title: Sequential cisplatin therapy and vaccination with HPV16 E6E7L2 fusion protein in saponin adjuvant GPI-0100 for the treatment of a model HPV16+ cancer.
abstract: Clinical studies suggest that responses to HPV16 E6E7L2 fusion protein (TA-CIN) vaccination alone are modest, and GPI-0100 is a well-tolerated, potent adjuvant. Here we sought to optimize both the immunogenicity of TA-CIN via formulation with GPI-0100 and treatment of HPV16+ cancer by vaccination after cisplatin chemotherapy. HPV16 neutralizing serum antibody titers, CD4+ T cell proliferative and E6/E7-specific CD8+ T cell responses were significantly enhanced when mice were vaccinated subcutaneously (s.c.) or intramuscularly (i.m.) with TA-CIN formulated with GPI-0100. Vaccination was tested for therapy of mice bearing syngeneic HPV16 E6/E7+ tumors (TC-1) either in the lung or subcutaneously. Mice treated with TA-CIN/GPI-0100 vaccination exhibited robust E7-specific CD8+ T cell responses, which were associated with reduced tumor burden in the lung, whereas mice receiving either component alone were similar to controls. Since vaccination alone was not sufficient for cure, mice bearing s.c. TC-1 tumor were first treated with two doses of cisplatin and then vaccinated. Vaccination with TA-CIN/GPI-0100 i.m. substantially retarded tumor growth and extended survival after cisplatin therapy. Injection of TA-CIN alone, but not GPI-0100, into the tumor (i.t.) was similarly efficacious after cisplatin therapy, but the mice eventually succumbed. However, tumor regression and extended remission was observed in 80% of the mice treated with cisplatin and then intra-tumoral TA-CIN/GPI-0100 vaccination. These mice also exhibited robust E7-specific CD8+ T cell and HPV16 neutralizing antibody responses. Thus formulation of TA-CIN with GPI-0100 and intra-tumoral delivery after cisplatin treatment elicits potent therapeutic responses in a murine model of HPV16+ cancer.
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Biology and Center for Cancer Research, Carver Research Foundation, Tuskegee University, Tuskegee, Alabama, United States of America.
authors.forename: Balasubramanyam
authors.initials: B
authors.lastname: Karanam
authors.affiliation: Department of Biostatistics, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Warner K
authors.initials: WK
authors.lastname: Huh
authors.affiliation: Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Sara I
authors.initials: SI
authors.lastname: Pai
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Oncology, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Chien-fu
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Oncology, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Oncology, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy* / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D030361:Papillomavirus Infections / Q000628:therapy* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000970:Antineoplastic Agents; D036022:Capsid Proteins; C068651:E6 protein, Human papillomavirus type 16; C484998:GPI0100; C063316:L2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D012503:Saponins; C059731:oncogene protein E7, Human papillomavirus type 16; D002945:Cisplatin