title: Eradication of large tumors expressing human papillomavirus E7 protein by therapeutic vaccination with E7 fused to the extra domain a from fibronectin.
abstract: Cervical carcinoma is one of the most common cancers in women worldwide. It is well established that chronic infection of the genital tract by various mucosatropic human papillomavirus (HPV) types causes cervical cancer. Cellular immunity to E7 protein from HPV (HPVE7) has been associated with clinical and cytologic resolution of HPV-induced lesions. Thus, we decided to test if targeting of HPVE7 to dendritic cells using a fusion protein containing the extra domain A (EDA) from fibronectin, a natural ligand for TLR4, and HPVE7 (EDA-HPVE7) might be an efficient vaccine for the treatment of cervical carcinoma. We found that EDA-HPVE7 fusion protein was efficiently captured by bone marrow derived dendritic cells in vitro and induced their maturation, with the upregulation of maturation markers and the production of IL-12. Immunization of mice with EDA-HPVE7 fusion protein induced antitumor CD8(+)  T cell responses in the absence of additional adjuvants. Repeated intratumoral administration of EDA-HPVE7 in saline was able to cure established TC-1 tumors of 5-7 mm in diameter. More importantly, intravenous injection with EDA-HPVE7 in combination with the TLR ligand polyinosinic-polycytidylic acid (pIC), or with low doses of cyclophosphamide and the TLR9 ligand CpG-B complexed in cationic lipids, were able to eradicate large established TC-1 tumors (1.2 cm in diameter). Thus, therapeutic vaccination with EDA-HPVE7 fusion protein may be effective in the treatment of human cervical carcinoma.
authors: Área de Hepatología y Terapia Génica, Centro de Investigación Médica Aplicada CIMA, Pamplona, Spain.
authors: Cristina
authors: C
authors: Mansilla
authors: Pedro
authors: P
authors: Berraondo
authors: Maika
authors: M
authors: Durantez
authors: Marta
authors: M
authors: Martínez
authors: Noelia
authors: N
authors: Casares
authors: Laura
authors: L
authors: Arribillaga
authors: Francesc
authors: F
authors: Rudilla
authors: Jessica
authors: J
authors: Fioravanti
authors: Teresa
authors: T
authors: Lozano
authors: Lorea
authors: L
authors: Villanueva
authors: Pablo
authors: P
authors: Sarobe
authors: Francisco
authors: F
authors: Borrás
authors: Claude
authors: C
authors: Leclerc
authors: Jesús
authors: J
authors: Prieto
authors: Juan José
authors: JJ
authors: Lasarte
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003520:Cyclophosphamide / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005353:Fibronectins / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D027383:Papillomaviridae / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000276:immunology* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D014614:Vaccines, Synthetic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; C513201:CpG-B 2006; D005353:Fibronectins; D009838:Oligodeoxyribonucleotides; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C572454:extra domain A fibronectin, mouse; D018664:Interleukin-12; D003520:Cyclophosphamide; D011070:Poly I-C