Original Article

Cancer Immunology, Immunotherapy

, Volume 62, Issue 7, pp 1175-1185

Intratumoral injection of therapeutic HPV vaccinia vaccine following cisplatin enhances HPV-specific antitumor effects

  • Sung Yong LeeAffiliated withDepartment of Pathology, Johns Hopkins Medical InstitutionsDepartment of Internal Medicine, Korea University Medical Center
  • , Tae Heung KangAffiliated withDepartment of Pathology, Johns Hopkins Medical InstitutionsDepartment of Immunology, College of Medicine, Konkuk University
  • , Jayne KnoffAffiliated withDepartment of Pathology, Johns Hopkins Medical Institutions
  • , Zhuomin HuangAffiliated withDepartment of Pathology, Johns Hopkins Medical Institutions
  • , Ruey-Shyang SoongAffiliated withDepartment of Pathology, Johns Hopkins Medical InstitutionsDepartment of General Surgery, Chang Gung Memorial HospitalChang Gung University, College of Medicine
  • , Ronald D. AlvarezAffiliated withDepartment of Obstetrics and Gynecology, University of Alabama at Birmingham
  • , Chien-Fu HungAffiliated withDepartment of Pathology, Johns Hopkins Medical InstitutionsDepartment of Oncology, Johns Hopkins Medical Institutions
  • , T.-C. WuAffiliated withDepartment of Pathology, Johns Hopkins Medical InstitutionsDepartment of Obstetrics and Gynecology, Johns Hopkins Medical InstitutionsDepartment of Molecular Microbiology and Immunology, Johns Hopkins Medical InstitutionsDepartment of Oncology, Johns Hopkins Medical Institutions Email author 

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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.

Keywords

Cisplatin Vaccine Vaccinia virus Human papillomavirus TA-HPV