title: Intratumoral injection of therapeutic HPV vaccinia vaccine following cisplatin enhances HPV-specific antitumor effects.
abstract: Despite the conventional treatments of radiation therapy and chemotherapy, the 5-year survival rates for patients with advanced-stage cervical cancers remain low. Cancer immunotherapy has emerged as an alternative, innovative therapy that may improve survival. Here, we utilize a preclinical HPV-16 E6/E7-expressing tumor model, TC-1, and employ the chemotherapeutic agent cisplatin to generate an accumulation of CD11c+ dendritic cells in tumor loci making it an ideal location for the administration of therapeutic vaccines. Following cisplatin treatment, we tested different routes of administration of a therapeutic HPV vaccinia vaccine encoding HPV-16 E7 antigen (CRT/E7-VV). We found that TC-1 tumor-bearing C57BL/6 mice treated with cisplatin and intratumoral injection of CRT/E7-VV significantly increased E7-specific CD8+ T cells in the blood and generated potent local and systemic antitumor immune responses compared to mice receiving cisplatin and CRT/E7-VV intraperitoneally or mice treated with cisplatin alone. We further extended our study using a clinical grade recombinant vaccinia vaccine encoding HPV-16/18 E6/E7 antigens (TA-HPV). We found that intratumoral injection with TA-HPV following cisplatin treatment also led to increased E7-specific CD8+ T cells in the blood as well as significantly decreased tumor size compared to intratumoral injection with wild type vaccinia virus. Our study has strong implications for future clinical translation using intratumoral injection of TA-HPV in conjunction with the current treatment strategies for patients with advanced cervical cancer.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, CRB II Room 309, 1550 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Jayne
authors.initials: J
authors.lastname: Knoff
authors.forename: Zhuomin
authors.initials: Z
authors.lastname: Huang
authors.forename: Ruey-Shyang
authors.initials: RS
authors.lastname: Soong
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D039521:CD11c Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002945:Cisplatin / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D015552:Injections, Intralesional; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000276:immunology / Q000378:metabolism; D030361:Papillomavirus Infections / Q000276:immunology / Q000628:therapy; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy*; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D039521:CD11c Antigen; D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D002945:Cisplatin