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Published on: March 8, 2012
Intravaginal HPV DNA vaccination with electroporation induces local CD8+ T-cell immune responses and antitumor
11] Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China [2] Departments of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Abstract:
Therapeutic human papillomavirus (HPV) vaccines have the potential to inhibit the progression of an established HPV infection to precancer and cancer lesions by targeting HPV oncoproteins. We have previously developed a therapeutic DNA vaccine encoding calreticulin (CRT) linked to E7, CRT/E7 DNA vaccine, for use in the treatment of HPV-associated lesions. Since the transfection efficiency of DNA vaccines administered in vivo is typically low, we examined the use of electroporation as well as different routes of administration to enhance antigen-specific tumor control. We tested the effects of the CRT/E7 DNA vaccine administered intramuscularly or intravaginally, with or without electroporation, on the generation of CD8+ T-cell immunity and therapeutic antitumor effects in HPV16 E7-expressing cervicovaginal tumor-bearing mice. We found that intravaginal vaccination of CRT/E7 DNA followed by electroporation-induced potent E7-specific CD8(+) T-cell responses in the cervicovaginal tract, compared with intramuscular injection followed by electroporation. Furthermore, tumor-bearing mice vaccinated intravaginally followed by electroporation had an enhanced survival, antitumor effects and local production of IFN-γ+CD8+ T cells compared with those vaccinated intramuscularly with electroporation. Thus, we show that intravaginal CRT/E7 DNA vaccination followed by electroporation generates the most potent therapeutic antitumor effects against an orthotopic E7-expressing tumor model. The current study will have significant clinical implications once a clinically applicable electroporation device for intravaginal use becomes available.
Insights
Intravaginal delivery of a therapeutic DNA vaccine targeting human papillomavirus (HPV) E7 oncoproteins, combined with electroporation, significantly enhances anti-tumor immunity and survival in mice with HPV-associated cervical cancer.
Area of Science:
- Immunology
- Vaccinology
- Oncology
Background:
- Therapeutic vaccines targeting human papillomavirus (HPV) oncoproteins aim to prevent HPV infection progression to precancer and cancer.
- A DNA vaccine encoding calreticulin (CRT) linked to E7 (CRT/E7 DNA vaccine) was previously developed for HPV-associated lesions.
- Low in vivo DNA vaccine transfection efficiency necessitates strategies to enhance antigen-specific tumor control.
Purpose of the Study:
- To evaluate the efficacy of the CRT/E7 DNA vaccine administered via different routes (intramuscular vs. intravaginal) with or without electroporation.
- To assess the impact on CD8+ T-cell immunity and therapeutic antitumor effects in a mouse model of HPV16 E7-expressing cervicovaginal tumors.
Main Methods:
- Mice bearing orthotopic HPV16 E7-expressing cervicovaginal tumors were vaccinated with CRT/E7 DNA vaccine.
- Vaccination was administered via intramuscular or intravaginal routes, with or without electroporation.
- Humoral and cellular immune responses, including CD8+ T-cell immunity and IFN-γ production, were analyzed.
Main Results:
- Intravaginal vaccination with CRT/E7 DNA followed by electroporation induced potent E7-specific CD8+ T-cell responses in the cervicovaginal tract.
- This approach significantly enhanced survival and antitumor effects compared to intramuscular vaccination with electroporation.
- Enhanced local production of IFN-γ+CD8+ T cells was observed with the intravaginal plus electroporation strategy.
Conclusions:
- Intravaginal CRT/E7 DNA vaccination combined with electroporation is the most effective strategy for therapeutic antitumor effects against orthotopic E7-expressing tumors.
- This approach holds significant clinical potential for treating HPV-associated cancers, pending development of clinical intravaginal electroporation devices.
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