Abstract

HPV-associated cancer incidence is significantly elevated in cervical and at othersitesinHIV+patients.HIV+patientsacquiremorefrequentmulti-typeinfections,includingmanygenotypes infrequentlyseeninhealthyindividuals,andnottargetedbythecurrentHPVpreventivevaccines.Wepreviously developedacandidatetherapeuticandpreventiveHPVvaccine,pNGVL4a-CRTE6E7L2(CRTE6E7L2),which comprisesaDNAvectorencodingtheheatshockproteincalreticulinfusedgeneticallywithHPV16E6andE7 (that are obligately expressed in HPV malignancies) as well as the L2 capsid protein (a broadly protective antigen). We showed that fusion with calreticulin (CRT) profoundly enhances the potency of DNA vaccines in generating HPV antigen-specific CD8+ T cell mediated immune responses even in CD4-depleted animals. In addition, vaccination with the CRTE6E7L2 DNA vaccine induces both L2-specific neutralizing antibodies and protectionfromexperimentalvaginalchallenge.ThesefeaturesmaketheCRTE6E7L2DNAvaccineparticularly promisingforuseinHIV+patients,achallenginggrouptotreat,andtopreventmultipletypesofHPVinfections. Although DNA vaccines are relatively safe and well suited for multiple administrations, they generally exhibit suboptimal immunogenicity when administered by conventional intramuscular needle injection, likely reflect inefficienthostcelltransduction.WehavepreviouslyshownthatelectroporationisamuchmoreeffectiveDNA vaccine administration method to generate HPV-specific CD8+ T cell immune responses as compared to conventionalintramuscularinjectionorepidermaldeliveryviagenegun.Thus,thegoalofthisproposalistouse the Ichor TriGrid? Delivery System Electroporation Device, which has been used in multiple clinical trials, for intramuscularadministrationoftheCRTE6E7L2DNAvaccineatescalatingdosesinbothHIV?andHIV+patients with HPV16-associated high-grade cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3), and to examine thesafety,virologic,anddiseaseoutcomes.
The SpecificAims ofthisstudyareto(1)evaluatethesafetyand toxicity of CRTE6E7L2 administered via electroporation in HIV? and HIV+ patients with HPV16+ CIN2/3;? (2) characterizetheHPV16E6/E7-specificcell-mediatedandhumoralimmuneresponsesinHIV?andHIV+patients with HPV16+ CIN2/3 vaccinated with CRTE6E7L2 via electroporation;? (3) characterize L2-specific humoral immune responses in HIV? and HIV+ patients with HPV16-associated CIN2/3 upon vaccination with CRTE6E7L2DNAvaccineviaelectroporation;?and(4)determinetheHPVloadandhistopathologicalchanges inthelesionanditsmicroenvironmentinHIV?andHIV+patientswithHPV16-associatedCIN2/3upontreatment withCRTE6E7L2DNAvaccineviaelectroporation.Thesuccessfulimplementationofourproposalwillprovide a new methodology for the treatment of HPV-associated high-grade squamous intraepithelial lesions in HIV? andHIV+patients.

Public Health Relevance

Humanpapillomavirus(HPV)type16infectioncauses50-60%ofallcervicalcancers(and~90%ofotherHPV- associatedanogenitalandoropharyngealcancers),andHIVco-infectionincreasesriskforcancerprogression. HereweproposetotestacandidatetherapeuticandpreventiveHPVvaccineinHIV?andHIV+womeninwhom bothHPV16andtheprecursorlesionofcervicalcancer(CIN2/3)havebeendetected.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA098252-16
Application #
9792861
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205

  Publications

Powell, T Clark; Dilley, Sarah E; Bae, Sejong et al. (2018) The Impact of Racial, Geographic, and Socioeconomic Risk Factors on the Development of Advanced-Stage Cervical Cancer. J Low Genit Tract Dis 22:269-273
Cheng, Max A; Farmer, Emily; Huang, Claire et al. (2018) Therapeutic DNA Vaccines for Human Papillomavirus and Associated Diseases. Hum Gene Ther 29:971-996
Lin, Yi-Hsin; Yang, Ming-Chieh; Tseng, Ssu-Hsueh et al. (2018) Integration of Oncogenes via Sleeping Beauty as a Mouse Model of HPV16+ Oral Tumors and Immunologic Control. Cancer Immunol Res :
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

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