DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma

Sloots, Arjen; Mastini, Cristina; Rohrbach, Florian; Weth, Robert; Curcio, Claudia; Burkhardt, Ute; Jäger, Elke; Forni, Guido; Cavallo, Federica; Wels, Winfried S.

doi:10.1158/1078-0432.ccr-08-1257

Cited by 24 publications

(16 citation statements)

References 44 publications

(60 reference statements)

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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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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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“…This is most likely due to central tolerance leading to the selective deletion of CTL clones reacting with the immunodominant epitope (45) and the suppressing activity of regulatory immune cells (46). Similar to CTLA-4 -targeted plasmid vaccines (42), scFv CD11c -neu CpG vaccination likely mediates antitumoral activity in BALB-neuT mice through neu-specific antibodies and possibly CD4 + T cells (43). Recently, it was shown that depletion of regulatory T cells enabled neu-specific CTL responses after vaccination of neu-transgenic FVB/N mice with a cellular vaccine expressing neu and granulocytemacrophage colony-stimulating factor (47).…”

Section: Discussionmentioning

confidence: 99%

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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“…In addition, protein vaccines targeted to DEC205 on DCs improved CD4 + T-cell responses and therefore provided help for DNA vaccines to induce CD8 + T-cell immunity [31]–[34]. Similar approaches were tested for tumor vaccines using fusion of CTLA-4 or CD28 and tumor antigens to enhance specific immunity to tumor antigens [35]–[37]. In addition, targeted protein vaccines of tumor antigens are also found to induce potent antitumor immunity [38].…”

Section: Discussionmentioning

confidence: 99%

DNA Immunization with Fusion of CTLA-4 to Hepatitis B Virus (HBV) Core Protein Enhanced Th2 Type Responses and Cleared HBV with an Accelerated Kinetic

Yin

Song

et al. 2011

PLoS ONE

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BackgroundTypically, DNA immunization via the intramuscular route induces specific, Th1-dominant immune responses. However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4) primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model. Thus, we addressed the question in the mouse model how the Th1/Th2 bias of primed immune responses by a DNA vaccine influences hepatitis B virus (HBV) clearance.Principal FindingsPlasmids expressing HBV core protein (HBcAg) or HBV e antigen and HBcAg fused to the extracellular domain of CTLA-4 (pCTLA-4-HBc), CD27, and full length CD40L were constructed. Immunizations of these DNA plasmids induced HBcAg-specific antibody and cytotoxic T-cell responses in mice, but with different characteristics regarding the titers and subtypes of specific antibodies and intensity of T-cell responses. The plasmid pHBc expressing HBcAg induced an IgG2a-dominant response while immunizations of pCTLA-4-HBc induced a balanced IgG1/IgG2a response. To assess the protective values of the immune responses of different characteristics, mice were pre-immunized with pCTLA-4-HBc and pHBc, and challenged by hydrodynamic injection (HI) of pAAV/HBV1.2. HBV surface antigen (HBsAg) and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups. The clearance of HBsAg was completed within 16 days in immunized mice while more than 50% of the control mice are still positive for HBsAg on day 22. Stronger HBcAg-specific T-cell responses were primed by pHBc correlating with a more rapid decline of HBcAg expression in liver tissue, while anti-HBs antibody response developed rapidly in the mice immunized with pCTLA-4-HBc, indicating that the Th1/Th2 bias of vaccine-primed immune responses influences the mode of viral clearance.ConclusionViral clearance could be efficiently achieved by Th1/Th2-balanced immune response, with a small but significant shift in T-cell and B-cell immune responses.

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DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma

Cited by 24 publications

References 44 publications

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

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

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

DNA Immunization with Fusion of CTLA-4 to Hepatitis B Virus (HBV) Core Protein Enhanced Th2 Type Responses and Cleared HBV with an Accelerated Kinetic

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