Peptide–Major Histocompatibility Complex class I presenting Cancer-Testis Antigen (pMHC-I/CTA)

Peptide–Major Histocompatibility Complex class I (pMHC-I) complexes presenting cancer-testis antigens (CTAs) represent a highly specific class of therapeutic targets in oncology. CTAs, such as NY-ESO-1, MAGE-A4, and PRAME, are proteins whose expression is typically restricted to the immune-privileged germ cells of the testes and fetal tissues, which do not express MHC class I molecules (Thomas R, et al., Expert Rev Vaccines, 2023). Consequently, when these intracellular proteins are processed and presented as peptides on the MHC-I molecules of tumor cells, they serve as neoantigen-like markers that are absent from healthy adult somatic tissues. This unique expression profile allows for the development of T-cell receptor (TCR) engineered therapies and bispecific T-cell engagers that can recognize and eliminate malignant cells with high precision (Gnjatic S, et al., Adv Cancer Res, 2006). In August 2024, the FDA approved Afamitresgene autoleucel, the first TCR-T therapy targeting the MAGE-A4/HLA-A*02 complex, validating this target class for solid tumors like synovial sarcoma (FDA, 2024). Despite their promise, these targets require patients to possess specific HLA genotypes (HLA restriction) and carry the risk of severe adverse events such as cytokine release syndrome or off-target cross-reactivity if the targeted peptide sequence resembles those found in vital organs.

Other names

pMHC-I/CTA complexHLA-peptide complexCancer-testis antigen-derived peptide-MHCMHC-I/CTACancer-testis antigen/HLA complex

Targeting of specific peptide-HLA complexes by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to induce T-cell mediated lysis of tumor cells.