title: Targeting tumor specific translocations in sarcomas in pediatric patients for immunotherapy.
abstract: In an effort to develop more effective therapies for various sarcomas in pediatric patients, the authors have focused on using recurrent tumor-specific translocations as potential novel tumor antigens. In general, these translocations generate fusion transcription factors. Because cytotoxic T cell lymphocyte receptors recognize peptide fragments bound to major histocompatibility complex Class 1 molecules, it is possible that unique peptides spanning the translocation breakpoint region may be processed, bound to major histocompatibility complex Class I molecules and displayed on the tumor cell surface where they could be susceptible to cytotoxic T cell lymphocyte killing. The authors have investigated the PAX-3-FKHR fusion product seen in alveolar rhabdomyosarcoma, and the EWS-FLI-1 fusion product seen in Ewing's sarcoma. Peptides spanning these fusion regions contain potential major histocompatibility complex Class 1 and Class II binding motifs suggesting they may serve as novel T cell antigens. Preliminary mouse experiments suggest that cytotoxic T cell lymphocytes specific for the PAX-3-FKHR fusion peptide can be generated and can recognize and kill tumor cells bearing the PAX-3-FKHR fusion protein. Clinical trials are ongoing to determine whether this approach will be useful.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1928, USA.
authors.forename: C
authors.initials: C
authors.lastname: Mackall
authors.forename: J
authors.initials: J
authors.lastname: Berzofsky
authors.forename: L J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002986:Clinical Trials as Topic; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014178:Translocation, Genetic / Q000235:genetics* / Q000276:immunology
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D011993:Recombinant Fusion Proteins