title: HER2/neu as a potential target for immunotherapy in gynecologic carcinosarcomas.
abstract: Carcinosarcomas of the female genital tract are rare tumors with an aggressive clinical behavior. Trastuzumab, a humanized monoclonal antibody, acts by binding to HER2/neu extracellular domain and exhibits therapeutic efficacy in HER2/neu-overexpressing cancers. Two uterine carcinosarcomas (UMMT-ARK-1, UMMT-ARK-2) and 2 ovarian carcinosarcomas (OMMT-ARK-1, OMMT-ARK-2) were established as primary tumor cell lines in vitro and evaluated for HER2/neu expression by immunohistochemistry, fluorescent in situ hybridization analysis, quantitative real-time polymerase chain reaction, and for membrane-bound complement regulatory proteins CD46, CD55, and CD59 by flow cytometry. Sensitivity to trastuzumab-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity was studied in 5-hr chromium release assays. HER2/neu expression was demonstrated in OMMT-ARK-1 and OMMT-ARK-2. OMMT-ARK-2 demonstrated an amplification of the c-erbB2 gene by fluorescent in situ hybridization analysis and a high sensitivity to ADCC (mean killing, 45.6%; range, 32.3%-72.6%). A lower level of killing was detected against the fluorescent in situ hybridization analysis-negative OMMT-ARK-1 cell line (mean, 26.5%; range, 21.0%-31.8%). CD46, CD55, and CD59 membrane-bound complement regulatory proteins were expressed at high levels in all primary mixed müllerian tumor cell lines, and all these tumors were found to be highly resistant to complement-dependent cytotoxicity with or without trastuzumab. Addition of untreated and heat-inactivated plasma did not significantly decrease ADCC against OMMT-ARK-2 cell line, suggesting that while the cell line is highly resistant to complement, irrelevant IgG does not significantly alter the ability of trastuzumab to mediate ADCC. Our results suggest that HER2/neu may represent a novel target for the immunotherapy of a subset of human carcinosarcomas refractory to salvage chemotherapy.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Guzzo
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.forename: Pei
authors.initials: P
authors.lastname: Hui
authors.forename: Luisa
authors.initials: L
authors.lastname: Carrara
authors.forename: Joyce
authors.initials: J
authors.lastname: Varughese
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.forename: Marta
authors.initials: M
authors.lastname: Betti
authors.forename: Paola
authors.initials: P
authors.lastname: Todeschini
authors.forename: Sara
authors.initials: S
authors.lastname: Gasparrini
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Roberto
authors.initials: R
authors.lastname: Angioli
authors.forename: Sergio
authors.initials: S
authors.lastname: Pecorelli
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018958:CD55 Antigens / Q000378:metabolism; D018957:CD59 Antigens / Q000378:metabolism; D002296:Carcinosarcoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D051916:Membrane Cofactor Protein / Q000378:metabolism; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018958:CD55 Antigens; D018957:CD59 Antigens; D051916:Membrane Cofactor Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human