A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors.
Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6(Δ)/E7(Δ)) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV-specific immune response. Moreover, E6(Δ)/E7(Δ) plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.
Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57104, USA.
B G
BG
Wieking
D W
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Vermeer
W C
WC
Spanos
K M
KM
Lee
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P
Vermeer
W T
WT
Lee
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Xu
E S
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Gabitzsch
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Balcaitis
J P
JP
Balint
F R
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Jones
J H
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Lee
D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology / Q000628:therapy; D053918:Papillomavirus Vaccines / Q000235:genetics / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*
D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16