Pretreatment with cisplatin enhances E7-specific CD8+ T-Cell-mediated antitumor immunity induced by DNA vaccination.
OBJECTIVE
Because the combination of multiple modalities for cancer treatment is more likely to generate more potent therapeutic effects for the control of cancer, we have explored the combination of chemotherapy using cisplatin, which is routinely used in chemotherapy for advanced cervical cancer, with immunotherapy using DNA vaccines encoding calreticulin (CRT) linked to human papillomavirus type 16 E7 antigen (CRT/E7) in a preclinical model.


METHODS
We characterized the combination of cisplatin with CRT/E7 DNA vaccine using different regimen for its potential ability to generate E7-specific CD8+ T-cell immune responses as well as antitumor effects against E7-expressing tumors.


RESULTS
Our results indicate that treatment of tumor-bearing mice with chemoimmunotherapy combining cisplatin followed by CRT/E7 DNA generated the highest E7-specific CD8+ T-cell immune response and produced the greatest antitumor effects and long-term survival as well as significant levels of E7-specific tumor-infiltrating lymphocytes compared with all the other treatment regimens. Furthermore, we found that treatment with cisplatin leads to the cell-mediated lysis of E7-expressing tumor cells in vitro and increased number of E7-specific CD8+ T-cell precursors in tumor-bearing mice. In addition, we observed that E7-specific CD8+ T cells migrate to and proliferate in the location of TC-1 tumors in mice treated with cisplatin.


CONCLUSIONS
Thus, our data suggest that chemoimmunotherapy using cisplatin followed by CRT/E7 DNA vaccine is an effective treatment against E7-expressing tumors and may potentially be translated into the clinical arena.
Tseng
Chih-Wen
CW
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Hung
Chien-Fu
CF
Alvarez
Ronald D
RD
Trimble
Cornelia
C
Huh
Warner K
WK
Kim
Daejin
D
Chuang
Chi-Mu
CM
Lin
Cheng-Tao
CT
Tsai
Ya-Chea
YC
He
Liangmei
L
Monie
Archana
A
Wu
T-C
TC
D000818:Animals; D019470:Biolistics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D037282:Calreticulin / Q000235:genetics; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D016133:Polymerase Chain Reaction; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*
D037282:Calreticulin; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16; D002945:Cisplatin