Nanoscale Coordination Polymers of Cyclic-di-nucleotides and Peptide Antigens for Effective Therapy of Metastatic Colorectal Cancer

环二核苷酸和肽抗原的纳米级配位聚合物可有效治疗转移性结直肠癌

基本信息

批准号：
10731680
负责人：
Wenbin Lin
金额：
$ 44.61万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731680
关键词：
Affect Agonist Antigen Presentation Antigens Biodistribution Bioinformatics CD8-Positive T-Lymphocytes Cancer Etiology Cancer Model Cancer Patient Cancer Vaccines Cells Cessation of life Chemicals Clinical Clinical Research Colorectal Cancer Combined Modality Therapy Cross-Priming Cytotoxic T-Lymphocytes DNA Dendritic Cells Development Diagnosis Dinucleoside Phosphates Disease Disseminated Malignant Neoplasm Distant Drug Kinetics Epithelial Cells Formulation Gene Activation Goals Human Hybrids Immune Immune system Immunologics Immunomodulators Immunotherapy Injections Interferon Type I Interferon-beta Ions Ligands MC38 Mediating Memory Metals Metastatic Neoplasm to the Liver Methods Microsatellite Instability Microsatellite Repeats Mismatch Repair Mismatch Repair Deficiency Modeling Morbidity - disease rate Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organ PD-1/PD-L1 PD-L1 blockade Patients Peptides Periodicity Permeability Phagocytes Plasma Proteins Polymers Progression-Free Survivals Proliferating Proteins Public Health Renal clearance function Research Resistance Second Messenger Systems Signal Transduction Stable Disease Stimulator of Interferon Genes Survival Rate System T cell infiltration T cell response T-Cell Activation Techniques Testing Time Treatment Efficacy Tumor Antigens Tumor Expansion Tumor Tissue Tumor-associated macrophages absorption anti-PD-L1 anti-PD-L1 antibodies anti-PD1 antibodies anti-cancer anti-tumor immune response biomaterial compatibility checkpoint therapy clinical application clinical candidate clinical development colon cancer patients design drug candidate effective therapy genome sequencing hydrophilicity immune activation immune checkpoint immune checkpoint blockade immunogenic improved in vivo individual patient insight intravenous injection melanoma metastatic colorectal monocyte mortality mouse model nanocarrier nanoparticle nanoscale nanotherapeutic neoantigens novel novel strategies novel therapeutics particle patient response patient subsets phosphoric diester hydrolase preclinical development response self assembly subcutaneous success synergism therapeutic vaccine tool treatment effect tumor tumor growth tumor microenvironment whole genome

项目摘要

Project Summary: New approaches, such as the emergence of immune checkpoint blockade over the past decade, hold great promise for patients with metastatic cancer. Indeed, PD-1/PD-L1 blockade has enjoyed remarkable clinical success for immunogenically “hot” tumors such as subsets of melanoma and non-small cell lung cancer patients; however, for patients with immunologically “cold” tumors, such as most advanced colorectal cancers, patient response rates can be as low as 5%. With the advent of whole genome sequencing and sophisticated bioinformatics techniques, patient-specific neoantigens in tumors can now be identified and provide the basis for many therapeutic vaccines in preclinical and clinical development. Neoantigen-based cancer vaccines can be tailored to individual patients by identifying their unique neoantigens. We have pioneered the development of nanoscale coordination polymers (NCPs), which are a class of hybrid nanoparticles formed by the self-assembly of metal ions and polydentate bridging ligands. NCPs preferentially accumulate in tumor tissues by taking advantage of the enhanced permeability and retention effect and possess several advantages over existing nanocarriers. The long-term goal of our collaborative research is to establish a new treatment paradigm for metastatic colorectal cancer, through the development and characterization of effective NCPs that can be delivered systemically. The overall goal of the proposed studies is to develop robust NCPs, namely, ZnCDN, for the systemic delivery of a neoantigen and hydrophilic cyclic dinucleotide (CDN) STING agonists, including CDA, ADU-S100, and MK-1454, to potentiate the antitumor immune effect of anti-PD-L1 immunotherapy for the effective treatment of mCRC. Increased understanding of the mechanisms involved in this combination therapy will provide critical insights to enhance the response rates and durability of immunotherapies for mCRC. We have designed ZnCDN NCP with a core of CDA and Zn2+ ions and a hydrophilic shell of PEG2000 to resist plasma protein absorption and clearance by the monocytic phagocytic system. As a result, ZnCDN can be administered to mice via intravenous injection to significantly accumulate in the TME. We will study three ZnCDN formulations with CDA, ADU-S100, and MK-1454 to obtain the best ZnCDN and evaluate its effects on tumor vasculature and intratumoal retention. We will evaluate immune activation in mouse models of mCRC, and elucidate the mechanisms of ZnCDN-mediated STING activation in the tumor microenvironment. In order to evaluate the delivery of tumor-specific antigens, we will incorporate tumor antigen peptides into NCPs to facilitate cross-priming of CD8+ T cells and enhance antitumor efficacy. Finally, we will elucidate the mechanism of STING activation with ZnCDN-antigen to overcome resistance to PD-1/PD-L1 blockade. Our labs have been working together on this project in the Ludwig Center for Metastasis Research for most of the past decade. This interdisciplinary endeavor could lead to a transformation in the treatment of mCRC.

