Synergistic antitumor effect of a human papillomavirus DNA vaccine harboring E6E7 fusion gene and vascular endothelial growth factor receptor 2 gene

Abstract

Human papillomavirus (HPV) has been identified as the primary etiological factor in cervical cancer as well as in subsets of anogenital and oropharyngeal cancers. The two HPV viral oncoproteins, E6 and E7, are uniquely and consistently expressed in all HPV-infected cells and are therefore promising targets for therapeutic vaccination. In order to achieve a synergistic antitumor and anti-angiogenesis effect, we designed and constructed a novel DNA vaccine that can express the HPV 16 E6E7 fusion protein and VEGFR2 in the same reading frame. A series of DNA plasmids encoding E6E7, VEGFR2 and their conjugates were constructed and injected into mice. The resultant humoral and cellular immune responses were detected by ELISA and enzyme-linked immunospot (ELISPOT), respectively. To evaluate the antitumor efficacy of these plasmids, tumor-bearing mice expressing the E6E7 fusion protein were constructed. After injection into the tumor-bearing mouse model, the plasmid harboring the E6E7 fusion gene and VEGFR2 showed stronger inhibition of tumor growth than the plasmid expressing E6E7 or VEGFR2 alone, which indicated that the combination of E6E7 and VEGFR2 could exert a synergistic antitumor effect. These observations emphasize the potential of a synergistic antitumor and anti-angiogenesis strategy using a DNA vaccine, which could be a promising approach for tumor immunotherapy.

Tumor vaccines: Toward multidimensional anti-tumor therapies

“…In fact, DNA vaccines encoding VEGFR2 and many other different tumor antigens have produced significant tumor treatment, protection and survival benefits in mouse tumor models such as metastatic melanoma, 88 , 89 lung cancer 90 and cervical cancer. 91 Among them, the DNA vaccine encoding VEGFR2 and mouse MHCI heavy chain (H-2D b ) 88 or IL-12 89 enhanced the immune system’s recognition of VEGFR2 antigen and CTL response, and reduced the intratumoral blood vessel density. Whether it was DNA vaccine encoding VEGFR2 and HPV16E6E7 antigen 91 /MUC1 antigen 90 or nanoliposomal VEGFR2 peptide vaccine, 92 it could reduce tumor vascular density and kill tumor cells by promoting VEGFR2-specific and E6E7/MUC1 antigen-specific CTL response.…”

“… 91 Among them, the DNA vaccine encoding VEGFR2 and mouse MHCI heavy chain (H-2D b ) 88 or IL-12 89 enhanced the immune system’s recognition of VEGFR2 antigen and CTL response, and reduced the intratumoral blood vessel density. Whether it was DNA vaccine encoding VEGFR2 and HPV16E6E7 antigen 91 /MUC1 antigen 90 or nanoliposomal VEGFR2 peptide vaccine, 92 it could reduce tumor vascular density and kill tumor cells by promoting VEGFR2-specific and E6E7/MUC1 antigen-specific CTL response. Importantly, these vaccines also increased the release of IFN- γ and IL-4 to enhance anti-tumor immunity mediated by Th1 and Th2 immune responses.…”

Promising immunotherapy: Highlighting cytokine‐induced killer cells

“…20 Oncotic virus-based vaccines Oncotic viruses capable of selectively infecting cancer cells and leading to direct lysis, can disrupt tumor vasculature and induce antitumor immune responses. 21 The association between immune activation and oncotic virus efficacy has brought interest in those viruses that have the potentiality of encoding immune stimulatory agents. 21 Of these viruses, talimogene laherparepvec (T-VEC) received FDA approval in 2015.…”

“…21 The association between immune activation and oncotic virus efficacy has brought interest in those viruses that have the potentiality of encoding immune stimulatory agents. 21 Of these viruses, talimogene laherparepvec (T-VEC) received FDA approval in 2015. T-VEC is an intratumor injection of herpes simplex virus type 1 which is genetically modified to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) in the tumor microenvironment leading into tumor lysis.…”

Trial watch: DNA-based vaccines for oncological indications

“…This vaccine was more efficient at controlling the growth of TC-1 tumors in vivo than vaccines targeting E6 and E7 or VEGFR2 alone. 199 Finally, Ahrends et al (from the Netherlands Cancer Institute-Amsterdam, The Netherlands) described a mechanism by which CD4 C T cells can be harnessed to improve CD8 C T cell responses upon intradermal DNA immunization via CD27 signaling. In particular, this group used HELP-E7SH DNA-based vaccines (which contain elements that enforce ER localization as well as several other immunostimulatory sequences) to generate an effective immune reaction against E7 from HPV16.…”