Role of Immunity in Efficacy of Chemotherapy Plus Trastuzumab

描述(由申请人提供)：本提案的主要目标是检查抗HER2疗法的免疫学机制。一般的假设是，曲妥珠单抗与化疗联合使用时，会主动免疫患者，导致产生与治疗效果相关的适应性免疫效应细胞或抗体。在肿瘤部位和区域淋巴结产生并释放到血液中的免疫效应物可能是曲妥珠单抗反应的潜在生物标志物。曲妥珠单抗在一定程度上具有免疫学作用机制，Knutson博士和Clynes博士的初步结果表明，适应性免疫反应是曲妥珠单抗临床作用的原因。免疫生物标记物的一个优点是，简单的抽血可能就足以检测到。我们的具体目标包括：1)确定乳腺癌患者在化疗和曲妥珠单抗治疗期间产生的抗HER2抗体反应是否与临床反应有关。我们将使用从接受化疗和曲妥珠单抗治疗的转移性乳腺癌患者收集的血清样本，对内源性HER2特异性抗体反应进行回顾性分析；2)确定接受化疗和曲妥珠单抗治疗的HER2+乳腺癌患者是否诱导了HER2特异性T细胞免疫反应。我们将进行一项前瞻性研究，评估接受化疗和曲妥珠单抗治疗的乳腺癌患者的T细胞和抗体免疫功能；3)确定联合化疗和曲妥珠单抗治疗的患者无瘤生存率和总生存率的改善是否与FC？患者的受体基因型别。

DESCRIPTION (provided by applicant): The primary objectives of this proposal examine immunologic mechanisms of anti-HER2 therapies. The general hypothesis is that trastuzumab, when combined with chemotherapy, actively immunizes patients leading to the generation of adaptive immune effector cells or antibodies that are associated with therapeutic efficacy. Immune effectors generated at tumor sites and regional lymph nodes and released into blood may be potential biomarkers of trastuzumab response. Trastuzumab has in part an immunologic mechanism of action, and preliminary results from Dr. Knutson and Dr Clynes suggest that an adaptive immune response is responsible for the clinical actions of trastuzumab. An advantage of immune biomarkers is that a simple blood draw may suffice for detection. Our specific aims include: 1) To determine whether anti-HER2 antibody responses, generated during chemotherapy and trastuzumab in breast cancer patients, are associated with clinical responses. We will perform retrospective analyses of endogenous HER2-specific antibody responses using serum samples collected from metastatic breast cancer patients treated with chemotherapy and trastuzumab; 2) To determine whether a HER2-specific T cell immune response is induced in HER2+ breast cancer patients treated with chemotherapy and trastuzumab. We will perform a prospective study evaluating T cell and antibody immunity in adjuvant and metastatic breast cancer patients treated with chemotherapy and trastuzumab; 3) To determine whether the improved disease-free survival and overall survival in patients treated in the adjuvant setting with combination of chemotherapy and trastuzumab is associated with the Fc? receptor genotype of the patient.