Article

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.

0 Bookmarks
 · 
95 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Radiation research. 06/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guérin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.
    Oncoimmunology. 09/2012; 1(6):894-907.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Small molecule Toll-like receptor (TLR) 7/8 agonists have demonstrated potential as vaccine adjuvants, since they directly activate APCs and can enhance both humoral and cellular immune responses, especially Th1 responses. Although the natural ligands for TLR7 and TLR8 are ssRNA, the vast majority of vaccine studies performed thus far have been performed with synthetic small molecule imidazoquinolines, such as imiquimod and resiquimod. Despite the approved clinical use of the topical TLR7 agonist, imiquimod (Aldara(®) Imiquimod 5% cream; 3M, MN, USA), for external genital warts, superficial basal cell carcinoma and actinic keratosis, no vaccines using TLR7, TLR8 or TLR7/8 agonists have progressed beyond early-phase clinical studies thus far. This review will highlight the nonclinical and clinical studies that indicate promise for TLR7/8 ligands as vaccine adjuvants, reasons for inconsistent results thus far, problems with current technology and potential paths forward for TLR7/8 agonists as vaccine adjuvants.
    Expert Review of Vaccines 07/2013; 12(7):809-19. · 4.22 Impact Factor

Full-text

View
0 Downloads
Available from
Nov 4, 2014