Abstract
Antigen-specific
immunotherapy and vascular disrupting agents, such as
5,6-dimethylxanthenone-4-acetic acid (
DMXAA), have emerged as attractive approaches for the treatment of
cancers. In the current study, we tested the combination of
DMXAA treatment with therapeutic human papillomavirus type 16 (HPV-16) E7
peptide-based vaccination for their ability to generate E7-specific CD8+ T-cell immune responses, as well as their ability to control E7-expressing
tumors in a subcutaneous and a cervicovaginal
tumor model. We found that the combination of
DMXAA treatment with E7 long
peptide (
amino acids 43-62) vaccination mixed with polyriboinosinic:polyribocytidylic generated significantly stronger E7-specific CD8+ T-cell immune responses and antitumor effects compared with treatment with
DMXAA alone or HPV
peptide vaccination alone in the subcutaneous model. Additionally, we found that the
DMXAA-mediated enhancement of E7-specific CD8+ T-cell immune responses generated by the therapeutic HPV
peptide-based
vaccine was dependent on the timing of administration of
DMXAA. Treatment with
DMXAA in
tumor-bearing mice was also shown to lead to increased dendritic cell maturation and increased production of inflammatory
cytokines in the
tumor. Furthermore, we observed that the combination of
DMXAA with
HPV-16 E7 peptide vaccination generated a significant enhancement in the antitumor effects in the cervicovaginal TC-1
tumor growth model, which closely resembles the tumor microenvironment of
cervical cancer. Taken together, our data demonstrated that administration of the vascular disrupting agent,
DMXAA, enhances therapeutic
HPV vaccine-induced cytotoxic T-lymphocyte responses and antitumor effects against E7-expressing
tumors in two different locations. Our study has significant implications for future clinical translation.