HLA-A*02:01-restricted New York esophageal squamous cell carcinoma 1 (NY-ESO-1) peptide complex (HLA-A*02:01/NY-ESO-1)

The HLA-A*02:01-restricted New York esophageal squamous cell carcinoma 1 (NY-ESO-1) peptide complex is a critical target in cancer immunotherapy, particularly for TCR-engineered T-cell therapies. NY-ESO-1 is a cancer-testis antigen (CTA) encoded by the CTAG1B gene; it is highly expressed in various cancers but restricted to immune-privileged germ cells in healthy adults [Gnjatic et al., 2006, PMID: 16322273]. The specific 9-amino acid peptide SLLMWITQC (residues 157-165) is processed and presented on the cell surface by the HLA-A*02:01 major histocompatibility complex (MHC) class I molecule [Jäger et al., 1998, PMID: 9461420]. This pMHC complex is recognized by specific T-cell receptors, making it a public neoantigen-like target for patients who are HLA-A*02:01 positive. In August 2024, the FDA granted accelerated approval to afamitresgene autoleucel (Tecelra), a TCR-T therapy targeting this complex for the treatment of synovial sarcoma [FDA, 2024]. Therapeutic success depends on high levels of NY-ESO-1 expression in the tumor and the presence of the specific HLA-A*02:01 allele, necessitating rigorous patient screening. Other modalities in development include bispecific T-cell engagers and TCR-mimetic antibodies that bypass the need for cellular engineering. Safety concerns primarily involve cytokine release syndrome and potential cross-reactivity with similar endogenous peptides.

Other names

HLA-A*02:01/NY-ESO-1(157-165)NY-ESO-1 peptide-MHC complexCTAG1B-HLA-A*02:01 complexSLLMWITQC-HLA-A*02:01

Engineered T-cell receptors (TCRs) or bispecific molecules bind specifically to the peptide-MHC complex, leading to the formation of an immunological synapse, T-cell activation, and subsequent granzyme/perforin-mediated lysis of the target tumor cell [D'Angelo et al., 2018, PMID: 29355071].