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Targeted MEK inhibition to enhance immunotherapy in cholangiocarcinoma

靶向 MEK 抑制可增强胆管癌的免疫治疗

基本信息

批准号：
10004585
负责人：
Nilofer Azad
金额：
$ 42.42万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004585
关键词：
Address Antigens Antitumor Response Apoptotic Area Biological Markers Biopsy Biopsy Specimen Blood specimen CD8-Positive T-Lymphocytes CD8B1 gene Cancer Therapy Evaluation Program Cell Compartmentation Cell Death Cell Line Cell Proliferation Cell Survival Cell physiology Cells Cholangiocarcinoma Clinical Clinical Data Clinical Research Clinical Trials Clinical Trials Network Cohort Studies Data Dependence Disease Environment Evaluable Disease Funding Gastrointestinal Neoplasms Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Human Immune Immune checkpoint inhibitor Immunologics Immunotherapy In Vitro Infiltration Interferon-alpha Interleukin-6 Investigational Therapies Laboratory Study Ligands MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Mediating Modeling Multi-Institutional Clinical Trial Myeloid Cells Myeloid-derived suppressor cells Oncology Outcome PD-L1 blockade PDL1 inhibitors Participant Patients Phase II Clinical Trials Phase Ib Trial Phenotype Population Prior Chemotherapy Randomized Ras/Raf Refractory Regimen Regulatory T-Lymphocyte Reporting Research Role Safety Sampling Series Signal Pathway Signal Transduction Site Somatic Mutation T-Cell Receptor T-Lymphocyte Testing Therapeutic Translating Tumor-Derived Tumor-infiltrating immune cells Universities Unresectable anti-PD-1 anti-PD-L1 anti-PD-L1 therapy anti-tumor immune response base cell motility cell type checkpoint inhibition chemokine chemotherapeutic agent clinically relevant cytokine density effective therapy effector T cell efficacy testing exhaustion experience gastrointestinal imaging approach immunoregulation improved in vivo in vivo Model inhibitor/antagonist innovation novel peripheral blood pre-clinical prevent programmed cell death ligand 1 programmed cell death protein 1 programs response spectrograph standard care standard of care success targeted agent trafficking tumor tumor microenvironment

项目摘要

Cholangiocarcinoma (CC) is an aggressive cancer that has been refractory to most chemotherapeutic or targeted agents. Our goal is to extend success of immunotherapy to CC, and identify relevant biomarkers for this approach. This proposal will translate pre-clinical findings showing that MEK inhibitors (MEKi) enhance infiltration of CD8+ T effector cells, prevent their exhaustive apoptotic cell death, and enhance efficacy of anti-PD-L1 Ab in tumor models. We hypothesize that MEKi will synergize with PD-L1 blockade to elicit anti-tumor responses via altering cytokine and chemokine signatures that promote CD8+ T cell infiltration and survival and decreased immunosuppressive cells in the tumor microenvironment (TME). We will conduct an innovative randomized phase 2 clinical trial to examine safety and efficacy of a MEKi (cobimetinib) in combination with an inhibitor of PD-L1 (atezolizumab) and atezolizumab monotherapy in patients with unresectable CC. This trial will be performed in the context of our approved NCI-sponsored UM1 clinical trials grant. Concurrent studies will elucidate the mechanism by which MEKi acts on T and myeloid cells, and augments efficacy of PD-L1 blockade. The trial will provide paired biopsies from patients with accessible tumor in which we can validate our mechanistic findings using innovative multi-spectral imaging. This will be the largest clinical study of CC in the second line. We will pursue three Specific Aims: 1) To conduct a randomized phase 2 clinical trial of the PD-L1 inhibitor atezolizumab in combination with the MEKi cobimetinib versus atezolizumab monotherapy in participants with unresectable CC. We have completed approval through the NCI Cancer Therapy Evaluation Program (CTEP) to conduct this randomized, multicenter clinical trial in 76 evaluable subjects who have received at least one prior chemotherapy. If successful, this regimen has potential to become the standard of care for CC in the second line. This trial will provide samples to evaluate the effect of MEKi on key biomarkers in the TME. 2) To determine how MEKi alter the TME to improve the response to anti-PD-L1 therapy. A unique panel of human CC cell lines will be used study how MEKi modulates tumor-derived chemokines that regulate T cell migration. Using clinical trial biopsies, we will evaluate CD8+ T cell infiltration and PD-L1 expression as integrated biomarkers. Multi- spectral IHC will characterize the impact of treatment on immune subsets and markers of exhaustive T cell death (i.e. Nur77) in the TME as well as the impact on immunosuppressive T regulatory cells and myeloid-derived suppressor cells. 3) To determine the role of systemic cytokines and immune cell populations in the response to MEKi and PD-L1 blockade. In vivo models will test if the efficacy of MEKi + anti-PD-L1 therapy is dependent on IFN-, a key cytokine regulator of T cell function and chemokine-mediated trafficking. In vitro studies will define if MEKi alters the impact of tumor-derived cytokines (e.g. IL-6, GM-CSF) on differentiation or function of suppressive myeloid cells. Finally, using patient peripheral blood samples we will determine the relevance of relationships between cytokine expression and various immune cell phenotype with clinical outcome.

