T-cell receptor recognizing PAX3-FOXO1–derived peptide epitopes (PAX3-FOXO1 TCR)

The T-cell receptor (TCR) recognizing PAX3-FOXO1–derived peptide epitopes is a specialized immune receptor, often engineered for adoptive cell therapy, that targets the unique neoantigenic sequences created by the PAX3-FOXO1 fusion protein. This fusion protein is the pathognomonic driver of alveolar rhabdomyosarcoma (aRMS), resulting from a t(2;13)(q35;q14) chromosomal translocation that joins the DNA-binding domain of PAX3 to the transactivation domain of FOXO1 (Hishii et al., 2002). The resulting junctional peptide sequence is entirely tumor-specific, making it an ideal target for TCR-T cell therapy as it minimizes the risk of attacking normal tissues. These TCRs are designed to recognize the fusion-derived peptides when presented on the surface of tumor cells by specific Major Histocompatibility Complex (MHC) molecules, such as HLA-A*02:01 or HLA-B*07:02 (Rodeberg et al., 2005). Upon binding, the TCR triggers T-cell activation, leading to the targeted destruction of aRMS cells through the release of cytotoxic granules and cytokines. While currently in the investigational and clinical stages, this therapeutic approach represents a promising strategy for treating aggressive, fusion-positive pediatric sarcomas that are often resistant to conventional therapies. Clinical evaluation of these TCRs is ongoing, notably in trials conducted by the National Cancer Institute (NCT04393974) to assess safety and efficacy in pediatric populations.

Other names

PAX3-FOXO1-specific T-cell receptorPAX3-FKHR-specific T-cell receptorBreakpoint-specific T-cell receptorP3F-TCRAlveolar rhabdomyosarcoma-specific TCR

Recognition of PAX3-FOXO1 fusion-derived peptides presented on MHC molecules, leading to T-cell activation and tumor cell lysis.