Project 2: Combination immunotherapy approaches to overcome therapeutic resistance in HER2-positive breast cancer

项目 2：克服 HER2 阳性乳腺癌治疗耐药性的联合免疫疗法

• 批准号: 10668343
• 负责人: IAN E KROP
• 金额: $ 29.26万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668343
• 关键词: Acceleration; Agonist; Animal Experiments; Antibodies; Biopsy Specimen; Blood specimen; Breast Carcinoma; CDK4 gene; Cancer Center; Cell Cycle; Clinical; Clinical Data; Clinical Trials; Collection; Combination immunotherapy; Cytotoxic Chemotherapy; Data; Development; Disease; Drug resistance; ERBB2 Gene Amplification; ERBB2 gene; Effector Cell; Environment; Genetically Engineered Mouse; Goals; HER2 inhibition; Human; Immune; Immune response; Immunocompetent; Immunologic Stimulation; Immunologics; Immunotherapeutic agent; Immunotherapy; Laboratories; Lymphocytic Infiltrate; Malignant Neoplasms; Mediator; Metastatic breast cancer; Minority; Modeling; Modernization; Mouse Mammary Tumor Virus; Mus; PD-1 blockade; PD-1 inhibitors; PD-L1 blockade; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Pre-Clinical Model; Randomized; Regimen; Research Personnel; Resistance; Resistance development; Running; Sampling; Signal Transduction; Specimen; Technology; Testing; Toxic effect; Transgenic Model; Trastuzumab; Triplet Multiple Birth; Tumor Antigens; Tumor Immunity; Tumor Tissue; Work; anti-tumor immune response; chemotherapy; co-clinical trial; design; efficacy evaluation; human model; immunogenic; improved; improved outcome; inhibitor; malignant breast neoplasm; mouse model; neoplastic cell; next generation sequencing; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pembrolizumab; phase 2 study; pre-clinical; prevent; primary endpoint; programmed cell death ligand 1; programmed cell death protein 1; randomized, clinical trials; rational design; resistance mechanism; synergism; targeted agent; therapy resistant; treatment strategy; tumor; tumor growth; virtual

PROJECT SUMMARY Despite significant advances in the management of metastatic HER2+ breast cancer (BC), it remains incurable. The reason for this is that cancers invariably develop resistance to standard therapies – both cytotoxic chemotherapies and those that specifically target HER2. Modern attempts to improve upon standard therapies have largely focused on agents that inhibit HER2 downstream signaling more potently, but these have yielded only incremental benefits. Therefore, new treatment approaches are urgently needed. Recently it has become clear that HER2+ BCs are immunogenic. HER2 is a strong tumor antigen, and a proportion of HER2+ BCs harbor a lymphocytic infiltrate, which predicts for improved outcomes. In addition, anti-HER2 antibodies exert their effects in part by stimulating immune effector cells. Collectively, these facts provide rationale for testing immunotherapy in HER2+ metastatic BC. Our co-investigator Dr. Loi recently conducted a phase II study of trastuzumab and pembrolizumab (a PD-1 inhibitor) in patients with HER2+ metastatic BC (PANACEA). The study met its primary endpoint and thus provides proof-of-principle for the use of immunotherapy in HER2+ disease – however, only a small minority of patients benefited. In Project 2, we will therefore study two novel therapeutic approaches designed to boost the anti-tumor immune response against HER2+ BC further: the use of CDK4/6 inhibitors, given together with trastuzumab and PD-1 blockade (Aim One); and the addition of PD- L1 blockade and a 4-1BB agonist to chemotherapy and trastuzumab (Aim Two). Both regimens are rationally designed, based on our convincing preclinical data showing that these approaches markedly amplify anti-tumor immunity. In each Aim, we will perform a randomized, multicenter phase II clinical trial to determine the efficacy of these novel approaches. Each Aim will also employ a “co-clinical trial” model, with mouse studies running in parallel to human trials. The animal experiments will be performed using our state-of-the-art transgenic model of human HER2- driven mammary carcinoma (MMTV-rtTA/tetO-HER2). Our mouse studies incorporate cutting- edge technologies to understand the mechanisms of activity for these novel immunotherapy approaches, as well as detailed studies of resistance mechanisms (including next-generation sequencing and multiplexed immunofluorescent profiling of tumor tissue). Meanwhile, the trials involve serial collection of tumor biopsies and blood samples. Biospecimens from mice and patients will be analyzed in parallel, with each informing the other. Ultimately, these studies will: (1) characterize the immune landscape of advanced HER2-positive BC in unprecedented detail; (2) determine whether either of the two novel approaches is an effective clinical strategy; (3) establish cellular mechanisms of activity for each regimen; and (4) explore mechanisms of therapeutic resistance. This work has the potential to uncover new therapies that enhance immune responses against HER2-positive BC, and thus significantly improve patient outcomes.

项目摘要 尽管转移性HER 2+乳腺癌（BC）的管理取得了重大进展，但它仍然无法治愈。 其原因是，癌症总是对标准疗法产生耐药性--这两种疗法都是细胞毒性的， 化疗和特异性靶向HER 2的那些。改进标准疗法的现代尝试 主要集中在更有效地抑制HER 2下游信号传导的药物上，但这些药物已经产生了 只有增量效益。因此，迫切需要新的治疗方法。最近，它已成为 明确HER 2 + BC具有免疫原性。HER 2是一种强肿瘤抗原，一部分HER 2 + BCs 有淋巴细胞浸润预示着预后会有所改善此外，抗HER 2抗体发挥 它们的作用部分是通过刺激免疫效应细胞。总的来说，这些事实为测试提供了依据 HER 2+转移性BC的免疫治疗。我们的合作研究者Loi博士最近进行了一项II期研究， 曲妥珠单抗和派姆单抗（PD-1抑制剂）治疗HER 2+转移性BC患者（PANACEA）。的 研究达到了其主要终点，因此为在HER 2+患者中使用免疫治疗提供了原理证明 然而，只有少数患者受益。因此，在项目2中，我们将研究两个新的 设计用于增强针对HER 2 + BC的抗肿瘤免疫应答的治疗方法， CDK 4/6抑制剂，与曲妥珠单抗和PD-1阻断剂一起给药（Aim One）; L1阻断剂和4-1BB激动剂对化疗和曲妥珠单抗（目的二）。两种方案都是合理的 设计，基于我们令人信服的临床前数据显示，这些方法显着放大抗肿瘤 免疫力在每个目标中，我们将进行一项随机、多中心II期临床试验，以确定疗效 of these novel新approaches方法.每个Aim还将采用“联合临床试验”模型， 与人体试验平行。动物实验将使用我们最先进的转基因模型进行 人HER 2驱动的乳腺癌（MMTV-rtTA/tetO-HER 2）。我们的老鼠研究包括切割- 了解这些新型免疫治疗方法的活性机制的边缘技术， 以及对耐药机制的详细研究（包括下一代测序和多路复用 肿瘤组织的免疫荧光分析）。与此同时，这些试验涉及一系列肿瘤活检样本的收集， 和血液样本将平行分析来自小鼠和患者的生物样本，每个样本将通知研究人员。 其他.最终，这些研究将：（1）表征晚期HER 2阳性BC的免疫状况， 前所未有的细节;（2）确定两种新方法中的任何一种是否是有效的临床策略; (3)建立每种治疗方案的细胞活性机制;（4）探索治疗机制 阻力这项工作有可能发现新的疗法，增强免疫反应， HER 2阳性BC，从而显著改善患者的预后。