Fusion-driven sarcoma neoantigens and tumor-associated antigens

Fusion-driven sarcoma neoantigens and tumor-associated antigens (TAAs) represent a specialized class of therapeutic targets for the treatment of mesenchymal malignancies. Fusion-driven neoantigens, such as the SS18-SSX fusion in synovial sarcoma or PAX3-FOXO1 in alveolar rhabdomyosarcoma, are created by chromosomal translocations that generate unique protein sequences entirely absent from the normal human proteome (Pollack et al., 2020, J Clin Oncol). In contrast, TAAs like NY-ESO-1 and MAGE-A4 are cancer-testis antigens that are aberrantly expressed in sarcomas but restricted to immune-privileged sites in healthy individuals (D'Angelo et al., 2018, Cancer Discovery). These targets are primarily addressed through adoptive cell therapies, specifically T-cell receptor (TCR) engineered T-cells, and therapeutic vaccines designed to stimulate a cytotoxic T-lymphocyte response (Merchant et al., 2023, Lancet Oncology). Drugs like afamitresgene autoleucel target these antigens by recognizing specific peptide fragments presented on the cell surface by Human Leukocyte Antigen (HLA) molecules. While highly promising for their specificity, these therapies face challenges such as HLA-restriction, potential off-target effects on healthy tissues expressing TAAs, and the complex immunosuppressive microenvironment of sarcomas (Chen et al., 2021, Front Immunol).

Other names

Sarcoma-specific fusion neoantigensSarcoma tumor-associated antigensFusion-derived peptidesSarcoma TAAs

T-cell receptor (TCR) mediated recognition of peptide-HLA complexes on the surface of tumor cells, leading to T-cell activation and targeted lysis of the malignant cells.