Successful therapeutic vaccination with integrase defective lentiviral vector expressing nononcogenic human papillomavirus E7 protein

Grasso, Felicia; Negri, Donatella; Mochi, Stefania; Rossi, Alessandra; Cesolini, Armando; Giovannelli, Andrea; Chiantore, Maria Vincenza; Leone, Pasqualina; Giorgi, Colomba; Cara, Andrea

doi:10.1002/ijc.27676

Cited by 37 publications

(39 citation statements)

References 41 publications

(52 reference statements)

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“…The distinct role of Th2 cells in tumor eradication in vivo has also been previously shown [31]. Immunization with mutant forms of E7 protein as a safer variant has been previously shown to induce effective antitumor activity [32,33]. In the present study, both E7 and E7GGG proteins formulated with Montanide ISA 266 elicited moderately effective immune response against TC-1 induced tumors.…”

Section: Discussionsupporting

confidence: 75%

Preparation and in vivo anti-tumor evaluation of human papillomavirus E7 adjuvanted with Montanide ISA 266 as a vaccine candidate

Shirazi

Roohvand

Arashkia

2016

vacres

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Introduction: Human papillomavirus (HPV) 16 E7 protein is expressed constitutively by HPV-infected tumor cells. Mutant versions of E7 are considered as safer candidates for immunotherapy of cervical cancer. Different strategies including formulation with adjuvants are used to induce a potent immune response against antigenic proteins. Methods: In this experimental study, we used Escherichia coli as a host to recombinantly express wild-type E7 and its mutant non-oncogenic form as E7GGG. We formulated both antigens with Montanide ISA 266 adjuvant and evaluated IFN-γ and IL-4 cytokines and antibody levels and also tumor regression in tumor-harboring C57BL/6 mice. Results: It was demonstrated that formulation of E7 and E7GGG antigens with Montanide ISA 266 resulted in a Th2-biased immune response. In the therapeutic mouse model, these formulations resulted in significant tumor regression compared to the control group. Conclusion: The formulation of the wild-type E7 and mutant E7GGG with Montanide ISA 266 might not be an optimal approach to regress TC-1 induced tumor; however, such combinations might be considered as an additive approach for stimulating the immune responses.

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Section: Discussionsupporting

confidence: 75%

Preparation and in vivo anti-tumor evaluation of human papillomavirus E7 adjuvanted with Montanide ISA 266 as a vaccine candidate

Shirazi

Roohvand

Arashkia

2016

vacres

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“…9,24 In the current study, immunization with HBcAg-E7 49-57 VLPs elicited almost complete suppression of the growth of tumors of diameter 2-3 mm. Considering that larger tumors might have a more severely immunosuppressive microenvironment, which may affect vaccine efficacy, we performed vaccinations when the tumor grew to ~5-6 or even 8-9 mm to further assess the potential of a VLP-based vaccine.…”

Section: Discussionsupporting

confidence: 51%

Chimeric HBcAg virus-like particles presenting a HPV 16 E7 epitope significantly suppressed tumor progression through preventive or therapeutic immunization in a TC-1-grafted mouse model

Chu¹,

Li²,

Long³

et al. 2016

IJN

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Background Therapeutic human papillomavirus (HPV) vaccines are currently being developed. However, no therapeutic efficacy has been achieved in clinical trials for the treatment of cervical intraepithelial neoplasia or cancer. One of the important issues in increasing vaccine efficacy is determining the best way to enhance tumor antigen-specific cellular immune responses. This study aimed to explore the virus-like particles (VLPs) of hepatitis B core antigen (HBcAg) as potential therapeutic vaccine carriers and to assess its immunological characteristics. Methods Chimeric VLPs presenting a HPV 16 cytotoxic T lymphocytes epitope E7 49–57 (amino acid 49–57 of the E7 protein) were prepared using recombinant genes. C57BL/6 mice were immunized with VLPs and grafted with tumor cells TC-1 which is an E7-expressing tumorigenic cell line. The dynamic tumor growth was monitored and anti-tumor immune responses were investigated. Results Using a preventive strategy, immunization with VLPs resulted in nearly complete suppression of tumor growth. In treatment studies, VLP immunization significantly suppressed the tumor progression in mice carrying 2–3 mm tumors and in those bearing even larger tumors with diameters up to 8–9 mm. The VLP structure was shown to be important to induce vigorous antitumor immunity and effects. In immunized mice, enhanced E7 49–57 -specific cellular immune responses were evidenced by increased interferon (IFN)-γ expression and decreased interleukin (IL)-4 expression in splenic lymphocytes, as well as an elevated number of effector cells expressing IFN-γ in response to the in vitro stimulation of the specific peptide E7 49–57 . In addition, effective immune memory after VLP immunization was maintained for at least 16 weeks, preventing significant tumor growth after subsequent TC-1 challenge. Conclusion While VLPs were highly immunogenic in stimulating humoral immunity, our results strongly indicated that VLPs, such as HBcAg particles, might also be potent therapeutic vaccine carriers to elicit robust cellular immune responses, even in the immunosuppressive microenvironment of a tumor.

