Phase II Study of Topical Imiquimod and Weekly Abraxane for the Treatment of Brea

描述（由申请人提供）：乳腺癌皮肤病变可以表现为局部胸壁复发或转移性疾病，可发生在高达30%的乳腺癌患者中。补救性化疗的总有效率最多为20-30%。因此，无论是局部的皮肤病变，如胸壁，还是远处转移的治疗仍然是一个挑战，进一步研究新的局部治疗策略是必要的。咪喹莫特是一种小分子免疫反应调节剂，产生类似致病菌的免疫信号，通过toll样受体配体（toll-like receptor ligand， TLR）-7触发免疫激活。咪喹莫特对多种皮肤恶性肿瘤具有临床活性。我们小组的临床前数据显示咪喹莫特在乳腺癌动物模型中增强对肿瘤抗原的免疫，并诱导肿瘤显著消退。传统的化疗，如紫杉醇，一种常用的转移性乳腺癌药物，也可能调节免疫功能。紫杉醇的免疫刺激作用包括刺激IL-12的产生和增强NK/LAK细胞活性。Abraxane是一种新的紫杉烷制剂，可以与咪喹莫特联合使用而不影响抗肿瘤免疫，因为它可以在不需要紫杉醇所需的免疫抑制类固醇预处理的情况下给药。我们假设咪喹莫特和abraxane联合化疗免疫治疗对胸壁或皮肤转移的乳腺癌患者的反应率比单独化疗高。这项建议的具体目的是：(1)确定外用咪喹莫特和Abraxane联合化疗免疫治疗复发性胸壁疾病或皮肤转移的乳腺癌患者的安全性和治疗效果；(2)研究外用咪喹莫特和Abraxane联合化疗免疫治疗是否能增强内源性肿瘤特异性免疫；(3)评估化学免疫治疗是否诱导肿瘤微环境中与肿瘤破坏性适应性免疫相关的分子改变。公共卫生相关性：胸壁复发或皮肤转移的乳腺癌很难治疗，对标准治疗反应不佳。我们建议对患有胸壁或皮肤乳腺癌的患者进行化学免疫治疗。咪喹莫特是一种被认为是一种生物制剂的药物，当应用于皮肤时，它会深刻地刺激局部免疫反应。Abraxane是治疗转移性乳腺癌的常用化疗药物，也可以刺激免疫系统。我们将测试咪喹莫特和abraxane联合治疗胸壁和皮肤乳腺癌转移是否安全有效。此外，我们将研究这种组合是否能增强针对患者肿瘤的免疫力；无论是在地方层面还是在系统层面。

DESCRIPTION (provided by applicant): Breast cancer cutaneous lesions can present either as a local chest wall recurrence or as a site of metastatic disease and will occur in up to 30% of breast cancer patients. Salvage chemotherapy results in overall response rates of 20-30%, at best. Thus, the treatment of cutaneous lesions whether locoregional, i.e. chest wall, or a distant metastasis remains a challenge, and further investigation of novel local treatment strategies are warranted. Imiquimod, a small molecule immune response modifier, generates an immune signal similar to that of pathogenic bacteria, triggering immune activation via toll-like receptor ligand (TLR)-7. Imiquimod has clinical activity against a variety of cutaneous malignancies. Pre-clinical data from our group has shown imiquimod to augment immunity to tumor antigens in an animal model of breast cancer and induce significant tumor regression. Conventional chemotherapy, such as paclitaxel, a commonly used agent in metastatic breast cancer, may also modulate immune function. Immunostimulatory effects of paclitaxel include stimulation of IL-12 production and enhanced NK/LAK cell activity. Abraxane, a new taxane formulation, can be used in conjunction with imiquimod without compromising anti-tumor immunity as it can be administered without the immunosuppressive steroid pre-treatment required with paclitaxel. We hypothesize chemoimmunotherapy with imiquimod and abraxane can lead to higher response rates in breast cancer patients with chest wall or cutaneous metastasis than chemotherapy alone. The specific aims of this proposal are to: (1) determine the safety and therapeutic efficacy of chemoimmunotherapy with topical imiquimod and Abraxane for the treatment of breast cancer patients with recurrent chest wall disease or cutaneous metastasis, (2) examine whether treatment with chemoimmunotherapy consisting of topical imiquimod and Abraxane augments endogenous tumor specific immunity, and (3) assess whether chemoimmunotherapy induces molecular alterations in the tumor microenvironment that have been associated with tumor destructive adaptive immunity. PUBLIC HEALTH RELEVANCE: Breast cancer that has recurred in the chest wall or metastasized in the skin is very difficult to treat and does not respond readily to standard therapy. We propose to treat patients who have chest wall or cutaneous breast cancer with chemoimmunotherapy. Imiquimod is a drug considered to be a biologic agent that profoundly stimulates a local immune response when applied to the skin. Abraxane is a commonly used chemotherapy in the treatment of metastatic breast cancer and can also stimulate the immune system. We will test whether the combination of imiquimod and abraxane is safe and effective in treating chest wall and cutaneous breast cancer metastasis. Moreover, we will study whether the combination boosts immunity directed against the patients tumor; both at the local and systemic level.