The TLR7 Agonist Imiquimod Enhances the Anti-Melanoma Effects of a Recombinant Listeria monocytogenes Vaccine

Division of Dermatology, Department of Medicine and Specialty Training and Advanced Research Program, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1747, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2005; 175(3):1983-90. DOI: 10.4049/jimmunol.175.3.1983
Source: PubMed


Activation of innate immune cells through TLR triggers immunomodulating events that enhance cell-mediated immunity, raising the possibility that ligands to these receptors might act as adjuvants in conjunction with T cell activating vaccines. In this report, topical imiquimod, a synthetic TLR7 agonist, significantly enhanced the protective antitumor effects of a live, recombinant listeria vaccine against murine melanoma. This tumor protective effect was not dependent on direct application to the tumor and was associated with an increase in tumor-associated and splenic dendritic cells. Additionally, the combination of imiquimod treatment with prior vaccination led to development of localized vitiligo. These findings indicate that activation of the innate immune system with TLR ligands stimulates dendritic cell activity resulting in a bypass of peripheral tolerance and enhanced antitumor activity. The results of these studies have broad implications for future designs of immunotherapeutic vaccines against tumors and the treatment of metastatic melanoma.

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Available from: Noah Craft, Sep 12, 2014
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    • "In addition 1V136 is orally bioavailable, and could potentially be combined with other treatments [5], [34]. The Food and Drug Administration (FDA) has approved topical TLR7 active therapies and experimental systemic treatments have been well tolerated in humans [35], [36], [37], [38], [39], [40], [41]. "
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    ABSTRACT: The Toll-like receptors (TLR) have been advocated as attractive therapeutic targets because TLR signaling plays dual roles in initiating adaptive immune responses and perpetuating inflammation. Paradoxically, repeated stimulation of bone marrow mononuclear cells with a synthetic TLR7 ligand 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (called 1V136) leads to subsequent TLR hyporesponsiveness. Further studies on the mechanism of action of this pharmacologic agent demonstrated that the TLR7 ligand treatment depressed dendritic cell activation, but did not directly affect T cell function. To verify this mechanism, we utilized experimental allergic encephalitis (EAE) as an in vivo T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP)(139-151) peptide had attenuated disease severity, reduced accumulation of mononuclear cells in the central nervous system (CNS), and limited demyelination, without any apparent systemic toxicity. Splenic T cells from treated mice produced less cytokines upon antigenic rechallenge. In the spinal cords of 1V136-treated EAE mice, the expression of chemoattractants was also reduced, suggesting innate immune cell hyposensitization in the CNS. Indeed, systemic 1V136 did penetrate the CNS. These experiments indicated that repeated doses of a TLR7 ligand may desensitize dendritic cells in lymphoid organs, leading to diminished T cell responses. This treatment strategy might be a new modality to treat T cell mediated autoimmune diseases.
    Full-text · Article · Sep 2012 · PLoS ONE
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    • "Cells were initially gated on live cells area by FSC x SSC analysis, then gated the CD3 positive/CD8 positive/Thy1.1 positive (staining for pmel-1 T cells), followed by TGFβ RII levels analysis. Intracellular IFN-γ staining was done as described previously [22]. Briefly, 1million cells were stimulated with 1 μM specific peptide (gp100(25–33)) or non-relevant peptide Ovalbumin, plus brefeldin A (BD Pharmingen) and 50 U/ml IL-2, for six hours at 37°C in 5% CO2. "
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    ABSTRACT: Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFbeta), which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFbeta by transduction with a TGFbeta dominant negative receptor II (DN), were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-gamma in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer.
    Full-text · Article · Jun 2012 · Journal of Translational Medicine
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    • "Imiquimod has been widely used off-label in cases of lentigo maligna (LM) and cutaneous metastatic melanoma (Naylor et al., 2003;Cotter et al., 2008;Buettiker et al., 2008;Powell et al., 2009). Additionally, others and we have demonstrated the ability of imiquimod to enhance vaccine-associated protection against melanoma in mice (Ma et al., 2010;Craft et al., 2005;Prins et al., 2006). Although surgical excision is generally the main treatment modality for both LM and invasive melanoma, imiquimod has been used in patients with confounding co-morbidities which limit their surgical candidacy, and in patients with tumors in anatomic areas that would lead to aesthetic or functional impairments. "
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    ABSTRACT: Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.
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