title: Enhancement of Ad-CRT/E7-mediated antitumor effect by preimmunization with L. lactis expressing HPV-16 E7.
abstract: Although current polyvalent vaccines can prevent development of cervical cancer, they cannot be used to treat patients who already have the disease. Adenovirus expressing calreticulin-E7 (Ad-CRT-E7) has shown promising results in the cervical cancer murine model. We also demonstrated that immunization with Lactococcus lactis encoding HPV-16 E7 (Ll-E7) anchored to its surface induces significant HPV-16 E7-specific immune response. Here, we assessed the combination of both approaches in the treatment of a cervical cancer animal model. Intranasal preimmunization of Ll-E7, followed by a single Ad-CRT/E7 application, induced ∼80% of tumor suppression in comparison with controls. Mice treated with a combination of Ll-E7 and Ad-CRT/E7 resulted in a 70% survival rate 300 days post-treatment, whereas 100% of the mice in the control groups died by 50 days. Significant CD8+ cytotoxic T-lymphocytes infiltration was detected in the tumors of mice treated with Ll-E7+Ad-CRT/E7. Tumors with regression showed a greater number of positive cells for in situ TUNEL staining than controls. Our results suggest that preimmunization with Ll-E7 enhances the Ad-CRT/E7-mediated antitumor effect. This treatment provides an enormous advantage over repeated applications of Ad-CRT/E7 by maintaining the effectiveness of the three-dose application of Ad-CRT/E7, but avoiding the high systemic toxicities associated with such repeat treatments.
authors.affiliation: 1 División de Genética, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social (IMSS) , Monterrey, Mexico .
authors.forename: Blanca R
authors.initials: BR
authors.lastname: Rangel-Colmenero
authors.forename: Jorge G
authors.initials: JG
authors.lastname: Gomez-Gutierrez
authors.forename: Julio
authors.initials: J
authors.lastname: Villatoro-Hernández
authors.forename: Laura M
authors.initials: LM
authors.lastname: Zavala-Flores
authors.forename: Deyanira
authors.initials: D
authors.lastname: Quistián-Martínez
authors.forename: Augusto
authors.initials: A
authors.lastname: Rojas-Martínez
authors.forename: Alma Y
authors.initials: AY
authors.lastname: Arce-Mendoza
authors.forename: Santos
authors.initials: S
authors.lastname: Guzmán-López
authors.forename: Roberto
authors.initials: R
authors.lastname: Montes-de-Oca-Luna
authors.forename: Odila
authors.initials: O
authors.lastname: Saucedo-Cárdenas
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D037282:Calreticulin / Q000008:administration & dosage; D061505:Cell Surface Display Techniques / Q000379:methods; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D005260:Female; D005822:Genetic Vectors; D007167:Immunotherapy / Q000379:methods*; D013294:Lactococcus lactis / Q000235:genetics; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000628:therapy*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D037282:Calreticulin; D004337:Drug Carriers; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic; C059731:oncogene protein E7, Human papillomavirus type 16