title: Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts.
abstract: Current therapeutic approaches to treatment of patients with bulky cervical cancer are based on conventional in situ ablative modalities including cisplatin-based chemotherapy and radiation therapy. The 5-year survival of patients with nonresectable disease is dismal. Because over 99% of squamous cervical cancer is caused by persistent infection with an oncogenic strain of human papillomavirus (HPV), particularly type 16 and viral oncoproteins E6 and E7 are functionally required for disease initiation and persistence, HPV-targeted immune strategies present a compelling opportunity in which to demonstrate proof of principle. Sublethal doses of radiation and chemotherapeutic agents have been shown to have synergistic effect in combination with either vaccination against cancer-specific antigens, or with passive transfer of tumor-specific cytotoxic T lymphocytes (CTLs). Here, we explored the combination of low-dose radiation therapy with DNA vaccination with calreticulin (CRT) linked to the mutated form of HPV-16 E7 antigen (E7(detox)), CRT/E7(detox) in the treatment of E7-expressing TC-1 tumors. We observed that TC-1 tumor-bearing mice treated with radiotherapy combined with CRT/E7(detox) DNA vaccination generated significant therapeutic antitumor effects and the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of treated mice. Furthermore, treatment with radiotherapy was shown to render the TC-1 tumor cells more susceptible to lysis by E7-specific CTLs. In addition, we observed that treatment with radiotherapy during the second DNA vaccination generated the highest frequency of E7-specific CD8(+) T cells in the tumors and spleens of TC-1 tumor-bearing mice. Finally, TC-1 tumor-bearing mice treated with the chemotherapy in combination with radiation and CRT/E7(detox) DNA vaccination generate significantly enhanced therapeutic antitumor effects. The clinical implications of the study are discussed.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Tseng
authors.forename: Cornelia
authors.initials: C
authors.lastname: Trimble
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.forename: Archana
authors.initials: A
authors.lastname: Monie
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Warner K
authors.initials: WK
authors.lastname: Huh
authors.forename: Talia
authors.initials: T
authors.lastname: Hoory
authors.forename: Mei-Cheng
authors.initials: MC
authors.lastname: Wang
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D037282:Calreticulin / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed / Q000276:immunology / Q000637:transplantation; D002472:Cell Transformation, Viral; D003131:Combined Modality Therapy; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D016233:Immunotherapy, Active; D008168:Lung; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D002583:Uterine Cervical Neoplasms; D019444:Vaccines, DNA / Q000627:therapeutic use*
chemical_list: D037282:Calreticulin; D016207:Cytokines; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16