Targeting tumor specific translocations in sarcomas in pediatric patients for immunotherapy.
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.
Mackall
C
C
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1928, USA.
Berzofsky
J
J
Helman
L J
LJ
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
D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D011993:Recombinant Fusion Proteins