Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model: causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy.
OBJECTIVE
The goal of this study was to investigate the therapeutic potentials of combining chemotherapy with human papillomavirus (HPV) E7 subunit vaccines in an animal tumor model and to determine the underlying therapeutic mechanisms.


METHODS
Animals bearing HPV E6/E7-expressing tumors were treated intratumorally with a selected cytotoxic drug, cisplatin, twice at 1-week interval and s.c. with E7 subunit vaccines thrice at 1-week interval. Tumor chemoimmunoresponse was measured by tumor size. Ag-specific CTL activities and tumor histology were checked in mice under treatments. Apoptosis, in vivo T-cell subset depletion, adoptive CTL transfer, and tumor regression were used to determine the mechanisms for antitumor therapeutic effects.


RESULTS
Combined therapy using cisplatin plus E7 subunit vaccines improved cure and recurrence rates of tumors and long-term antitumor immunity dramatically more than single therapy alone. In particular, both components of E7 subunit vaccines were required for induction of Ag-specific CTL as well as therapeutic synergy when combined with cisplatin. This therapeutic synergy was abrogated by depletion of CD8(+) T cells in vivo and was concomitant with histologic changes (such as heavy infiltration of lymphocytes and reduced tumor cell density). Finally, the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing was found to be responsible for therapeutic synergy.


CONCLUSIONS
E7 subunit vaccines plus cisplatin mediate antitumor therapeutic synergy through the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing. Moreover, E7-based therapeutic vaccines have the potential to improve chemotherapy in patients with cervical cancer.
Bae
Sung Hwa
SH
Department of Hematology-Oncology, Catholic University of Daegu, Namgu, Korea.
Park
Young-Ja
YJ
Park
Jae-Bok
JB
Choi
Youn Seok
YS
Kim
Mi Suk
MS
Sin
Jeong-Im
JI
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines; D002945:Cisplatin / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D005260:Female; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000737:chemistry*; D053918:Papillomavirus Vaccines / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D013997:Time Factors
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D002945:Cisplatin