Alphavirus-based therapeutic immunization against cervical neoplasia: unraveling immunological mechanisms

PhD ceremony: Mr. M. Walczak, 14.30 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Alphavirus-based therapeutic immunization against cervical neoplasia: unraveling immunological mechanisms

Promotor(s): prof. C.A.H.H. Daemen, prof. H.W. Nijman, prof. J.C. Wilschut

Faculty: Medical Sciences

Cervical cancer is caused by persistent infection with high-risk human papillomavirus (HPV). Prophylactic HPV-vaccination can prevent cervical cancer. Since available prophylactic HPV-vaccines cannot clear existing HPV-infections and commonly used methods to treat cervical cancer have reached the ceiling of their efficacy and may induce severe side effects, it is of great interest to develop novel therapeutic strategies to treat cervical cancer patients. One of these strategies may be immunotherapy as it is known that cellular immunity plays an important role in clearing HPV infection. Recombinant Semliki Forest virus replicon particles encoding a fusion protein of E6 and E7 from HPV type 16 (SFVeE6,7) represent a promising potential candidate for the therapeutic immunization against HPV-induced cervical cancer. In this thesis, tumor-specific immune responses induced by rSFV replicon particles were investigated and selected immunological mechanisms that influence these responses were elucidated. These immune responses were not (or only marginally) hampered by vector-specific immunity and regulatory T cells and could not be further improved using heterologous prime-boost immunization protocols. On the other hand, local tumor irradiation stimulated specific T cell trafficking (induced by rSFV immunization) into the tumor. Taken together, these pre-clinical studies indicate that rSFV replicon particles induce potent T cell immunity. Therefore therapeutic immunization based on the use of rSFV appears to be a promising and feasible approach to treat HPV-induced neoplasia. Clinical trials are required to prove the efficacy of rSFV in humans.