ANTIBODY THERAPY FOR BREAST CANCER: INVESTIGATION OF IMMUNE MODULATION WITH IL-21

乳腺癌抗体治疗：IL-21 免疫调节研究

• 批准号: 7313944
• 负责人: WILLIAM E. CARSON
• 金额: $ 39.21万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313944
• 关键词: Aftercare; Antibody Therapy; Cell membrane; Cells; Clinical; Clinical Trials; Diagnosis; ERBB2 gene; Gene Expression; Immune; Immune response; Immunoglobulin Constant Region; Immunoglobulin G; Interferon Type II; Interferons; Investigation; Lead; Locally Metastatic; Membrane Microdomains; Mitogen-Activated Protein Kinases; Monoclonal Antibodies; Mus; NK Cell Activation; Natural Killer Cells; Paclitaxel/Trastuzumab; Patients; Personal Satisfaction; Production; Proto-Oncogenes; Role; Signal Transduction; T-Lymphocyte; Testing; Transcription Factor AP-1; Trastuzumab; Treatment Efficacy; United States; cancer therapy; chemokine; chemotherapy; cytokine; design; immunoregulation; interleukin-21; malignant breast neoplasm; neoplastic cell; peripheral blood; pre-clinical; receptor; research study; response; success; tumor; tumor eradication

Of the 215,000 new cases of breast cancer that will be diagnosed in the United States in 2006, about 25% will over-express the HER2/neu proto-oncogene. Only about half of these patients will benefit from administration of the humanized anti-HER2/neu monoclonal antibody (mAb)trastuzumab with chemotherapy and none will be cured. There is no clear mechanism of action for trastuzumab therapy although it is possible that innate immune cells bearing receptors (R) for the Fc (or "constant") region of immunoglobulin are involved. We hypothesized that co-stimulation of these FcR-bearing cells with specific activating factors would significantly enhance the immune response to Ab-coated tumor cells. Indeed, we found that treatment of natural killer (NK) cells with interleukin-21 (IL-21) and immobilized IgG led to synergistic production of interferon-gamma (IFN-K) and T cell-attracting chemokines as compared to cells treated with IL-21 or IgG alone. Co-stimulation of NK cells in this manner via the IL-21R and FcpRllla led to prolonged activation of the mitogen-activated protein (MAP) kinase Erk (which was critical for NK cell cytokine secretion) and synergistic induction of the AP-1 transcription factor. We also found that the synergistic production of IFN-K by co-stimulated NK cells was dependent upon the presence of specialized signaling platforms within the NK cell membrane called lipid rafts. Our murine studies showed that IL-21 significantly enhanced the anti-tumor activity of a murine anti-HER2/neu breast cancer mAb and that this effect was dependent upon endogenously-produced IFN-K. Other cytokines have been employed in combination with mAbs with modest success, but the unique actions of IL-21 make it a superior choice for use in the setting of trastuzumab therapy: IL-21 is well-tolerated, is able to activate both NK cells and CDS* T cells, and induces a unique array of immune activating cytokines. In this proposal we will investigate the role of lipid rafts and Erk-induced AP-1 in stimulating IFN- y gene expression and the mechanism by which IFN-y promotes survival in mice receiving IL-21 and the anti-HER2 mAb. We also plan to conduct a clinical trial of IL-21 in combination with trastuzumab/paclitaxel in patients with metastatic and locally-advanced breast cancers. Patient tumors and peripheral blood immune cells will be evaluated before and after treatment in order to identify the mechanisms responsible for tumor eradication. The pre-clinical and clinical experiments proposed in this project are designed to elucidate the specific mechanisms by which administration of IL-21 enhances the activity of trastuzumab. This information should lead to further clinical trials that will test the efficacy of this therapeutic combination in patients with HER2 (+) breast cancer. We believe that these studies will identify new strategies for modulating NK cell activation in response to Ab- coated targets and that this information will lead to improvements in the mAb therapy of cancer.

在2006年在美国诊断出的215,000例新的乳腺癌病例中，约有25％ 将过表达HER2/NEU原型癌基因。这些患者中只有大约一半会从中受益 施用人源化抗HER2/NEU单克隆抗体（MAB）曲妥珠单抗 化学疗法，无法治愈。曲妥珠单抗治疗没有明确的作用机制 尽管有可能带有FC（或“常数”）区域的先天免疫细胞（R） 涉及免疫球蛋白。我们假设这些含FCR细胞与特定 激活因子将显着增强对AB涂层肿瘤细胞的免疫反应。确实，我们 发现用白介素21（IL-21）和固定IgG的天然杀手（NK）细胞的处理导致 与细胞相比 单独用IL-21或IgG处理。通过IL-21R和Fcprllla以这种方式共同刺激NK细胞导致 有丝分裂原活化蛋白（MAP）激酶ERK的长时间激活（对于NK细胞至关重要 AP-1转录因子的细胞因子分泌）和协同诱导。我们还发现 共同刺激的NK细胞对IFN-K的协同产生取决于专业的存在 NK细胞膜中的信号平台称为脂质筏。我们的鼠研究表明IL-21 显着增强了鼠抗Her2/neu乳腺癌mab的抗肿瘤活性，这是 效应取决于生产的IFN-K。其他细胞因子已在 结合MAB的成功率谦虚，但IL-21的独特动作使其成为卓越的选择 在曲妥珠单抗治疗的环境中使用：IL-21的耐受性良好，能够激活NK细胞和CDS* T细胞，并诱导独特的免疫激活细胞因子。在此提案中，我们将调查 脂质筏和ERK诱导的AP-1在刺激基因表达和机制中的作用 IFN-Y促进接受IL-21和抗HER2 MAB的小鼠的生存。我们还计划进行临床 IL-21与曲妥珠单抗/紫杉醇结合的试验在转移和局部促进的患者中 乳腺癌。患者肿瘤和周围血液免疫细胞将在之前和之后评估 治疗以确定负责消除肿瘤的机制。临床前和临床 该项目中提出的实验旨在阐明特定机制 IL-21的给药增强了曲妥珠单抗的活性。这些信息应导致进一步的临床 试验将测试这种治疗组合在HER2（+）乳腺癌患者中的功效。我们 认为这些研究将确定针对AB-调节NK细胞激活的新策略 涂层靶标，此信息将导致癌症mAb治疗的改善。