Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9

Aurisicchio, Luigi; Peruzzi, Daniela; Conforti, Antonella; Dharmapuri, Sridhar; Biondo, Antonella; Giampaoli, Saverio; Fridman, Arthur; Bagchi, Ansu; Winkelmann, Christopher T.; Gibson, Raymond E.; Kandimalla, Ekambar R.; Agrawal, Sudhir; Ciliberto, Gennaro; Monica, Nicola La

doi:10.1158/1078-0432.ccr-08-2628

Cited by 44 publications

(33 citation statements)

References 50 publications

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“…This may be important because Garbi et al have shown that proper activation of endothelium is crucial for the extravasation of tumor-specific T cells from the blood into cancerous tissues (49). The results are also in agreement with the recent two studies documenting that DNA or peptide vaccine in combination with TLR-9 agonists could effectively prevent and treat spontaneous mammary carcinomas in neu-transgenic mice (48,50).…”

Section: Discussionsupporting

confidence: 84%

Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice

Wei

Wang

Zhang

et al. 2009

Clinical Cancer Research

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Purpose: CD11c is an antigen receptor predominantly expressed on dendritic cells (DC), to which antigen targeting has been shown to induce robust antigen-specific immune responses. To facilitate targeted delivery of tumor antigens to DCs, we generated fusion proteins consisting of the extracellular domain of human HER or its rat homologue neu, fused to the single-chain fragment variable specific for CD11c (scFv Dendritic cells (DC) are key initiators and modulators ofadaptive T-cell responses due to their outstanding ability to capture and process antigen, to present antigen-derived peptides in the context of MHC molecules to naive T cells, and to deliver appropriate costimulatory signals that dictate either immunogenic or tolerogenic T-cell stimulation (1, 2).These unique features of DCs to regulate adaptive immunity suggest that significant clinical benefits could be gained from directly targeting antigens to DCs in vivo (3, 4). Coupling of antigens to ligands or antibodies that specifically bind to DC receptors has been widely investigated as a means of such targeting (3 -5). The outcome of the immune response induced by targeting antigens to DCs depends on multiple parameters, including the specific receptor targeting, distribution of the targeted receptor among DC subsets, and the presence or absence of coadministered adjuvant (6 -16). Using such an approach, a lowered requirement for antigen dose in stimulating immune responses in mice has been observed after targeting a variety of molecules, including MHC class II, CD11c, DEC205, DCIR2, Dectin-1/2, CD80/86, F4/80-like receptor, CIRE, mannose receptor, and CD36 (7 -16). In addition, in vitro and in vivo studies have shown that antibodies specific for the mannose receptor or DC-SIGN can effectively deliver antigen to human DCs, indicating that this strategy will also be applicable to human vaccination (17,18).Overexpression of the HER-2 receptor tyrosine kinase has been found in various human malignancies, including breast, ovarian and gastric carcinomas, non -small cell lung cancer, and salivary gland cancers,

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Section: Discussionsupporting

confidence: 84%

Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice

Wei

Wang

Zhang

et al. 2009

Clinical Cancer Research

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“…23,40,41 Given the importance of antibodies in anti-HER-2/neu immunity, potent immunotherapy regimens against HER-2/neu-positive tumors may be designed by combining hN'-neu-shFoxo3 DNA vaccination with passive immunization with anti-p185neu antibodies. Furthermore, other strategies that can elicit both strong antibody and T-cell immune responses to the HER-2/neu antigen, such as the addition of mLAG-3Ig 42 or a TLR-9 43 agonist in the DNA vaccination or the fusion of the extracellular domain of the CTLA-4 to the HER-2/neu, 44 may confer synergistic antitumor effects against HER-2/neu-positive tumors and could be attractive regimens for translation to a clinical setting. In summary, for the first time, we present evidence demonstrating that the silencing of Foxo3 in DCs in vivo by the HER-2/neu DNA vaccine represents an innovative and effective approach to enhance the HER-2/neu antigen-specific CD8 + T-cell immune responses and therapeutic antitumor effects.…”

Section: Discussionmentioning

confidence: 99%

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

Chang

Yen

et al. 2010

Gene Ther

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The transcription factor Forkhead box O3 (Foxo3) has a critical role in suppressing the expansion of antigen-specific effector T-cell populations; hence, Foxo3 is a potential target for enhancing the antitumor immunity of cancer vaccines. In this report, we evaluated the potential of RNA interference (RNAi)-mediated silencing of Foxo3 in antigen-presenting cells as an adjuvant for HER2/neu DNA cancer vaccines. Bicistronic plasmids expressing the N-terminal extracellular domain of human HER-2/neu and the Foxo3 short hairpin RNA (hN'-neu-Foxo3 shRNA) or the scrambled control (hN'-neu-scramble shRNA) were subcutaneously injected into mice by gene gun administration to elicit antitumor immunity against p185neu-overexpressing MBT-2 bladder tumor cells. We found that mice treated with hN'-neu-Foxo3 shRNA showed greater reductions in tumor growth and longer survival times than mice treated with hN'-neu-scramble shRNA, indicating that the silencing of Foxo3 enhanced the antitumor efficacy of the HER-2/neu cancer vaccine. Cytotoxicity analyses further revealed that the Foxo3 shRNA-enhanced antitumor effect was associated with significant increases in the number of functional CD8 + T cells and in the levels of cytotoxic T lymphocytes activity. Interleukin-6 was induced by hN'-neu-Foxo3 shRNA treatment but did not have a critical role in the antitumor effect of the hN'-neu-Foxo3 shRNA vaccine. Moreover, in vivo lymphocyte depletion analyses confirmed that the antitumor efficacy of the hN'-neu-Foxo3 shRNA vaccine depended on functional CD8 + T cells. Finally, Foxo3 suppression was shown to markedly improve the effect of the HER-2/neu DNA vaccine in limiting the growth and lung metastases of MBT-2 cells. Overall, these results support RNAi-mediated silencing of Foxo3 as an effective strategy to enhance the therapeutic antitumor effect of HER-2/neu DNA vaccines against p185neu-positive tumors.

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“…This might be caused partly by the immunosuppressive environment of tumors (13). However, preclinical data suggests that by increasing costimulatory "danger" signals, immunosuppressive mechanisms could be overridden (4,13,14). Oncolytic replication provides strong danger signals and lysis of tumor cells releases tumor-associated antigens for sampling (15).…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

et al. 2010

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Granulocyte macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific cytotoxic T-cells through antigen-presenting cells. Oncolytic tumor cell-killing can produce a potent costimulatory danger signal and release of tumor epitopes for antigen-presenting cell sampling. Therefore, an oncolytic adenovirus coding for GMCSF was engineered and shown to induce tumor-specific immunity in an immunocompetent syngeneic hamster model. Subsequently, 20 patients with advanced solid tumors refractory to standard therapies were treated with Ad5-D24-GMCSF. Of the 16 radiologically evaluable patients, 2 had complete responses, 1 had a minor response, and 5 had disease stabilization. Responses were frequently seen in injected and noninjected tumors. Treatment was well tolerated and resulted in the induction of both tumor-specific and virus-specific immunity as measured by ELISPOT and pentamer analysis. This is the first time that oncolytic virus-mediated antitumor immunity has been shown in humans. Ad5-D24-GMCSF is promising for further clinical testing.

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Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9

Cited by 44 publications

References 50 publications

Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice

Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

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