Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer.

Medicine, NYU School of Medicine.
Clinical Cancer Research (Impact Factor: 7.84). 07/2012; DOI: 10.1158/1078-0432.CCR-12-1149
Source: PubMed

ABSTRACT PURPOSE: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local anti-tumor immunity and induces the regression of breast cancer skin metastases.EXPERIMENTAL DESIGN: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 days/week for 8 weeks. Safety and immunological correlates were secondary objectives.RESULTS: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1-2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response (20%; 95% CI 3% - 56%). Responders showed histological tumor regression with evidence of an immune-mediated response, demonstrated by changes in the tumor lymphocytic infiltrate and locally produced cytokines. CONCLUSIONS: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a pro-immunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest even superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve anti-tumor immune and clinical responses.

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    ABSTRACT: Radiotherapy can convert malignant cells into an in situ anticancer vaccine, but is often inadequate at generating sufficient pro-inflammatory signals to optimally activate innate and adaptive immune responses. Topical imiquimod is a powerful pro-inflammatory agent with clinical activity against superficial skin cancers. These two modalities appear to complement each other, hence achieving local and systemic tumor control.
    Oncoimmunology. 10/2013; 2(10):e25997.
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    ABSTRACT: Introduction: Toll-like receptors (TLRs) are a crucial part of the innate immunity and present the first line of defense against pathogens. In humans, there are ten TLRs, with TLR3, 7, 8 and 9 located in intracellular vesicles and the remaining expressed on the cell surface. These transmembrane protein receptors recognize a wide range of pathogen components. A large number of TLR agonists, either derived from pathogen components or modified synthetic molecules, were developed and investigated for their ability to stimulate an immune response. Areas covered: This review includes an updated summary (2011 - 2013) of TLR agonists that have been published in patent applications and/or progressed to clinical studies, with an emphasis on their chemical structure, immune response, prophylactic and therapeutic outcomes. Expert opinion: A number of factors have contributed to the design and development of TLR agonists such as solving the crystal structures of TLR bound to their ligands, improvements in our understanding of the signaling pathway activated after TLR stimulation and the identification of the native ligands of all human TLRs. Some of the TLR agonists have been approved for human use by the FDA while others have reached clinical studies in Phases I, II and III. Generally, immunotherapy based on TLR agonists is very promising for the prevention and/or treatment of several disorders including cancer, allergy and microbial infections. However, many TLR agonists were withdrawn from further studies as they either lacked efficacy or caused serious side effects.
    Expert Opinion on Therapeutic Patents 01/2014; · 3.53 Impact Factor
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    ABSTRACT: The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed.
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