Oncogenic human papillomaviruses (HPVs) are the etiologic agents of 99% of cervical cancer, but HPV16 is the most important type as it causes half of all cervical cancer cases and >90% of HPV-associated cancers at other sites. The inability of licensed vaccines to eliminate existing HPV infections is a major unmet medical need since there is a considerable burden of HPV-associated disease worldwide, and implementation of HPV vaccination in the US has been limited. HPV-associated cancer incidence is also significantly elevated in cervical and at other sites in HIV+ patients. HIV+ patients acquire more frequent multi-type infections, including many genotypes infrequently seen in healthy individuals, and not targeted by the current HPV vaccines. In this SPORE we developed a candidate therapeutic and preventive HPV vaccine, pNGVL4ahCRTE6E7L2, which comprises a DNA vector encoding calreticulin (CRT) fused genetically with HPV16 E6, E7 (that are expressed in all HPV infected cells) and L2 capsid protein (a broadly protective antigen). Fusion with the heat shock protein CRT has been shown to enhance the potency of DNA vaccines, even in CD4 depleted animals, making the pNGVL4a-hCRTE6E7L2 DNA vaccine particularly promising for use in HIV+ patients, a particularly challenging group to treat. Although DNA vaccines are relatively safe, they generally exhibit suboptimal immunogenicity when administered by conventional intramuscular needle injection, likely reflecting inefficient host cell transduction. We have previously shown that electroporation was the most effective DNA vaccine administration method to generate HPV-specific CD8+ T cell immune responses, compared to conventional intramuscular injection and epidermal delivery via gene gun. Here we propose to use the Ichor TriGrid Electroporation Device, which has been used in multiple clinical trials, for intramuscular administration of pNGVL4a-hCRTE6E7L2 DNA vaccine at escalating doses in HIV- and HIV+ patients with HPV16-associated high-grade cervical intraepithelial neoplasia (CIN 2/3) and to examine the safety, virologic and disease outcomes. The systemic and local immune responses will be correlated with these outcomes as well as lesional expression of PD-L1, a pathway associated with immune escape.
HIV+ and otherwise immunocompromised patients exhibit more severe and progressive HPV infections than healthy individuals, and consequently cervical cancer has been designated an HIV-associated malignancy. Here we examine a novel vaccine construct delivered via a new methodology intedned for the treatment of HPV-associated high-grade SIL lesions, even in HIV+ patients, and to prevent new HPV infections.
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