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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：
10455691
负责人：
IAN E KROP
金额：
$ 28.35万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455691
关键词：
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 Human Immune Immune response Immunocompetent Immunologics Immunotherapeutic agent Immunotherapy Laboratories Lead Lymphocytic Infiltrate Malignant Neoplasms Mediator of activation protein 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 Randomized Clinical Trials 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 base chemotherapy co-clinical trial design 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 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.

项目总结