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.

2006 年美国将诊断出 215,000 例乳腺癌新病例，其中约 25% 会过度表达 HER2/neu 原癌基因。这些患者中只有大约一半会受益 人源化抗 HER2/neu 单克隆抗体 (mAb) 曲妥珠单抗与 化疗也无法治愈。曲妥珠单抗治疗尚无明确的作用机制 尽管先天免疫细胞可能携带 Fc（或“恒定”）区域的受体 (R) 免疫球蛋白参与其中。我们假设这些带有 FcR 的细胞与特定的共刺激 激活因子将显着增强对抗体包被肿瘤细胞的免疫反应。确实，我们 发现用白细胞介素 21 (IL-21) 和固定化 IgG 处理自然杀伤 (NK) 细胞会导致 与细胞相比，协同产生干扰素-γ (IFN-K) 和 T 细胞吸引趋化因子 单独用 IL-21 或 IgG 治疗。以这种方式通过 IL-21R 和 FcpRIIIa 共刺激 NK 细胞导致 丝裂原激活蛋白 (MAP) 激酶 Erk 的长时间激活（这对于 NK 细胞至关重要） 细胞因子分泌）和 AP-1 转录因子的协同诱导。我们还发现 共刺激的 NK 细胞协同产生 IFN-K 取决于特化因子的存在 NK 细胞膜内的信号平台称为脂筏。我们的小鼠研究表明 IL-21 显着增强了鼠抗 HER2/neu 乳腺癌单克隆抗体的抗肿瘤活性，并且该 效果取决于内源产生的 IFN-K。其他细胞因子已被用于 与 mAb 组合取得了一定的成功，但 IL-21 的独特作用使其成为以下药物的最佳选择： 用于曲妥珠单抗治疗：IL-21 耐受性良好，能够激活 NK 细胞和 CDS* T 细胞，并诱导一系列独特的免疫激活细胞因子。在本提案中，我们将调查 脂筏和 Erk 诱导的 AP-1 在刺激 IFN-γ 基因表达中的作用及其机制 IFN-γ 可促进接受 IL-21 和抗 HER2 mAb 的小鼠的存活。我们还计划进行临床 IL-21 联合曲妥珠单抗/紫杉醇治疗转移性和局部晚期患者的试验 乳腺癌。患者肿瘤和外周血免疫细胞将在治疗前后进行评估 治疗以确定消除肿瘤的机制。临床前和临床 该项目提出的实验旨在阐明具体机制 IL-21的施用增强了曲妥珠单抗的活性。这些信息应该会导致进一步的临床 试验将测试这种治疗组合对 HER2 (+) 乳腺癌患者的疗效。我们 相信这些研究将确定调节 NK 细胞激活以响应 Ab-的新策略 涂层靶标，这些信息将导致癌症单克隆抗体疗法的改进。