Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract.

Abstract

PURPOSE:

Two viral oncoproteins, E6 and E7, are expressed in all human papillomavirus (HPV)-infected cells, from initial infection in the genital tract to metastatic cervical cancer. Intramuscular vaccination of women with high-grade cervical intraepithelial neoplasia (CIN2/3) twice with a naked DNA vaccine, pNGVL4a-sig/E7(detox)/HSP70, and a single boost with HPVE6/E7 recombinant vaccinia vaccine (TA-HPV) elicited systemic HPV-specific CD8 T-cell responses that could traffic to the lesion and was associated with regression in some patients (NCT00788164).

EXPERIMENTAL DESIGN:

Here, we examine whether alteration of this vaccination regimen by administration of TA-HPV vaccination in the cervicovaginal tract, rather than intramuscular (IM) delivery, can more effectively recruit antigen-specific T cells in an orthotopic syngeneic mouse model of HPV16(+) cervical cancer (TC-1 luc).

RESULTS:

We found that pNGVL4a-sig/E7(detox)/HSP70 vaccination followed by cervicovaginal vaccination with TA-HPV increased accumulation of total and E7-specific CD8(+) T cells in the cervicovaginal tract and better controlled E7-expressing cervicovaginal TC-1 luc tumor than IM administration of TA-HPV. Furthermore, the E7-specific CD8(+) T cells in the cervicovaginal tract generated through the cervicovaginal route of vaccination expressed the α4β7 integrin and CCR9, which are necessary for the homing of the E7-specific CD8(+) T cells to the cervicovaginal tract. Finally, we show that cervicovaginal vaccination with TA-HPV can induce potent local HPV-16 E7 antigen-specific CD8(+) T-cell immune responses regardless of whether an HPV DNA vaccine priming vaccination was administered IM or within the cervicovaginal tract.

CONCLUSIONS:

Our results support future clinical translation using cervicovaginal TA-HPV vaccination.

• Authors: Yun-Yan Sun, Shiwen Peng, Liping Han, Jin Qiu, Liwen Song, Yachea Tsai, Benjamin Yang, Richard B S Roden, Cornelia L Trimble, Chien-Fu Hung, T-C Wu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 3 Pg. 657-69 (Feb 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26420854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Biomarkers
• Papillomavirus E7 Proteins
• Papillomavirus Vaccines
• Vaccines, DNA
• human papillomavirus vaccine, TA

Topics

• Animals
• Biomarkers
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Chemotaxis, Leukocyte (immunology)
• Dendritic Cells (immunology, metabolism)
• Disease Models, Animal
• Female
• Genital Neoplasms, Female (etiology, mortality, prevention & control)
• Humans
• Immunization
• Immunization, Secondary
• Immunophenotyping
• Mice
• Mice, Knockout
• Papillomaviridae (genetics, immunology)
• Papillomavirus E7 Proteins (immunology)
• Papillomavirus Infections (complications, prevention & control)
• Papillomavirus Vaccines (administration & dosage, immunology)
• Phenotype
• Vaccines, DNA (administration & dosage, immunology)