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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Anti-tumor effects of genetic vaccines against HPV major oncogenes
Marcelo Nazário Cordeiro1, Francesca Paolini, Silvia Massa
1a Federal University of Pernambuco; Department of Genetics; Laboratory of Molecular Studies and Experimental Therapy (LEMTE); Pernambuco, Brazil.
Abstract:
Expression of HPV E5, E6 and E7 oncogenes are likely to overcome the regulation of cell proliferation and to escape immunological control, allowing uncontrolled growth and providing the potential for malignant transformation. Thus, their three oncogenic products may represent ideal target antigens for immunotherapeutic strategies. In previous attempts, we demonstrated that genetic vaccines against recombinant HPV16 E7 antigen were able to affect the tumor growth in a pre-clinical mouse model. To improve this anti-HPV strategy we developed a novel approach in which we explored the effects of E5-based genetic immunization. We designed novel HPV16 E5 genetic vaccines based on two different gene versions: whole E5 gene and E5Multi. The last one is a long multi epitope gene designed as a harmless E5 version. Both E5 genes were codon optimized for mammalian expression. In addition, we demonstrated that HPV 16 E5 oncogene is expressed in C3 mouse cell line making it an elective model for the study of E5 based vaccine. In this mouse model the immunological and biological activity of the E5 vaccines were assessed in parallel with the activity of anti-E7 and anti-E6 vaccines already reported to be effective in an immunotherapeutic setting. These E7 and E6 vaccines were made with mutated oncogenes, the E7GGG mutant that does not bind pRb and the E6F47R mutant that is less effective in inhibiting p53, respectively. Results confirmed the immunological activity of genetic formulations based on attenuated HPV16 oncogenes and showed that E5-based genetic immunization provided notable anti-tumor effects.
Insights
Human papillomavirus (HPV) oncogenes E5, E6, and E7 drive cancer. This study shows that E5-based genetic vaccines offer a promising new approach for effective anti-tumor immunotherapy against HPV-induced malignancies.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Human papillomavirus (HPV) oncoproteins E5, E6, and E7 promote uncontrolled cell proliferation and immune evasion, leading to malignant transformation.
- These oncogenes are potential targets for cancer immunotherapy.
- Previous studies showed efficacy of genetic vaccines against HPV16 E7 antigen in preclinical models.
Purpose of the Study:
- To investigate the therapeutic potential of novel HPV16 E5-based genetic vaccines.
- To evaluate the immunological and anti-tumor effects of E5 genetic immunization in a preclinical mouse model.
- To compare the efficacy of E5 vaccines with existing E6 and E7 vaccines.
Main Methods:
- Development of HPV16 E5 genetic vaccines using whole E5 gene and a multi-epitope E5 gene (E5Multi), both codon-optimized for mammalian expression.
- Utilized the C3 mouse cell line expressing HPV16 E5 oncogene as a model system.
- Assessed vaccine efficacy in parallel with mutated E6 and E7 vaccines (E6F47R and E7GGG) in a preclinical mouse model.
Main Results:
- Confirmed the immunological activity of genetic vaccines based on attenuated HPV oncogenes.
- Demonstrated that HPV16 E5-based genetic immunization elicited significant anti-tumor effects.
- Showcased the expression of HPV 16 E5 oncogene in the C3 mouse cell line, validating it as a suitable model.
Conclusions:
- E5-based genetic immunization represents a viable and effective immunotherapeutic strategy against HPV-induced tumors.
- Novel E5 genetic vaccines demonstrate notable anti-tumor activity, complementing existing E6 and E7 vaccine approaches.
- The study validates the use of attenuated HPV oncogenes in genetic vaccine design for cancer immunotherapy.
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