T-cell receptor specific for Epidermal growth factor receptor variant III (EGFRvIII) peptide-MHC complex (EGFRvIII-TCR)

T-cell receptors (TCRs) specific for the EGFRvIII peptide-MHC complex are engineered immune receptors designed to target a specific mutation found in glioblastoma and other cancers. The EGFRvIII mutation is a tumor-specific variant characterized by the deletion of exons 2-7 of the EGFR gene, which creates a unique glycine-containing neoepitope not found in healthy tissue (Sampson et al., 2014, Nature). These TCRs are engineered to recognize this specific peptide when presented by the Major Histocompatibility Complex (MHC), typically HLA-A*02:01. When expressed in patient-derived T cells, these TCRs enable the immune system to identify and kill EGFRvIII-positive tumor cells with high precision. Clinical trials have demonstrated that TCR-T cells can infiltrate the central nervous system and exert anti-tumor activity (Johnson et al., 2015, Sci Transl Med). However, their success is often limited by the high degree of intratumoral heterogeneity and the emergence of antigen-null clones (O'Rourke et al., 2017, Sci Transl Med). This target represents a significant focus in neuro-oncology for developing personalized immunotherapy against aggressive brain tumors. The interaction between the TCR and the peptide-MHC complex is the critical determinant of therapeutic efficacy and specificity. Ongoing research aims to optimize TCR affinity and overcome the immunosuppressive microenvironment of the brain. Overall, these TCRs provide a blueprint for targeting neoantigens in solid tumors.

Other names

EGFRvIII-specific TCRAnti-EGFRvIII TCREGFRvIII-targeted T-cell receptorEGFRvIII-pMHC-specific TCR

The mechanism of action involves the specific recognition of the EGFRvIII neoepitope (sequence: LEEKKGNYVVTDH) presented by HLA-A*02:01 MHC molecules on the surface of tumor cells by the engineered T-cell receptor. This binding event triggers the activation of the CD3 signaling complex, leading to the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) and subsequent activation of downstream pathways such as ZAP-70. This signaling cascade results in T-cell proliferation, the secretion of pro-inflammatory cytokines like interferon-gamma (IFN-gamma), and the release of cytotoxic granules containing perforin and granzymes, which induce apoptosis in the target tumor cell (Johnson et al., 2015, Sci Transl Med; PubMed: 25122652).