Targeting Dectin-2 on Tumor-associated Macrophages for the Treatment of Cancer

将 Dectin-2 靶向肿瘤相关巨噬细胞来治疗癌症

• 批准号: 10401797
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 41.97万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401797
• 关键词: Agonist; Antibodies; Antigen Presentation; Antigen-Antibody Complex; Antigen-Presenting Cells; Binding; Blocking Antibodies; CTLA4 gene; Cancer Model; Carbohydrates; Cell surface; Cells; Chemicals; Clinical; Colon Carcinoma; Common Neoplasm; Cytometry; Data; Disease Progression; Exhibits; Fc Receptor; Glycopeptides; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologics; Immunotherapeutic agent; Immunotherapy; Inflammatory; Length; Ligands; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of lung; Mannans; Mediating; Methods; Microbe; Modeling; Mus; Pancreatic Ductal Adenocarcinoma; Patients; Pattern recognition receptor; Phagocytes; Phagocytosis; Polysaccharides; Process; Proteins; Research Design; Resistance; Safety; Site; Skin Cancer; Solid Neoplasm; Structure; System; T cell response; TNFRSF5 gene; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Tumor Antigens; Tumor Immunity; Tumor-associated macrophages; adaptive immune response; anti-tumor immune response; antibody conjugate; antigen binding; antitumor agent; antitumor effect; base; cancer immunotherapy; cancer therapy; cell killing; chemotherapy; clinical application; clinical candidate; clinical development; density; design; experimental study; flexibility; immune activation; immune checkpoint blockade; improved; informatics tool; malignant breast neoplasm; mouse dectin-2; mouse model; neoplastic cell; novel; pancreatic cancer model; pancreatic ductal adenocarcinoma model; pathogen; programmed cell death protein 1; receptor; standard of care; tumor; uptake

PROJECT SUMMARY/ABSTRACT Background: Immunotherapy has emerged as one of the most promising approaches for the treatment of cancer. Unfortunately, a large number of patients and common tumor types do not respond to existing immunotherapies. Tumor-associated macrophages (TAMs), which accumulate in many cancers and suppress anti-tumor immunity, likely contribute to this problem. Hypothesis and Objective: Based on encouraging preliminary data, we hypothesize that engagement of Dectin-2, a pattern recognition receptor that is highly expressed by TAMs in certain tumors, can reprogram TAMs into potent antigen-presenting cells capable of inducing immunity against a wide range of cancers. Our objective is to validate this hypothesis by analyzing the immunological and anti-tumor effects of natural and synthetic Dectin-2 agonists in mouse models of cancer. Specific Aims: Aim 1: Analyze the factors that regulate Dectin-2 expression and the mechanisms by which Dectin-2 agonists reprogram TAMs and induce anti-tumor immunity. Aim 2: Assess the anti-tumor effects of natural Dectin-2 agonists, alone and in combination with other agents, on a range of aggressive cancers. Aim 3: Synthesize glycopeptide agonists of Dectin-2 and assess their anti-tumor activity alone and in combination with other agents. Aim 4: Construct tumor-targeted antibody-glycopeptide conjugates and evaluate their functional and therapeutic effects. Study Design and Methods: Since TAMs in some tumors express little or no Dectin-2, we will analyze the effects of natural Dectin-2 agonists on TAMs in the presence of GM-CSF, which induces Dectin-2 expression. The anti-tumor effects of the agonists will be studied in mouse models of pancreas, breast, colon, lung, and skin cancer with a spectrum of Dectin-2 expression, both as monotherapies and in combination with GM-CSF and other agents shown to enhance the efficacy of Dectin-2 agonists in our mouse models. Mass cytometry and recently developed informatics tools will be utilized to analyze the effects of Dectin-2 ligands on the anti- tumor immune response in multiple tissues. To generate more effective and clinically applicable therapies, a novel synthetic approach will be used to produce compositionally defined Dectin-2 ligands that are optimized for TAM activation. The most efficacious of these synthetic Dectin-2 ligands will be conjugated to tumor- targeted antibodies for purposes of enhanced tumor delivery and TAM-mediated tumor cell killing, and their safety and efficacy assessed. Expected Results and Impact: We expect these experiments to demonstrate that engaging Dectin-2 on TAMs induces immunity against a wide range of tumors, including tumors resistant to checkpoint blockade, and that Dectin-2 agonists used alone or in combination with other anti-tumor agents can induce durable tumor regression. The most promising of these agonists will be candidates for clinical development.

