Vaccination is the most effective medical intervention to reduce human morbidity and mortality due to infectious diseases. The development of efficacious vaccines for treatment or prevention of cancer has been less successful, which is in part due to a lack of well-defined tumor-specific antigens. Most cervical cancers, the second most common cause of malignancies in women worldwide, are associated with genital infections by human papilloma viruses (HPV) strains, 16 or 18 that express two oncoproteins, i.e., E6 and E7 which might provide highly suitable target antigens for immunological intervention.
The aim of this application is to test three different vaccine prototypes, i.e., DNA vaccines, vaccinia virus recombinants and E1-deleted replication defective adenovirus recombinants expressing the E6 or E7 protein of human papilloma virus (HPV)-16, in a mouse model for their efficacy in limiting the spread of E6 and E7 expressing tumors. The applicant's long-term goal is to develop a vaccine for treatment of women with HPV-16 associated cervical cancer. She has developed a mouse tumor model to study vaccines to E6 and E7 of HPV-16. The applicant also generated a number of vaccines, i.e., DNA vaccines, recombinant vaccinia and E1-deleted adenoviral vaccines, expressing the oncoproteins of HPV-16. All of these types of expression systems, that have distinctive advantages and disadvantages as vaccine carriers, were shown to induce partial protection against a low dose tumor challenge. The applicant's hypothesis is that a combination of different types of vaccines given as prime-boost regimens either alone or with a cytokine adjuvant might significantly improve the efficacy of vaccination in providing long-term protective immunity against HPV-16 E6 and E7 transformed tumors. To test this hypothesis she will initially compare the three different types of vaccines given individually analyzing basic parameters such as the kinetics of the response, dose-response curves, different routes of immunization, effect of pre-existing immunity to the vaccine carrier, and induction of different types of immune responses. The applicant will then test the effect of different vaccine combinations including interleukin(IL)-12 as an adjuvant on solid and metastatic tumors both in a prophylactic immunization model as well as in treatment of already established tumors. In case the applicant's hypothesis is correct, data gathered within the realm of this application will serve as the basis for a clinical Phase I trial.
