Tumor-associated antigens in fusion-driven sarcomas (TAA)

Tumor-associated antigens (TAAs) in fusion-driven sarcomas represent a distinct class of therapeutic targets found in mesenchymal tumors characterized by specific chromosomal translocations. These antigens primarily include cancer-testis antigens (CTAs) such as NY-ESO-1 and MAGE-A4, which exhibit high expression in synovial sarcoma and myxoid/round cell liposarcoma while remaining largely absent in healthy adult tissues (Pollack et al., 2020). Additionally, the unique peptide sequences created at the breakpoint of fusion proteins, such as SS18-SSX or EWS-FLI1, function as neoantigens that are entirely specific to the malignant cells (D'Angelo et al., 2018). Due to the typically low mutational burden of these sarcomas, these TAAs are primary candidates for T-cell receptor (TCR) engineered T-cell therapies, which recognize intracellular proteins presented via the HLA system (Hong et al., 2023). Clinical development has focused on agents like afamitresgene autoleucel, which targets MAGE-A4, and letetresgene autoleucel, targeting NY-ESO-1, showing significant efficacy in heavily pretreated patients. The successful application of these therapies requires precise patient selection based on both the presence of the specific fusion driver and the expression of the target antigen (Gnjatic et al., 2006).

Other names

Cancer-testis antigensSarcoma-associated antigensFusion-derived neoantigensCTAsNY-ESO-1MAGE-A4PRAMESS18-SSX neoantigenEWS-FLI1 neoantigen

T-cell receptor (TCR) engineered T-cell therapy targeting peptide-HLA complexes; vaccine-induced T-cell activation; antibody-drug conjugate (ADC) mediated cytotoxicity.