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

局部用咪喹莫特和每周 Abraxane 治疗 Brea 的 II 期研究

• 批准号: 7631940
• 负责人: LUPE G SALAZAR
• 金额: $ 28.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631940
• 关键词: Abraxane; Agonist; Animal Model; Animals; Anogenital venereal warts; Antibodies; Antigen-Presenting Cells; Basal cell carcinoma; Beds; Breast Cancer Treatment; Breast Carcinoma Metastatic to the Skin; Cancer Patient; Cell surface; Chemical Modifier; Chest Wall Disorder; Chest wall structure; Clinical; Clinical Data; Cutaneous; Cytotoxic T-Lymphocytes; Dendritic Cells; Disease; Distant; Distant Metastasis; Drug Formulations; Excision; Gene Expression; Growth; Hypersensitivity; Imiquimod; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppressive Agents; Immunotherapy; In complete remission; Interferon Type II; Interleukin-12; Investigation; Lead; Lesion; Ligands; Liposomes; Lymphokine-Activated Killer Cells; Major Histocompatibility Complex; Malignant Neoplasms; Mammary Neoplasms; Mastectomy; Mediating; Metastatic Skin Cancer; Modality; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Population; Production; Property; Radiation therapy; Rattus; Reaction; Recurrence; Relapse; Reporting; Safety; Serum; Signal Transduction; Site; Skin; Steroids; T-Cell Proliferation; T-Lymphocyte; Taxane Compound; Testing; Therapeutic; Thick; Toll-like receptors; Topical application; Transgenic Mice; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Up-Regulation; chemotherapeutic agent; chemotherapy; cytokine; immune function; macrophage; malignant breast neoplasm; neoplastic cell; novel; pathogenic bacteria; pre-clinical; preclinical study; prevent; public health relevance; response; small molecule; taxane; treatment strategy; tumor; tumor growth

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.

描述（由申请人提供）：乳腺癌皮肤病变可以作为当地胸壁复发或转移性疾病的部位呈现，并将发生在多达30％的乳腺癌患者中。打捞化疗的总体反应率充其量为20-30％。因此，无论局部区域，即胸壁还是遥远的转移的治疗，对皮肤病变的治疗仍然是一个挑战，并且有必要进一步研究新的局部治疗策略。咪喹莫德（Imiquimod）是一种小分子免疫反应修饰剂，会产生与致病细菌相似的免疫信号，从而通过Toll-like受体配体（TLR）-7触发免疫激活。咪喹莫德具有针对各种皮肤恶性肿瘤的临床活性。来自我们小组的临床前数据已显示咪喹莫德在乳腺癌动物模型中增强对肿瘤抗原的免疫力，并诱导明显的肿瘤消退。常规化学疗法，例如转移性乳腺癌中常用的紫杉醇，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的产生和增强的NK/LAK细胞活性。 Abraxane是一种新的紫杉烷配方，可以与咪喹莫德（Imiquimod）一起使用，而无需损害抗肿瘤免疫力，因为它可以在不使用紫杉醇所需的免疫抑制类固醇预处理的情况下给药。我们假设用咪喹莫德和阿布沙烷的化学免疫疗法比单独的化学疗法相比，胸壁或皮肤转移的乳腺癌患者的反应率更高。该建议的具体目的是：（1）确定化学免疫疗法用局部氨基氨基氨基酯和阿布拉辛的安全性和治疗功效，用于治疗患有复发性胸壁疾病或皮肤转移的乳腺癌患者，（2）是否检查了用于局部性毒素和废料quimod tumiquors tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore tumore（3）化学免疫疗法诱导与肿瘤破坏性适应性免疫相关的肿瘤微环境中的分子改变。公共卫生相关性：在胸壁上复发或在皮肤中转移的乳腺癌很难治疗，并且对标准疗法不容易反应。我们建议治疗患有胸壁或皮肤乳腺癌的患者，并通过化学免疫疗法治疗。咪喹莫德（Imiquimod）是一种被认为是一种生物学剂，当应用于皮肤时会深刻刺激局部免疫反应。 Abraxane是一种用于治疗转移性乳腺癌的常用化疗，也可以刺激免疫系统。我们将测试咪喹莫德和阿布沙烷的组合是否安全有效地治疗胸壁和皮肤乳腺癌转移。此外，我们将研究该组合是否会增强针对患者肿瘤的免疫力。在本地和系统层面。