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

基本信息

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
项目类别：
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

项目摘要

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HER2+乳腺癌（BC）的治疗取得了重大进展，但仍无法治愈。原因是癌症总是会产生对标准疗法的抗性 - 两者都有细胞毒性化学疗法和专门针对HER2的化学疗法。现代尝试改进标准疗法在很大程度上集中于抑制HER2下游信号的药物，但这些均产生只有增量福利。因此，迫切需要新的治疗方法。最近它已经成为清楚地表明HER2+ BC是免疫原性的。 HER2是强烈的肿瘤抗原，而HER2+ BC的一部分携带淋巴细胞浸润，可预测预后的改善。此外，抗HER2抗体运动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理由 HER2+转移性BC的免疫疗法。我们的共同投资者LOI博士最近进行了II期研究 HER2+转移性BC患者（Panacea）患者的曲妥珠单抗和Pembrolizumab（PD-1抑制剂）。这研究符合其主要终点，因此为在HER2+中使用免疫疗法提供了原则证明疾病 - 但是，只有少数患者受益。因此，在项目2中，我们将研究两本小说旨在提高针对HER2+ BC的抗肿瘤免疫反应的治疗方法进一步：使用与曲妥珠单抗和PD-1封锁一起给出的CDK4/6抑制剂（目标一）；以及添加PD- L1封锁和4-1BB激动剂对化学疗法和曲妥珠单抗（目标二）。两种方案都是合理的根据我们令人信服的临床前数据设计，表明这些方法显着放大了反肿瘤免疫学。在每个目标中，我们都将执行一项随机，多中心II期临床试验以确定效率这些新颖的方法。每个目标还将采用“共同临床试验”模型，而小鼠的研究进行了与人类试验平行。动物实验将使用我们的最先进的转基因模型进行人类HER2驱动的乳腺癌（MMTV-RTTA/TETO-HER2）。我们的小鼠研究结合了剪切边缘技术了解这些新型免疫疗法方法的活动机制，如以及抗电阻机制的详细研究（包括下一代测序和多路复用肿瘤组织的免疫荧光分析）。意思是，试验涉及肿瘤活检的串行收集和血液样本。小鼠和患者的生物测量将平行分析，每种都会通知其他。最终，这些研究将：（1）表征高级HER2阳性BC的免疫景观前所未有的细节；（2）确定两种新方法中的任何一种是否都是有效的临床策略；（3）建立每种方案活性的细胞机制；（4）探索治疗机制反抗。这项工作有可能发现新的疗法，以增强对抗的免疫反应 HER2阳性BC，因此可以显着改善患者的预后。