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: 8090410
• 负责人: LUPE G SALAZAR
• 金额: $ 27.31万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090410
• 关键词: Abraxane; Agonist; Animal Model; Animals; Anogenital venereal warts; Antibodies; Antigen-Presenting Cells; Basal cell carcinoma; Beds; Breast; 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; Health; Hypersensitivity; Imiquimod; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; 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; Population; Production; Property; Radiation therapy; Rattus; Reaction; Recurrence; Reporting; Safety; Serum; Signal Transduction; Site; Skin; Steroids; T cell response; T-Lymphocyte; Taxane Compound; Testing; Therapeutic; Thick; Toll-like receptors; Topical application; Transgenic Mice; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Up-Regulation; adaptive immunity; chemotherapeutic agent; chemotherapy; cytokine; immune activation; immune function; macrophage; malignant breast neoplasm; neoplastic cell; novel; pathogenic bacteria; phase 2 study; pre-clinical; preclinical study; prevent; 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）：乳腺癌皮肤病变可表现为局部胸壁复发或转移性疾病部位，发生于高达30%的乳腺癌患者中。挽救性化疗的总体反应率最多为20- 30%。因此，无论是局部（即胸壁）还是远处转移的皮肤病变的治疗仍然是一个挑战，需要进一步研究新的局部治疗策略。咪喹莫特是一种小分子免疫反应调节剂，产生类似于病原菌的免疫信号，通过toll样受体配体（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。来自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力并诱导显著的肿瘤消退。传统的化疗，如紫杉醇，一种常用的药物在转移性乳腺癌，也可以调节免疫功能。紫杉醇的免疫刺激作用包括刺激IL-12产生和增强NK/LAK细胞活性。Abraxane是一种新的紫杉烷制剂，可以与咪喹莫特结合使用，而不会损害抗肿瘤免疫力，因为它可以在没有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的化学免疫治疗可以导致胸壁或皮肤转移的乳腺癌患者比单独化疗更高的反应率。这项建议的具体目标是：（1）确定局部使用咪喹莫特和Abraxane的化学免疫疗法用于治疗具有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功效，（2）检查由局部使用咪喹莫特和Abraxane组成的化学免疫疗法的治疗是否增强内源性肿瘤特异性免疫，和（3）评估化学免疫疗法是否诱导肿瘤微环境中的分子改变，所述分子改变与肿瘤破坏性适应性免疫相关。公共卫生相关性：胸壁复发或皮肤转移的乳腺癌很难治疗，标准治疗也不容易见效。我们建议用化学免疫疗法治疗胸壁或皮肤乳腺癌患者。咪喹莫特是一种被认为是生物制剂的药物，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，我们将研究该组合是否在局部和全身水平上增强针对患者肿瘤的免疫力。