Notch ligands in regulation of anti-cancer immunity

Notch配体在抗癌免疫调节中的作用

基本信息

批准号：
8743193
负责人：
DAVID P. CARBONE
金额：
$ 30.48万
依托单位：
OHIO STATE UNIVERSITY
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：
2013-09-26 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743193
关键词：
Biological Assay Cancer Patient Cell Differentiation Induction Cell physiology Cells Cellular Immunity Clinical Data Defect Dendritic Cells Disease Disease remission Effector Cell Epidermal Growth Factor Receptor Erlotinib Evaluation Gene Expression Profile Genes Genetic Genetic Engineering Hematopoiesis Hematopoietic Human ITGAX gene Immune Immune response Immunity Immunosuppression Immunotherapy Investigation Knockout Mice Ligands Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Memory Modality Modeling Molecular Mus Mutant Strains Mice Non-Small-Cell Lung Carcinoma Notch Signaling Pathway Oncogenes Outcome Pathway interactions Patients Pattern Peripheral Peripheral Blood Mononuclear Cell Predictive Value Prevalence Progression-Free Survivals Publishing Reagent Recurrence Regulation Regulatory T-Lymphocyte Relapse Research Role Signal Transduction Specific qualifier value System T cell differentiation T cell response T-Cell Development T-Lymphocyte Testing Therapeutic Translating Translations Treatment Efficacy Tumor Immunity base cancer therapy clinical efficacy clinically relevant clinically significant combinatorial fascinate improved inhibitor/antagonist mouse model notch protein novel novel therapeutic intervention novel therapeutics preclinical study prognostic public health relevance response tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Integrating immunotherapy with targeted therapies in cancer treatment presents a novel combinatorial strategy where complementary modes of action of two distinct modalities suggest fascinating possibilities for therapeutic synergy. Strong line of evidence suggests that anti-tumor immunity is critical for clinical responses toward conventional and pathway-targeted cancer treatments. Immunotherapies may serve to consolidate the impressive clinical responses from targeted therapies into durable remissions via induction of long-lasting immune responses. The proposed research is based on our published and preliminary our data that define a novel Notch-mediated molecular mechanism of cancer-associated immunosuppression, combined with candidate systemic therapeutics, which overcomes this immunosuppression. We revealed that tumors and down-regulates expression of Delta-like (DLL) Notch ligand in the hematopoietic compartment, and the resulting decreased Notch activation leads to defects in T cells. Genetic or therapeutic enhancement of DLL1- mediated Notch signaling was sufficient to correct tumor-induced defects in T lymphocyte differentiation, improve T cell responses and memory, and produce significant tumor inhibition. We generated and tested in mouse tumor models a prototypic therapeutic reagent, soluble clustered (multivalent) DLL1, that demonstrated immune and therapeutic efficacy. Erlotinib, an inhibitor of EGF receptor (EGFR), has shown significant clinical responses and survival benefit in the treatment of in Non-Small Cell Lung Cancer (NSCLC), however disease recurrence remains a key outstanding problem. We hypothesize that adequate Notch signaling in the immune microenvironment is crucial for the induction of anti-tumor immunity and that ligand-specific pharmacological enhancement of Notch signaling can be exploited to significantly improve progression-free survival after EGFR-targeted therapy via induction of robust and long-lasting anti-tumor immune responses. We intend to test this idea in the following specific aims: 1) Determine the roles of Notch ligand expression in dendritic cells in the regulation of anti-tumor immune responses. 2) Evaluate the clinical efficacy of combination of anti-EGFR targeted therapy with pharmacologically enhanced DLL1/Notch signaling and the ability of multivalent DLL1 to rescues defective T cells, induce sustained immune responses, and durable remission. 3) Evaluate significance of Notch system in regulation of Th cell differentiation and induction of long-lasting remission in NSCLC patients after targeted therapy. We plan to focus on the above aims to achieve a molecular understanding of the role of Notch, DLL1 and other Notch ligands in anti-tumor immunity and to evaluate the therapeutic and prognostic potential that modulation and evaluation of this system could offer. The proposed pre-clinical studies will give us leads to enable the translation of these findings into clinically relevant therapeutics and prognostic assays.

描述（由申请人提供）：在癌症治疗中将免疫疗法与靶向疗法相结合提出了一种新颖的组合策略，其中两种不同方式的互补作用模式表明了治疗协同作用的令人着迷的可能性。强的一系列证据表明，抗肿瘤免疫对于传统和通路靶向癌症治疗的临床反应至关重要。免疫疗法可以通过诱导持久的免疫反应，将靶向治疗的令人印象深刻的临床反应巩固为持久的缓解。拟议的研究基于我们已发表的初步数据，这些数据定义了一种新颖的Notch介导的癌症相关免疫抑制分子机制，并结合候选的系统疗法，克服了这种免疫抑制。我们发现，肿瘤会下调造血室中 Delta 样 (DLL) Notch 配体的表达，由此导致的 Notch 激活减少会导致 T 细胞缺陷。 DLL1介导的Notch信号传导的遗传或治疗增强足以纠正肿瘤诱导的T淋巴细胞分化缺陷，改善T细胞反应和记忆，并产生显着的肿瘤抑制作用。我们在小鼠肿瘤模型中生成并测试了一种原型治疗试剂——可溶性簇状（多价）DLL1，它证明了免疫和治疗功效。厄洛替尼是一种 EGF 受体 (EGFR) 抑制剂，在非小细胞肺癌 (NSCLC) 的治疗中显示出显着的临床反应和生存获益，但疾病复发仍然是一个关键的突出问题。我们假设免疫微环境中足够的Notch信号传导对于诱导抗肿瘤免疫至关重要，并且Notch信号传导的配体特异性药理学增强可用于通过诱导强效和抗肿瘤免疫来显着改善EGFR靶向治疗后的无进展生存期。持久的抗肿瘤免疫反应。我们打算在以下具体目标中测试这个想法：1）确定树突状细胞中Notch配体表达在调节抗肿瘤免疫反应中的作用。 2) 评估抗EGFR靶向治疗与药理学增强的DLL1/Notch信号传导相结合的临床疗效以及多价DLL1拯救缺陷T细胞、诱导持续免疫反应和持久缓解的能力。 3)评估Notch系统在NSCLC患者靶向治疗后调节Th细胞分化和诱导持久缓解的意义。我们计划重点关注上述目标，以从分子角度理解Notch、DLL1和其他Notch配体在抗肿瘤免疫中的作用，并评估该系统的调节和评估可能提供的治疗和预后潜力。拟议的临床前研究将为我们提供线索，使我们能够将这些发现转化为临床相关的治疗方法和预后分析。