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Abstract
Human papillomavirus (HPV) infections are particularly problematic for HIV + and solid organ transplant patients with compromised CD4+ T cell-dependent immunity as they produce more severe and progressive disease compared to healthy individuals. There are no specific treatments for chronic HPV infection, resulting in an urgent unmet need for a modality that is safe and effective for both immunocompromised and otherwise normal patients with recalcitrant disease. DNA vaccination is attractive because it avoids the risks of administration of live vectors to immunocompromised patients, and can induce potent HPV-specific cytotoxic T cell responses. We have developed a DNA vaccine (pNGVL4a-hCRTE6E7L2) encoding calreticulin (CRT) fused to E6, E7 and L2 proteins of HPV-16, the genotype associated with approximately 90% vaginal, vulvar, anal, penile and oropharyngeal HPV-associated cancers and the majority of cervical cancers. Administration of the DNA vaccine by intramuscular (IM) injection followed by electroporation induced significantly greater HPV-specific immune responses compared to IM injection alone or mixed with alum. Furthermore, pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation of mice carrying an intravaginal HPV-16 E6/E7-expressing syngeneic tumor demonstrated more potent therapeutic effects than IM vaccination alone. Of note, administration of the DNA vaccine by IM injection followed by electroporation elicited potent E6 and E7-specific CD8+ T cell responses and antitumor effects despite CD4+ T cell-depletion, although no antibody response was detected. While CD4+ T cell-depletion did reduce the E6 and E7-specific CD8+ T cell response, it remained sufficient to prevent subcutaneous tumor growth and to eliminate circulating tumor cells in a model of metastatic HPV-16+ cancer. Thus, the antibody response was CD4-dependent, whereas CD4+ T cell help enhanced the E6/E7-specific CD8+ T cell immunity, but was not required. Taken together, our data suggest that pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation warrants testing in otherwise healthy patients and those with compromised CD4+ T cell immunity to treat HPV-16-associated anogenital disease and cancer.
Highlights
Of the over one hundred known Human papillomaviruses (HPVs), a dozen high risk types are associated with cancer
We observed that alum did not further enhance the generation of antigenspecific T cells elicited by IM injection of CRTE6E7L2 DNA vaccine with electroporation (Figure 1B and C)
The mice were boosted with the same regimen twice at a 2-week interval. (C) One week after the last vaccination, serum was collected for the analysis of HPV16 E7-specific antibody response by enzyme-linked immunosorbent assay (ELISA). (D) HPV16 E7-specific CD8+ T cell responses were analyzed by staining PBMCs with HPV16 E7aa49-57 peptide loaded H2-Db tetramer followed by flow cytometry analysis. (E) Two weeks after last vaccination, the mice were challenged with 5 × 104 TC-1 cells subcutaneously
Summary
Of the over one hundred known Human papillomaviruses (HPVs), a dozen high risk types are associated with cancer. These oncogenic types infect the genital mucosa and are sexually transmitted. The oncogenic HPVs are the primary etiologic agents of cervical cancer and are known to cause a subset of head and neck, vaginal, vulvar, anal and penile cancers [1,2,3]. HPV-associated diseases are a significant problem for HIV+ and otherwise immunocompromised patients who are less able to clear their HPV infections than healthy individuals. There remains an urgent need for a therapy to effectively treat chronic oncogenic HPV infection, HPV-16, and associated diseases using an approach that is safe and effective even for immunocompromised patients [7]
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