Imiquimod and resiquimod in a mouse model: adjuvants for DNA vaccination by particle-mediated immunotherapeutic delivery

Thomsen, Lindy L.; Topley, Peter; Daly, Maria; Brett, Sara; Tite, J P

doi:10.1016/j.vaccine.2003.09.052

Cited by 96 publications

(64 citation statements)

References 25 publications

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“…These results are consistent with and in support of observations that imiquimod strongly augmented the mounting of a cellular immune response in cutaneous vaccinations with nontumoral antigens (Lore et al, 2003;Thomsen et al, 2004;Zuber et al, 2004), thus employing the same principle as other adjuvants which utilize TLR-dependent signaling cascades in order to enhance activation of cytotoxic T cells (Schwarz et al, 2003). Imiquimodenhanced activation and immigration of cytotoxic T cells has been observed in vaccination studies with melanoma antigens (Shackleton et al, 2004).…”

Section: Cellular Immune Reactions Induced By Imidazoquinolinessupporting

confidence: 87%

TLR7 and TLR8 as targets in cancer therapy

2008

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Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/ 8-mediated activation of the central transcription factor nuclear factor-jB, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2-and caspase-dependent proapoptotic activity against tumor cells.

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Section: Cellular Immune Reactions Induced By Imidazoquinolinessupporting

confidence: 87%

TLR7 and TLR8 as targets in cancer therapy

2008

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“…[14][15][16][17][18][19] The positive effect of Imiquimod and its derivative resiquimod on immune responses to immunization using DNA as the vaccine agent has recently been reported. 18 Both these compounds were found to induce significant increases in cytokine production from antigen-specific T cells when administered in combination with vaccination using plasmid DNA encoding chicken ovalbumin, compared with vaccination without these adjuvants. 18 However, no data has been reported in that paper on their protective effectiveness as …”

Section: Discussionmentioning

confidence: 99%

“…18 Both these compounds were found to induce significant increases in cytokine production from antigen-specific T cells when administered in combination with vaccination using plasmid DNA encoding chicken ovalbumin, compared with vaccination without these adjuvants. 18 However, no data has been reported in that paper on their protective effectiveness as …”

Section: Discussionmentioning

confidence: 99%

“…16,17 A recent investigation has shown the effectiveness of Imiquimod and its derivative resiquimod in inducing immune responses to immunization using a plasmid DNA-encoding chicken ovalbumin. 18 The aim of this study was to evaluate the potential of Imiquimod and the related compound S-27609 as adjuvants in association with an HER2/neu DNA vaccine in a transgenic murine model of HER2/neupositive mammary carcinoma (FVB/neuT transgenic mice). To perform this study, Imiquimod and S-27609 were administered to FVB/neuT mice in association with a plasmid vaccine encoding the extracellular and transmembrane HER2/neu domains; the antitumour effect and the immune response elicited by this vaccination strategy were then analysed.…”

Section: Introductionmentioning

confidence: 99%

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Imiquimod and S-27609 as adjuvants of DNA vaccination in a transgenic murine model of HER2/neu-positive mammary carcinoma

et al. 2005

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DNA vaccination against HER-2/neu is an effective way to induce an immune response able to oppose the spontaneous development of mammary tumours occurring in HER-2/neu transgenic mice. In this study, we have evaluated the potential of Imiquimod and the analogue S-27609 as adjuvants of DNA vaccination against HER-2/neu in transgenic mice. The association of a DNA vaccine encoding a portion of rat HER2/neu with either Imiquimod or S-27609 was found to delay the development of spontaneous mammary tumours and to reduce their incidence, in comparison with DNA vaccination alone. Almost 80 or 40% of tumour-free mice were found at the end of measurement time in mice vaccinated and supplemented with Imiquimod or S-27609, respectively. The antitumour preventive effect was associated with increased antibody and cell-mediated immune responsiveness against HER-2/neu. In mice vaccinated and supplemented with Imiquimod, a small but significant increase of rat p185 neu -specific cytotoxicity and of IFN-g and IL-2-producing CD8T cells, together with a reduction of IL-4-producing CD4T cells, and a switch from an IgG1 towards a IgG2a phenotype of anti-p185 neu antibodies, suggested a TH1 polarization of the immune response. The immunoregulatory efficacy of S-27609 was lower than that observed for Imiquimod. These data highlight the potential of Imiquimod, and, to a lower extent, of S-27609, as immunological adjuvants of therapeutic DNA vaccines.

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“…or s.c. injection of TLR7/8 agonists as adjuvants resulted in enhanced CTL and Th1 antibody responses [69, 134 -136]. In addition to models with viral antigens, s.c. injection of the TLR7/8 agonists imiquimod, resiquimod, poly(U), and ORNs resulted in enhanced antigen-specific T-cell activation and Th1 antibody responses in ovalbumin (OVA) mouse models [60,[137][138][139]. However, more attention has been paid to topical administration of imidazoquinolines, evaluated in OVA, HIV-1, and melanoma models.…”

Section: How Can Cancer Vaccine Approaches Benefit From Tlr7/8 Ligands?mentioning

confidence: 99%

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

et al. 2008

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After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

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Imiquimod and resiquimod in a mouse model: adjuvants for DNA vaccination by particle-mediated immunotherapeutic delivery

Cited by 96 publications

References 25 publications

TLR7 and TLR8 as targets in cancer therapy

TLR7 and TLR8 as targets in cancer therapy

Imiquimod and S-27609 as adjuvants of DNA vaccination in a transgenic murine model of HER2/neu-positive mammary carcinoma

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

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