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

ABSTRACT: 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 antitumor immunity and induces the regression of breast cancer skin metastases.A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives.Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%-56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines.Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses.

SUBMITTER: Adams S

PROVIDER: S-EPMC3580198 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Adams Sylvia S Kozhaya Lina L Martiniuk Frank F Meng Tze-Chiang TC Chiriboga Luis L Liebes Leonard L Hochman Tsivia T Shuman Nicholas N Axelrod Deborah D Speyer James J Novik Yelena Y Tiersten Amy A Goldberg Judith D JD Formenti Silvia C SC Bhardwaj Nina N Unutmaz Derya D Demaria Sandra S

Clinical cancer research : an official journal of the American Association for Cancer Research 20120705 24

<h4>Purpose</h4>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 antitumor immunity and induces the regression of breast cancer skin metastases.<h4>Experimental design</h4>A prospective clinical trial was designed to evaluate the local tumor response ...[more]

PMID: 22767669

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Project description:ImportanceSalvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod.ObjectiveTo evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall.Design, setting, and particpantsA single arm phase 2 clinical trial of 15 patients with breast cancer previously treated in an academic medical center setting between 2009 and 2012 for chest wall disease that had recurred.InterventionsImiquimod cream, 5%, was applied topically to a designated target lesion once per day for 4 consecutive days on days 1 through 4, 8 through 11, 15 through 18, and 22 through 25 of a 28-day cycle, for 12 weeks. Albumin bound paclitaxel, 100 mg/m2, was given intravenously on days 1, 8, and 15, and repeated every 28 days over the 12-week period.Main outcomes and measuresThe primary endpoint was safety and ORR. Secondary endpoints included the generation of tumor-infiltrating lymphocytes and modulation of immune cell populations.ResultsThe median age at baseline of the 15 study participants was 54 years (range, 46-92 years). Fourteen patients were evaluable. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a compete response and another 5 (36%) were partial responders for an overall response rate of 72% (10 of 14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1)+ peripheral blood T cells (PD-1+ cluster of differentiation [CD]4+; 95% CI, 2.68-6.63; P < .001 and PD-1+CD8+; 95% CI, 1.13-8.35; P = .01) and monocytic myeloid derived suppressor cells (mMDSC) (95% CI, 3.62-12.74; P = .001) greater than controls predicted suboptimal clinical response.Conclusions and relevanceChemoimmunomodulation with a TLR-7 agonist and albumin bound paclitaxel is effective in inducing disease regression in treatment-refractory breast cancer chest wall metastases but responses are short-lived. Preexisting levels of cells indicating either T-cell exhaustion or systemic immunosuppression may be markers of selection for responsive patients.Trial registrationclinicaltrials.gov Identifier: NCT00821964.

Project description:BackgroundImmune-mediated melanoma regression relies on melanoma-reactive T cells infiltrating tumor. Cancer vaccines increase circulating melanoma-reactive T cells, but little is known about vaccine-induced circulating lymphocytes (viCLs) homing to tumor or whether interventions are needed to enhance infiltration. We hypothesized that viCLs infiltrate melanoma metastases, and intratumoral interferon (IFN)-γ or Toll-like receptor 7 (TLR7) agonism enhances infiltration.MethodsPatients on two clinical trials (Mel51 (NCT00977145), Mel53 (NCT01264731)) received vaccines containing 12 class I major histocompatibility complex-restricted melanoma peptides (12MP). In Mel51, tumor was injected with IFN-γ on day 22, and biopsied on days 1, 22, and 24. In Mel53, dermal metastases were treated with topical imiquimod, a TLR7 agonist, for 12 weeks, and biopsied on days 1, 22, and 43. For patients with circulating T-cell responses to 12MP by IFN-γ ELISpot assays, DNA was extracted from peripheral blood mononuclear cells (PBMCs) pre-vaccination and at peak T-cell response, and from tumor biopsies, which underwent T-cell receptor sequencing. This enabled identification of clonotypes induced in PBMCs post-vaccination (viCLs) and present in tumor post-vaccination, but not pre-vaccination.ResultsSix patients with T-cell responses post-vaccination (Mel51 n = 4, Mel53 n = 2) were evaluated for viCLs and vaccine-induced tumor infiltrating lymphocytes (viTILs). All six patients had viCLs, five of whom were evaluable for viTILs in tumor post-vaccination alone. Mel51 patients had viTILs identified in day 22 tumors, post-vaccination and before IFN-γ (median = 2, range = 0-24). This increased in day 24 tumors after IFN-γ (median = 30, range = 4-74). Mel53 patients had viTILs identified in day 22 tumors, post-vaccination plus imiquimod (median = 33, range = 2-64). Three of five evaluable patients across both trials had viTILs with vaccination alone. All five had enhancement of viTILs with tumor-directed therapy. viTILs represented 0.0-2.9% of total T cells after vaccination alone, which increased to 0.6-8.7% after tumor-directed therapy.ConclusionCancer vaccines induce expansion of new viCLs, which infiltrate melanoma metastases in some patients. Our findings identify opportunities to combine vaccines with tumor-directed therapies to enhance T-cell infiltration and T cell-mediated tumor control. These combinations hold promise in improving the therapeutic efficacy of antigen-specific therapies for solid malignancies.

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

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

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