Article

Topical Imiquimod has Therapeutic and Immunomodulatory Effects Against Intracranial Tumors

Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Journal of immunotherapy (Hagerstown, Md.: 1997) (Impact Factor: 4.01). 03/2011; 34(3):264-9. DOI: 10.1097/CJI.0b013e318209eed4
Source: PubMed

ABSTRACT

Topical imiquimod cream (trade name: Aldara) is a Toll-like receptor (TLR) 7 agonist that is approved for the treatment of cutaneous tumors. Aldara is also used as a vaccine adjuvant in clinical trials in patients with glioma and other tumors. The main mechanism of action ascribed to Aldara has been the local activation of TLR7(+) cells near the application site. Here we report the unexpected finding that Aldara has therapeutic and immunomodulatory activity as a single agent in mice bearing intracranial tumors. Repeated administration of Aldara onto the skin significantly increased the survival of mice bearing intracranial GL261 glioma and EMT6 breast carcinoma. Aldara treatment was associated with a reduction in the number CD4(+)Foxp3(+) regulatory T cells in the blood and brain tumor site. Mice treated with Aldara exhibited a generalized lymphopenia in the blood amidst an increase in brain tumor infiltrating CD4(+) and CD8(+) T cells and dendritic cells. Brain-infiltrating CD8(+) T cells were tumor reactive as demonstrated by degranulation and interferon-γ secretion in a GL261-dependent manner. In addition, soluble imiquimod directly inhibited the proliferation of GL261 cells in a TLR7-independent manner. This is the first report demonstrating that topical application of imiquimod can enhance T-cell responses to intracranial tumors as a single agent. The results must be interpreted with caution considering anatomical and biological differences between mice and humans. Nevertheless, Aldara that is being used as a vaccine adjuvant in clinical trials may have direct antitumor effects that are independent of exogenous antigen. Further studies in humans are warranted.

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Available from: Zhengming Xiong, Aug 17, 2014
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    • "These results support the hypothesis that skin TLR7 ligand application principally is able to modulate systemic leukocyte numbers. Additionally, repeated skin administration of imiquimod in mice has been reported to significantly improve the survival of animals bearing intracranial tumors [20] supporting the concept of systemic immunomodulation after skin TLR7 triggering. In agreement with this concept, we did find significant modulation of respiratory leukocyte cytokine production capacity even at low imiquimod doses (0.12 mg/d) that did exert no or only minor effects on respiratory leukocyte numbers. "
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