title: GTL001 and bivalent CyaA-based therapeutic vaccine strategies against human papillomavirus and other tumor-associated antigens induce effector and memory T-cell responses that inhibit tumor growth.
abstract: GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8+T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8+T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines.
authors.affiliation: Genticel, 516 rue Pierre et Marie Curie, Labège, 31670 Toulouse, France. Electronic address: michael.esquerre@evotec.com.
authors.forename: Michaël
authors.initials: M
authors.lastname: Esquerré
authors.affiliation: Genticel, 516 rue Pierre et Marie Curie, Labège, 31670 Toulouse, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Momot
authors.affiliation: Genticel, 516 rue Pierre et Marie Curie, Labège, 31670 Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Goubier
authors.affiliation: Genticel, 516 rue Pierre et Marie Curie, Labège, 31670 Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Gonindard
authors.affiliation: Genticel, 516 rue Pierre et Marie Curie, Labège, 31670 Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Leung-Theung-Long
authors.affiliation: Genticel, 516 rue Pierre et Marie Curie, Labège, 31670 Toulouse, France.
authors.forename: Yolande
authors.initials: Y
authors.lastname: Misseri
authors.affiliation: Genticel, 5 rue Tronchet, 75008 Paris, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Bissery
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000008:administration & dosage* / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D005260:Female; D007156:Immunologic Memory; D007271:Injections, Intradermal; D008545:Melanoma / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010051:Ovarian Neoplasms / Q000517:prevention & control; D050725:Papillomavirus E7 Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D030361:Papillomavirus Infections / Q000150:complications*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D037361:Adenylate Cyclase Toxin; D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D004337:Drug Carriers; C052633:E7 protein, Human papillomavirus type 18; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D014614:Vaccines, Synthetic; C059731:oncogene protein E7, Human papillomavirus type 16; D010047:Ovalbumin
keywords: Cervical cancer; Human papillomavirus; Memory T-cell response; Therapeutic vaccine; Tumour model; Tumour-associated antigen