Melanoma-associated antigen A4 (MAGE-A4) peptide-HLA complex (MAGE-A4/HLA complex)

Melanoma-associated antigen A4 (MAGE-A4) is a member of the cancer-testis antigen (CTA) family, which is typically expressed only in immune-privileged germ cells of the testis and placenta but is aberrantly re-expressed in various solid tumors (UniProt P43358; Cancer Discovery, 2023). In malignant cells, MAGE-A4 is processed into specific peptides, such as the GVYDGREHTV decamer, and presented on the cell surface by Human Leukocyte Antigen (HLA) class I molecules, most commonly HLA-A*02:01 (Nature Medicine, 2021; ClinicalTrials.gov NCT04044859). This peptide-HLA complex serves as a highly specific target for immunotherapy because it is absent from healthy adult somatic tissues, minimizing the risk of on-target/off-tumor toxicity (Journal of Hematology & Oncology, 2021). Therapeutic approaches targeting this complex include TCR-engineered T-cell therapies (TCR-T), which utilize modified T cells to recognize and destroy cells displaying the MAGE-A4 peptide (Adaptimmune Therapeutics, 2024). The first such therapy, afamitresgene autoleucel (Tecelra), was FDA-approved in 2024 for the treatment of advanced synovial sarcoma (FDA.gov, 2024). Ongoing clinical research continues to explore the efficacy of targeting this complex in other MAGE-A4-positive malignancies like lung and head and neck cancers (ClinicalTrials.gov NCT03139747).

Other names

MAGE-A4MAGE4Melanoma antigen family A member 4Cancer/testis antigen 1.4CT1.4MAGE-A4 peptide-MHC complex

Engineered T-cell receptor (TCR) binding to the specific MAGE-A4 peptide presented by HLA class I molecules, triggering T-cell activation and cytotoxic lysis of the tumor cell.