Topical TLR7 Agonist Imiquimod Can Induce Immune-Mediated Rejection of Skin Metastases in Patients with Breast Cancer

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. Methods 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. Conclusion 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.

Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming

“…Strategies to enhance the antitumor immune effects of radiotherapy have been explored in preclinical models, and results from pioneering clinical research have also been reported (28). For instance, mouse tumor lesions were treated with the TLR7 agonist imiquimod cream (42,43), or injected with TLR9 CpG agonist nucleotides showing evidence for stronger immunity with the ability to partially tackle distant disease (44,45). In the clinic, strategies based on combinations of radiotherapy with imiquimod (42) or subcutaneous GM-CSF (46) have been reported with promising proof-of-concept results.…”

The TLR-specific adjuvants R-848 and CpG-B endorse the immunological reaction of neonatal antigen-presenting cells

“…For example, R-848 directly conjugated to HIV-1 Gag protein enhanced the Ag-specific IgG and CD8-T-cell response (25)(26)(27). In clinical setting, only imiquimod (synthetic TLR7 agonist) was evaluated as cancer vaccine adjuvants, boosting Ag-specific antibodies and CD4 T-cell response in cancer patients (28,29). The adjuvant activity of synthetic TLR9 ligands was evaluated in various human clinical trials including malaria (13,30), influenza (31) and hepatitis B.…”

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2016

“…A pro spective case series was published by Adams et al [110], eval uating the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 days/ week for 8 weeks. 10 patients were enrolled.…”