Explore the therapeutic potential of small-molecule immune modulators

探索小分子免疫调节剂的治疗潜力

基本信息

批准号：
10054173
负责人：
CHUO CHEN
金额：
$ 38.8万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054173
关键词：
ADME Study Alkylation Antibodies Antineoplastic Agents Binding Binding Proteins CD8-Positive T-Lymphocytes Cause of Death Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Chemotherapy and/or radiation Cross Presentation Cytotoxic T-Lymphocytes Data Dendritic Cells Development Dinucleoside Phosphates Effectiveness Evaluation Future Gene Activation Goals Heart Diseases Human Immune Targeting Immune response Immune system Immunity Immunization Immunologic Adjuvants Immunomodulators Immunotherapeutic agent Immunotherapy In Vitro Innate Immune System Investigational Drugs Knowledge Literature Lymphatic Lymphatic System Malignant Neoplasms Mannose Maps Metabolic Methods Modality Modification Mus Natural Immunity Patients Periodicity Permeability Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Property Proteins Proteomics Published Comment Publishing Radiation Research Risk Role Safety Second Messenger Systems Site Stimulator of Interferon Genes System Therapeutic Time Toxic effect Triglycerides Tumor Antigens Work absorption analog anti-PD-L1 antibodies anti-cancer base cancer immunotherapy cancer therapy chemotherapy comparative efficacy design drug development fighting immune checkpoint immune checkpoint blockade improved in vivo interest novel programmed cell death ligand 1 programs response small molecule systemic inflammatory response targeted delivery treatment strategy tumor tumor microenvironment

项目摘要

The overarching goal of our research program is to facilitate the development small-molecule drugs. The focus of this study is to explore the therapeutic potential of the cyclic dinucleotide class of immunopotentiators in cancer. Cancer is the second leading cause of death, contributing to 22.5% of total deaths in the US. Recently, immune checkpoint blockade has emerged as a powerful treatment modality for cancer, showing remarkable efficacy and response rate. Unlike the traditional radiation or chemotherapies, it utilizes our bodies’ own immune system to fight cancer. However, many patients do not have sufficient immunity to benefit from this new treatment strategy. Our team has recently identified cGAMP to be the endogenous small-molecule that activates the innate immune system and demonstrated its antitumor activity in mice. Based on this work, several synthetic analogs have been developed by pharmaceutical companies to mimic this natural immunopotentiator. The accumulated effort has led to two Phase I clinical trials to evaluate the safety and tolerance of cGAMP analogs in human. Despite the rapid progress, the full functional profile of cGAMP is still not clear. In this project, we will establish a proteomic approach to extensively map drug-protein interactions for cGAMP and its metabolically stable analogs including the investigational drug MIW815. This work will help shed lights on the potential new functions of cGAMP and the potential off-target effects of synthetic cyclic dinucleotides. Additionally, we believe that selective activation of a specific group of dendritic cells by cGAMP or its analogs will help reduce the risk of systemic inflammation, the major concern of the immune stimulation therapies. We will thus develop a conjugation strategy for site-specific delivery of cGAMP to improve efficacy, reduce toxicity, and help understand the roles of dendritic cells at different sites in anticancer immunity. Overall, the results of this study will inform future development of cGAMP analogs for their safe use in human and provide information on the role of innate immunity in cancer.

我们研究计划的总体目标是促进小分子药物的开发。本研究的目的是探索环状二核苷酸类免疫增强剂的治疗潜力癌症是第二大死亡原因，占美国总死亡人数的 22.5%。免疫检查点阻断已成为一种强大的癌症治疗方式，显示出显着的效果与传统的放射或化疗不同，它利用我们身体自身的功效和反应率。然而，许多患者没有足够的免疫力来受益于此。我们的团队最近发现 cGAMP 是一种内源性小分子，激活先天免疫系统并在小鼠中证明了其抗肿瘤活性。制药公司已经开发了几种合成类似物来模仿这种天然物质累积的努力已经进行了两项 I 期临床试验来评估安全性和有效性。 cGAMP 类似物在人类中的耐受性尽管进展迅速，但 cGAMP 的完整功能特征仍然未知。在这个项目中，我们将建立一种蛋白质组学方法来广泛绘制药物-蛋白质相互作用的图谱。 cGAMP 及其代谢稳定的类似物，包括研究药物 MIW815，这项工作将有所帮助。揭示了 cGAMP 的潜在新功能以及合成环化合物的潜在脱靶效应此外，我们认为 cGAMP 选择性激活特定组的树突细胞。或其类似物将有助于降低全身炎症的风险，这是免疫刺激的主要问题因此，我们将开发一种用于 cGAMP 的位点特异性递送的缀合策略，以提高疗效，降低毒性，并有助于了解树突状细胞在抗癌免疫中不同部位的作用。这项研究的结果将为 cGAMP 类似物的未来开发提供信息，以使其安全地用于人类和提供有关先天免疫在癌症中的作用的信息。