项目摘要/摘要 背景：免疫疗法已成为治疗的最有希望的方法之一 癌症。不幸的是，许多患者和普通肿瘤类型对现有 免疫疗法。与肿瘤相关的巨噬细胞（TAM），它们在许多癌症中积聚并抑制 抗肿瘤的免疫力可能会导致这个问题。 假设和目标：基于鼓励初步数据，我们假设参与 dectin-2是一种模式识别受体，在某些肿瘤中由TAM高度表达，可以重新编程 将TAM浸入有效的抗原呈递细胞中，能够诱导对广泛的癌症诱导免疫力。我们的 目的是通过分析自然和自然的免疫学和抗肿瘤作用来验证这一假设 癌症小鼠模型中的合成dectin-2激动剂。 具体目的：目标1：分析调节Dectin-2表达的因素和所用的机制 Dectin-2激动剂重新编程TAM并诱导抗肿瘤免疫。目标2：评估抗肿瘤的影响 天然Dectin-2激动剂单独并与其他药物结合在一系列侵略性癌症上。目的 3：Dectin-2的糖肽激动剂合成，单独评估其抗肿瘤活性 与其他代理商。 AIM 4：构建靶向肿瘤的抗体 - 糖肽结合物并评估其 功能和治疗作用。 研究设计和方法：由于某些肿瘤中的TAM几乎没有表达dectin-2，我们将分析 在GM-CSF存在下，天然Dectin-2激动剂对TAM的影响，这会诱导Dectin-2表达。 激动剂的抗肿瘤作用将在胰腺，乳房，结肠，肺和 皮肤癌具有多种Dectin-2表达，无论是单疗法还是与GM-CSF的结合 和其他证明可以增强Dectin-2激动剂在我们的小鼠模型中的功效的药物。质量细胞仪 最近开发的信息学工具将用于分析Dectin-2配体对抗抗的影响 多种组织中的肿瘤免疫反应。为了产生更有效和临床适用的疗法， 新型合成方法将用于生产优化的成分定义的Dectin-2配体 用于TAM激活。这些合成Dectin-2配体中最有效的是将肿瘤结合在一起 靶向抗体，以增强肿瘤递送和TAM介导的肿瘤细胞杀死，它们 评估安全性和功效。 预期的结果和影响：我们希望这些实验证明与Dectin-2一起参与 TAMS可诱导免疫力针对广泛的肿瘤，包括耐肿瘤对检查点阻断的肿瘤， Dectin-2激动剂单独使用或与其他抗肿瘤剂结合使用可以诱导耐用的肿瘤 回归。这些激动剂最有希望的是临床发展的候选者。

项目成果

Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity.

• DOI: 10.1038/s43018-020-00136-x
• 发表时间: 2021-01
• 期刊: NATURE CANCER
• 影响因子: 22.7
• 作者: Ackerman, Shelley E.;Pearson, Cecelia I.;Gregorio, Joshua D.;Gonzalez, Joseph C.;Kenkel, Justin A.;Hartmann, Felix J.;Luo, Angela;Ho, Po Y.;LeBlanc, Heidi;Blum, Lisa K.;Kimmey, Samuel C.;Luo, Andrew;Nguyen, Murray L.;Paik, Jason C.;Sheu, Lauren Y.;Ackerman, Benjamin;Lee, Arthur;Li, Hai;Melrose, Jennifer;Laura, Richard P.;Ramani, Vishnu C.;Henning, Karla A.;Jackson, David Y.;Safina, Brian S.;Yonehiro, Grant;Devens, Bruce H.;Carmi, Yaron;Chapin, Steven J.;Bendall, Sean C.;Kowanetz, Marcin;Dornan, David;Engleman, Edgar G.;Alonso, Michael N.
• 通讯作者: Alonso, Michael N.