胆管癌 (CC) 是一种侵袭性癌症，大多数化疗或靶向治疗都难以治愈代理。我们的目标是将免疫疗法的成功扩展到 CC，并为此确定相关的生物标志物方法。该提案将转化显示 MEK 抑制剂 (MEKi) 增强浸润的临床前研究结果 CD8+ T 效应细胞，防止其彻底凋亡细胞死亡，并增强抗 PD-L1 Ab 的功效肿瘤模型。我们假设 MEKi 将与 PD-L1 阻断剂协同作用，通过改变促进 CD8+ T 细胞浸润和存活的细胞因子和趋化因子特征，并减少肿瘤微环境（TME）中的免疫抑制细胞。我们将进行一项创新的随机 2 期临床试验，旨在检验 MEKi（cobimetinib）与抑制剂联合使用的安全性和有效性 PD-L1（atezolizumab）和 atezolizumab 单药治疗不可切除的 CC 患者。此次审判将在我们批准的 NCI 赞助的 UM1 临床试验拨款的背景下进行。并行研究将阐明 MEKi 作用于 T 细胞和骨髓细胞并增强 PD-L1 阻断功效的机制。该试验将提供来自患有可触及肿瘤的患者的配对活检，我们可以在其中验证我们的机制使用创新的多光谱成像的发现。这将是二线最大规模的CC临床研究。我们将追求三个具体目标：1）进行 PD-L1 抑制剂的随机 2 期临床试验 atezolizumab 联合 MEKi cobimetinib 对比 atezolizumab 单药治疗受试者不可切除的CC。我们已通过 NCI 癌症治疗评估计划 (CTEP) 的批准在 76 名可评估受试者中进行这项随机、多中心临床试验，这些受试者之前至少接受过化疗。如果成功，该方案有可能成为第二阶段 CC 的护理标准线。该试验将提供样本来评估 MEKi 对 TME 中关键生物标志物的影响。 2）确定 MEKi 如何改变 TME 以改善抗 PD-L1 治疗的反应。一组独特的人类 CC 细胞系将用于研究 MEKi 如何调节肿瘤衍生的趋化因子，从而调节 T 细胞迁移。使用临床试验活检中，我们将评估 CD8+ T 细胞浸润和 PD-L1 表达作为综合生物标志物。多- 光谱 IHC 将表征治疗对免疫亚群和彻底 T 细胞死亡标志物的影响（即 Nur77）在 TME 中的作用以及对免疫抑制 T 调节细胞和骨髓来源的影响抑制细胞。 3) 确定系统细胞因子和免疫细胞群在响应中的作用 MEKi 和 PD-L1 阻断。体内模型将测试 MEKi + 抗 PD-L1 疗法的功效是否取决于 IFN-γ，T 细胞功能和趋化因子介导的运输的关键细胞因子调节剂。体外研究将定义如果 MEKi 改变肿瘤来源的细胞因子（例如 IL-6、GM-CSF）对肿瘤分化或功能的影响抑制性骨髓细胞。最后，使用患者外周血样本，我们将确定以下各项的相关性：细胞因子表达和各种免疫细胞表型与临床结果之间的关系。