项目概要：新方法，例如过去出现的免疫检查点封锁事实上，PD-1/PD-L1 阻断疗法为转移性癌症患者带来了巨大希望。在免疫原性“热”肿瘤（例如黑色素瘤和非小细胞亚群）方面取得了显着的临床成功肺癌患者；然而，对于患有免疫学“冷”肿瘤的患者，例如最晚期的患者随着全基因组测序的出现，结直肠癌患者的缓解率可低至 5%。和复杂的生物信息学技术，现在可以识别肿瘤中的患者特异性新抗原并为许多基于新抗原的治疗性疫苗的临床前和临床开发提供基础。通过识别患者独特的新抗原，可以为患者量身定制癌症疫苗。我们率先开发了纳米级配位聚合物 (NCP)，这是一类由金属离子和多齿桥连配体自组装形成的杂化纳米颗粒。利用增强的渗透性和滞留性优先积聚在肿瘤组织中效果和一些比现有纳米载体具有的优势是我们合作的长期目标。研究旨在通过开发建立转移性结直肠癌的新治疗范例以及可系统交付的有效 NCP 的特征。拟议研究的总体目标是开发强大的 NCP，即 ZnCDN，用于系统性递送新抗原和亲水性环二核苷酸 (CDN) STING 激动剂，包括 CDA、ADU-S100、和MK-1454，增强抗PD-L1免疫疗法的抗肿瘤免疫作用，以有效治疗增加对这种联合疗法所涉及机制的了解。为提高转移性结直肠癌免疫疗法的反应率和持久性提供重要见解。我们设计了具有 CDA 和 Zn2+ 离子核心以及 PEG2000 亲水壳的 ZnCDN NCP， ZnCDN 可以抵抗单核细胞吞噬系统的血浆蛋白吸收和清除。通过静脉注射给予小鼠以在 TME 中显着积累，我们将研究三种。 ZnCDN 配方与 CDA、ADU-S100 和 MK-1454 以获得最佳 ZnCDN 并评估其对我们将评估 mCRC 小鼠模型中的肿瘤血管系统和瘤内滞留。并阐明肿瘤微环境中 ZnCDN 介导的 STING 激活机制。为了评估肿瘤特异性抗原的传递，我们将把肿瘤抗原肽整合到 NCP 中，以促进 CD8+ T 细胞的交叉启动并增强抗肿瘤功效。用 ZnCDN 抗原激活 STING 克服 PD-1/PD-L1 阻断耐药性的机制。我们的实验室一直在路德维希转移研究中心共同致力于这个项目这一跨学科的努力可能会导致转移性结直肠癌治疗的转变。