Enhanced Therapeutic Effects Conferred by an Experimental DNA Vaccine Targeting Human Papillomavirus-Induced Tumors

被引:23
作者
Diniz, Mariana O. [1 ]
Cariri, Francisco A. M. O. [1 ]
Aps, Luana R. M. M. [1 ]
Ferreira, Luis C. S. [1 ]
机构
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Vaccine Dev Lab, BR-05508900 Sao Paulo, Brazil
关键词
T-CELL RESPONSES; CERVICAL INTRAEPITHELIAL NEOPLASIA; IMMUNE-RESPONSES; FUSION PROTEIN; IN-VIVO; CANCER PATIENTS; GLYCOPROTEIN-D; CTL RESPONSES; TYPE-16; E6; GM-CSF;
D O I
10.1089/hum.2013.102
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Human papillomavirus (HPV) infection is responsible for all cervical cancer cases, other anogenital cancers, and head and neck tumors. The epidemiological relevance of HPV-induced tumors reinforces the need for the development of therapeutic antitumor vaccines. Clinical trials with different vaccine formulations, particularly DNA vaccines, have provided promising results but have still been unable to achieve the immunogenicity required for use in infected patients. In experimental conditions, anticancer HPV-specific vaccines induced E7-specific CD8(+) T-cell responses but did not confer full therapeutic antitumor protection in mice with transplanted HPV-expressing TC-1 cells, which are the most frequently used nonclinical protection correlate for antitumor effects. Our group has developed a DNA vaccine strategy based on the fusion of HPV oncoproteins to the herpes virus gD protein. This vaccine promoted the induction of antigen-specific cytotoxic CD8(+) T-cell responses and partial antitumor therapeutic effects based on the blockade of coinhibitory signals and the enhancement of coactivation mechanisms. In the present study, we report conditions leading to full therapeutic antitumor effects using the TC-1 cell murine model after a single vaccine dose. The combination of a coadministered plasmid encoding IL-2, optimization of the coding sequence for mammalian cells, and the use of different delivery routes resulted in enhancements of the E7-specific cytotoxic CD8(+) T-cell responses and full therapeutic protection under experimental conditions. The combination of these strategies augmented the potency of the DNA vaccine formulation to levels not previously achieved by other therapeutic antitumor vaccines under similar experimental conditions, including some that have been taken to clinical trials.
引用
收藏
页码:861 / 870
页数:10
相关论文
共 59 条
[41]   Purified Herpes Simplex Type 1 Glycoprotein D (gD) Genetically Fused with the Type 16 Human Papillomavirus E7 Oncoprotein Enhances Antigen-Specific CD8+ T Cell Responses and Confers Protective Antitumor Immunity [J].
Porchia, Brum. F. M. M. ;
Diniz, Mariana O. ;
Cariri, Francisco A. M. O. ;
Santana, Vinicius C. ;
Amorim, Jaime H. ;
Balan, Andrea ;
Braga, Catarina J. M. ;
Ferreira, Luis Carlos S. .
MOLECULAR PHARMACEUTICS, 2011, 8 (06) :2320-2330
[42]   EXPERIENCE WITH THE USE OF HIGH-DOSE INTERLEUKIN-2 IN THE TREATMENT OF 652 CANCER-PATIENTS [J].
ROSENBERG, SA ;
LOTZE, MT ;
YANG, JC ;
AEBERSOLD, PM ;
LINEHAN, WM ;
SEIPP, CA ;
WHITE, DE .
ANNALS OF SURGERY, 1989, 210 (04) :474-485
[43]   Involvement of HVEM receptor in activation of nuclear factor κB by herpes simplex virus 1 glycoprotein D [J].
Sciortino, Maria Teresa ;
Medici, Maria Antonietta ;
Marino-Merlo, Francesca ;
Zaccaria, Daniela ;
Giuffre-Cuculletto, Maria ;
Venuti, Assunta ;
Grelli, Sandro ;
Mastino, Antonio .
CELLULAR MICROBIOLOGY, 2008, 10 (11) :2297-2311
[44]   Immunotherapy of human cervical high-grade cervical intraepithelial neoplasia with microparticle-delivered human papillomavirus 16 E7 plasmid DNA [J].
Sheets, EE ;
Urban, RG ;
Crum, CP ;
Hedley, ML ;
Politch, JA ;
Gold, MA ;
Muderspach, LI ;
Cole, GA ;
Crowley-Nowick, PA .
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2003, 188 (04) :916-926
[45]   Regulation of T-helper-1 versus T-helper-2 activity and enhancement of tumor immunity by combined DNA-based vaccination and nonviral cytokine gene transfer [J].
Song, K ;
Chang, Y ;
Prud'homme, GJ .
GENE THERAPY, 2000, 7 (06) :481-492
[46]   The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation [J].
Steinberg, Marcos W. ;
Cheung, Timothy C. ;
Ware, Carl F. .
IMMUNOLOGICAL REVIEWS, 2011, 244 :169-187
[47]   Enhancement of the immunogenicity of an alphavirus replicon-based DNA vaccine against classical swine fever by electroporation and coinjection with a plasmid expressing porcine interleukin 2 [J].
Tian, Da-Yong ;
Sun, Yuan ;
Wai, Sing Fai ;
Lee, Fuk Ki ;
Meng, Qi-Lin ;
Suen, Kar Man ;
Wang, Nan ;
Han, Wen ;
Li, Su ;
Li, Yong-Feng ;
Li, Dan ;
Ling, Li-Jun ;
Liao, Ya-Jin ;
Qiu, Hua-Ji .
VACCINE, 2012, 30 (24) :3587-3594
[48]   The combination of GM-CSF and IL-2 as local adjuvant shows synergy in enhancing peptide vaccines and provides long term tumor protection [J].
Toubaji, Antoun ;
Hill, Sarah ;
Terabe, Masaki ;
Qian, Jiahua ;
Floyd, Tamara ;
Simpson, R. Mark ;
Berzofsky, Jay A. ;
Khleif, Samir N. .
VACCINE, 2007, 25 (31) :5882-5891
[49]   Serological response to an HPV16 E7 based therapeutic vaccine in women with high-grade cervical dysplasia [J].
Van Doorslaer, Koenraad ;
Reimers, Laura L. ;
Studentsov, Yevgeniy Y. ;
Einstein, Mark H. ;
Burk, Robert D. .
GYNECOLOGIC ONCOLOGY, 2010, 116 (02) :208-212
[50]   Vaccine-Induced Effector-Memory CD8+ T Cell Responses Predict Therapeutic Efficacy against Tumors [J].
van Duikeren, Suzanne ;
Fransen, Marieke F. ;
Redeker, Anke ;
Wieles, Brigitte ;
Platenburg, Gerard ;
Krebber, Willem-Jan ;
Ossendorp, Ferry ;
Melief, Cornelis J. M. ;
Arens, Ramon .
JOURNAL OF IMMUNOLOGY, 2012, 189 (07) :3397-3403