumor cells, triggering T-cell receptor signaling, cytokine release, and granzyme/perforin-mediated lysis of the target cell (Mittendorf et al., 2014, Cancer).