Role of Immunity in Efficacy of Chemotherapy Plus Trastuzumab

描述（由申请方提供）：本提案的主要目的是检查抗HER 2治疗的免疫学机制。一般假设是，曲妥珠单抗与化疗联合使用时，可主动免疫患者，导致产生与疗效相关的适应性免疫效应细胞或抗体。在肿瘤部位和局部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应答的潜在生物标志物。曲妥珠单抗部分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。免疫生物标志物的一个优点是简单的抽血就足以进行检测。我们的具体目标包括：1）确定乳腺癌患者化疗和曲妥珠单抗期间产生的抗HER 2抗体应答是否与临床应答相关。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中采集的血清样本对内源性HER 2特异性抗体应答进行回顾性分析; 2）确定接受化疗和曲妥珠单抗治疗的HER 2+乳腺癌患者中是否诱导了HER 2特异性T细胞免疫应答。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辅助和转移性乳腺癌患者的T细胞和抗体免疫; 3）确定在辅助环境中接受化疗和曲妥珠单抗联合治疗的患者的无病生存期和总生存期是否与Fc？患者的受体基因型。 公共卫生相关性：HER 2阳性乳腺癌非常具有侵袭性，占所有乳腺癌病例的15-20%。曲妥珠单抗是一种针对HER 2蛋白的抗体，它彻底改变了这些癌症的治疗方法，但并非所有HER 2阳性患者都对曲妥珠单抗有反应，因此，需要更好地预测曲妥珠单抗反应的其他组织和血液检查，以更有效地个性化治疗。我们建议评估血液免疫细胞作为曲妥珠单抗反应的指标，这可能有助于确定最有可能从曲妥珠单抗中获益的患者。

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. PUBLIC HEALTH RELEVANCE: HER2-positive breast cancers are very aggressive and account for 15-20% of all breast cancer cases. Trastuzumab, an antibody against the HER2 protein, has revolutionized the treatment for these cancers, but not all HER2-positive patients respond to trastuzumab and therefore, additional tissue and blood tests that can better predict the response to trastuzumab are needed to more effectively personalize therapy. We propose to evaluate blood immune cells as indicators of trastuzumab response that may help identify those patients most likely to benefit from trastuzumab.