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“…The filters were saturated overnight with 5% non fat dry milk (NFDM) in PBST (PBS with 0.1% Tween 20) and then incubated with a rabbit anti-OVA polyclonal antibody (AB1225, Millipore) for 1 hr at room temperature, followed by incubation for 1 hr at room temperature with an anti-rabbit HRP-conjugated IgG (Sigma). The immunocomplexes were visualized using chemiluminescence ECL detection system (Luminata Crescendo Western HRP Substrate, Millipore) [30].…”

Section: Methodsmentioning

confidence: 99%

“…Several reports have shown that IDLVs are suitable for delivery of vaccine antigens in preventive vaccine strategies [23]–[29], demonstrating that immunization with IDLVs induced strong and protective antigen-specific immune responses, in absence of vector integration. Moreover, we recently demonstrated that therapeutic vaccination with IDLV expressing HPV-E7 as a tumor antigen results in eradication of TC-1 derived tumor in tumor-bearing mice [30]. However, while the efficacy of intramuscular immunization with IDLV at inducing systemic antigen-specific immune responses after a single immunization is well established, no data are available concerning the mucosal immune responses.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Mucosal Responses after Intramuscular Immunization with Integrase Defective Lentiviral Vector

et al. 2014

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Many infectious agents infiltrate the host at the mucosal surfaces and then spread systemically. This implies that an ideal vaccine should induce protective immune responses both at systemic and mucosal sites to counteract invasive mucosal pathogens. We evaluated the in vivo systemic and mucosal antigen-specific immune response induced in mice by intramuscular administration of an integrase defective lentiviral vector (IDLV) carrying the ovalbumin (OVA) transgene as a model antigen (IDLV-OVA), either alone or in combination with sublingual adjuvanted OVA protein. Mice immunized intramuscularly with OVA and adjuvant were compared with IDLV-OVA immunization. Mice sublingually immunized only with OVA and adjuvant were used as a positive control of mucosal responses. A single intramuscular dose of IDLV-OVA induced functional antigen-specific CD8+ T cell responses in spleen, draining and distal lymph nodes and, importantly, in the lamina propria of the large intestine. These results were similar to those obtained in a prime-boost regimen including one IDLV immunization and two mucosal boosts with adjuvanted OVA or vice versa. Remarkably, only in groups vaccinated with IDLV-OVA, either alone or in prime-boost regimens, the mucosal CD8+ T cell response persisted up to several months from immunization. Importantly, following IDLV-OVA immunization, the mucosal boost with protein greatly increased the plasma IgG response and induced mucosal antigen-specific IgA in saliva and vaginal washes. Overall, intramuscular administration of IDLV followed by protein boosts using the sublingual route induced strong, persistent and complementary systemic and mucosal immune responses, and represents an appealing prime-boost strategy for immunization including IDLV as a delivery system.

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Successful therapeutic vaccination with integrase defective lentiviral vector expressing nononcogenic human papillomavirus E7 protein

Cited by 37 publications

References 41 publications

Preparation and in vivo anti-tumor evaluation of human papillomavirus E7 adjuvanted with Montanide ISA 266 as a vaccine candidate

Preparation and in vivo anti-tumor evaluation of human papillomavirus E7 adjuvanted with Montanide ISA 266 as a vaccine candidate

Chimeric HBcAg virus-like particles presenting a HPV 16 E7 epitope significantly suppressed tumor progression through preventive or therapeutic immunization in a TC-1-grafted mouse model

Optimization of Mucosal Responses after Intramuscular Immunization with Integrase Defective Lentiviral Vector

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