Melanoma-associated antigen 3-specific T cell receptor (MAGE-A3 TCR)

The Melanoma-associated antigen 3 (MAGE-A3)-specific T cell receptor (TCR) is an engineered or naturally occurring receptor used in T-cell receptor therapy (TCR-T) to target MAGE-A3-expressing malignancies. MAGE-A3 is a cancer-testis antigen (CTA) that is highly expressed in various cancers, including melanoma, non-small cell lung cancer, and multiple myeloma, while remaining absent in most healthy tissues (UniProt P12735). In therapeutic applications, patient T cells are modified to express this TCR, which recognizes MAGE-A3 peptides presented by specific Human Leukocyte Antigen (HLA) molecules, such as HLA-A*01:01 or HLA-A*02:01. Recognition of the peptide-MHC complex triggers T cell activation, leading to the secretion of pro-inflammatory cytokines and the direct lysis of tumor cells. However, clinical development has been complicated by significant safety concerns, most notably off-target cross-reactivity. For instance, a MAGE-A3 TCR trial was halted after patients experienced fatal cardiotoxicity due to the TCR's unexpected recognition of a peptide from the muscle protein Titin (Linette et al., 2013, Blood). Additionally, neurotoxicity has been observed when the TCR cross-reacts with MAGE-A12 expressed in the central nervous system (Morgan et al., 2013, J. Immunother.).

Other names

MAGE-A3-specific T cell receptorMAGE-A3-targeted TCRAnti-MAGE-A3 TCRT cell receptor recognizing MAGE-A3-derived peptide

Engineered T cells expressing the MAGE-A3-specific TCR recognize and bind to MAGE-A3 peptides presented by specific HLA molecules on tumor cells, inducing T cell activation and cytotoxic lysis of the target cells.