Anti-tumor effects of genetic vaccines against HPV major oncogenes

Cordeiro, Marcelo Nazário; Paolini, Francesca; Massa, Silvia; Curzio, Gianfranca; Illiano, Elena; Silva, A.J.D.; Franconi, Rosella; Bissa, Massimiliano; Morghen, Carlo De Giuli; Freitas, Antonio Carlos de; Venuti, Aldo

doi:10.4161/hv.34303

Cited by 16 publications

(15 citation statements)

References 45 publications

(56 reference statements)

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“…The present study also confirms the data from our previous research where similar results were obtained after immunizing mice with only the DNA E6F47RCP and E7GGGCP vaccines by electroporation (Cordeiro et al, 2015). In contrast to that study, most of the mice remained tumor-free up to day 19 p.i.., instead of 13 days p.i., which can be ascribed to the different inoculation systems and the use of the different tumor cells for challenge.…”

Section: Discussionsupporting

confidence: 38%

Prime–boost therapeutic vaccination in mice with DNA/DNA or DNA/Fowlpox virus recombinants expressing the Human Papilloma Virus type 16 E6 and E7 mutated proteins fused to the coat protein of Potato virus X

Illiano

Bissa

Paolini³

et al. 2016

Virus Research

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Highlights FP-E6F47RCP and FP-E7GGGCP correctly express transgenes in different cell lines  After the genetic immunization, tumor volume was lower than in the control mice  Genetic immunization delayed tumor appearance compared to control mice  After DNA/FP vaccination, better results were obtained by E6/E7 single immunogens AbstractThe therapeutic antitumor potency of a prime-boost vaccination strategy was explored, based on the mutated, nontransforming forms of the E6 (E6F47R) and E7 (E7GGG) oncogenes of Human Papilloma Virus type 16 (HPV16), fused to the Potato virus X (PVX) coat protein (CP) sequence. Previous data showed that CP fusion improves the immunogenicity of tumor-associated antigens and may thus increase their efficacy.After verifying the correct expression of E6F47RCP and E7GGGCP inserted into DNA and Fowlpox virus recombinants by Western blotting and immunofluorescence, their combined use was evaluated for therapy in a pre-clinical mouse model of HPV16-related tumorigenicity. Immunization protocols were applied using homologous (DNA/DNA) or heterologous (DNA/Fowlpox) prime-boost vaccine regimens. The humoral 3 immune responses were determined by ELISA, and the therapeutic efficacy evaluated by the delay in tumor appearance and reduced tumor volume after inoculation of syngeneic TC-1* tumor cells. Homologous DNA/DNA genetic vaccines were able to better delay tumor appearance and inhibit tumor growth when DNAE6F47RCP and DNAE7GGGCP were administered in combination. However, the heterologous DNA/Fowlpox vaccination strategy was able to delay tumor appearance in a higher number of animals when E6F47RCP and in particular E7GGGCP were administered alone.

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Section: Discussionsupporting

confidence: 38%

Prime–boost therapeutic vaccination in mice with DNA/DNA or DNA/Fowlpox virus recombinants expressing the Human Papilloma Virus type 16 E6 and E7 mutated proteins fused to the coat protein of Potato virus X

Illiano

Bissa

Paolini³

et al. 2016

Virus Research

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“…20 No difference was detected in CD8C T cell response (data not shown) whereas an higher CD4C T cell response was detected with E5 vaccines respect to E6 or E7 vaccines. This high response was particularly detected with pVAX-E5CP vaccine (Fig.…”

Section: Immunological Response To E5 Vaccinesmentioning

confidence: 83%

“…This improvement was fully achieved. Indeed, previous vaccines made with same E5 or E5Multi sequences were able only to decrease tumor burden 20 whereas new CP fused vaccines were able to cure same C3 tumors. Future development of this therapeutic strategy could be the intra-tumor administration of DNA vaccine as well as heterologous (DNA/protein) prime-boost schedules to be applied together with chemo-radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…In therapeutic setting, all mouse groups were challenged s.c. with 5 £ 10 5 C3-Luc cells and, thereafter, treated with vaccines as in previous report. 20 The mice were monitored by imaging to detect tumor growth. All efforts were made to minimize the number of animals and their suffering.…”

Section: Animals and Vaccination Schedulementioning

confidence: 99%

“…10 6 splenocytes were added to microtiter well that had been pre-coated overnight at 4 C with anti-mouse-IFN-g antibody (5 mg/ml) along with IL-2 (50 units/ml; Sigma-Aldrich Italia, Milan, Italy). Stimulation was performed in triplicates at 37 C for 24-72 h, with the E5-, E6-or E7-specific peptides 20 (synthesized by GenScript, Piscataway, USA). A mixture of phorbol myristate acetate and ionomycin was used to detect splenocyte responsiveness.…”

Section: Ifn-gamma Enzyme-linked Immuno-spot Assay (Elispot)mentioning

confidence: 99%

See 2 more Smart Citations

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.

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Immunotherapy of HPV-associated cancer: DNA/plant-derived vaccines and new orthotopic mouse models

Venuti¹,

Curzio²,

Mariani³

et al. 2015

Cancer Immunol Immunother

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Under the optimistic assumption of high-prophylactic HPV vaccine coverage, a significant reduction of cancer incidence can only be expected after decades. Thus, immune therapeutic strategies are needed for persistently infected individuals who do not benefit from the prophylactic vaccines. However, the therapeutic strategies inducing immunity to the E6 and/or E7 oncoprotein of HPV16 are more effective for curing HPV-expressing tumours in animal models than for treating human cancers. New strategies/technologies have been developed to improve these therapeutic vaccines. Our studies focussed on preparing therapeutic vaccines with low-cost technologies by DNA preparation fused to either plant-virus or plant-toxin genes, such as saporin, and by plant-produced antigens. In particular, plant-derived antigens possess an intrinsic adjuvant activity that makes these preparations especially attractive for future development. Additionally, discrepancy in vaccine effectiveness between animals and humans may be due to non-orthotopic localization of animal models. Orthotopic transplantation leads to tumours giving a more accurate representation of the parent tumour. Since HPV can cause cancer in two main localizations, anogenital and oropharynx area, we developed two orthotopic tumour mouse models in these two sites. Both models are bioluminescent in order to follow up the tumour growth by imaging and are induced by cell injection without the need to intervene surgically. These models were utilized for immunotherapies with genetic or plant-derived therapeutic vaccines. In particular, the head/neck orthotopic model appears to be very promising for studies combining chemo-radio-immune therapy that seems to be very effective in patients.

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Anti-tumor effects of genetic vaccines against HPV major oncogenes

Cited by 16 publications

References 45 publications

Prime–boost therapeutic vaccination in mice with DNA/DNA or DNA/Fowlpox virus recombinants expressing the Human Papilloma Virus type 16 E6 and E7 mutated proteins fused to the coat protein of Potato virus X

Prime–boost therapeutic vaccination in mice with DNA/DNA or DNA/Fowlpox virus recombinants expressing the Human Papilloma Virus type 16 E6 and E7 mutated proteins fused to the coat protein of Potato virus X

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Immunotherapy of HPV-associated cancer: DNA/plant-derived vaccines and new orthotopic mouse models

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