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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Boitano, Teresa K L; Smith, Haller J; Rushton, Tullia et al. (2018) Impact of enhanced recovery after surgery (ERAS) protocol on gastrointestinal function in gynecologic oncology patients undergoing laparotomy. Gynecol Oncol 151:282-286
Anchoori, Ravi K; Jiang, Rosie; Peng, Shiwen et al. (2018) Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. ACS Omega 3:11917-11929
Ooki, Akira; Dinalankara, Wikum; Marchionni, Luigi et al. (2018) Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma. Oncogene 37:5967-5981
Ahn, Julie; Bishop, Justin A; Roden, Richard B S et al. (2018) The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis. Laryngoscope 128:E27-E32
Silver, Michelle I; Rositch, Anne F; Phelan-Emrick, Darcy F et al. (2018) Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30-65 years. Cancer Causes Control 29:43-50
Yang, J-Ming; Bhattacharya, Sayak; West-Foyle, Hoku et al. (2018) Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation. Nat Commun 9:4673
Xing, Deyin; Zheng, Gang; Schoolmeester, John Kenneth et al. (2018) Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix. Am J Surg Pathol 42:750-760
Qiu, Jin; Peng, Shiwen; Ma, Ying et al. (2018) Epithelial boost enhances antigen expression by vaccinia virus for the generation of potent CD8+ T cell-mediated antitumor immunity following DNA priming vaccination. Virology 525:205-215
Ooki, Akira; Begum, Asma; Marchionni, Luigi et al. (2018) Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. Int J Cancer 143:113-126
Leath 3rd, Charles A; Monk, Bradley J (2018) Twenty-first century cervical cancer management: A historical perspective of the gynecologic oncology group/NRG oncology over the past twenty years. Gynecol Oncol 150:391-397

Showing the most recent 10 out of 291 publications