Cervical cancer is the leading cause of
cancer-related deaths among women worldwide. Current prophylactic
vaccines based on HPV (Human papillomavirus) late gene
protein L1 are ineffective in therapeutic settings. Therefore, there is an acute need for the development of therapeutic
vaccines for HPV associated
cancers. The HPV E7
oncoprotein is expressed in
cervical cancer and has been associated with the cellular transformation and maintenance of the transformed phenotype. As such, E7
protein represents an ideal target for the development of therapeutic
subunit vaccines against
cervical cancer. However, the low antigenicity of this
protein may require potent adjuvants for therapeutic efficacy. We recently generated a novel chimeric form of the 4-1BBL costimulatory molecule engineered with core
streptavidin (SA-4-1BBL) and demonstrated its safe and pleiotropic effects on various cells of the immune system. We herein tested the utility of SA-4-1BBL as the immunomodulatory component of HPV-16 E7
recombinant protein based therapeutic
vaccine in the E7 expressing TC-1
tumor as a model of
cervical cancer in mice. A single subcutaneous vaccination was effective in eradicating established
tumors in approximately 70% of mice. The therapeutic efficacy of the
vaccine was associated with robust primary and memory CD4(+) and CD8(+) T cell responses, Th1
cytokine response, infiltration of CD4(+) and CD8(+) T cells into the
tumor, and enhanced NK cell killing. Importantly, NK cells played an important role in
vaccine mediated
therapy since their physical depletion compromised
vaccine efficacy. Collectively, these data demonstrate the utility of SA-4-1BBL as a new class of multifunctional
immunomodulator for the development of therapeutic
vaccines against
cancer and
chronic infections.