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.

项目摘要：新方法，例如过去的Immunocheckpoint的出现十年，对转移性癌症患者保持着巨大的希望。确实，PD-1/PD-L1封锁享受了免疫性“热”肿瘤（例如黑色素瘤和非小细胞）的显着临床成功肺癌患者；但是，对于具有免疫学“冷”肿瘤的患者，例如最先进的患者结直肠癌，患者反应率可以低至5％。随着整个基因组测序的冒险现在可以鉴定出精致的生物信息学技术，肿瘤中患者特异性的新抗原和为临床前和临床发育中的许多治疗疫苗提供基础。基于新抗原癌症疫苗可以通过鉴定其独特的新抗原来为个别患者量身定制。我们率先开发了纳米级协调聚合物（NCP），这是一类由金属离子和多源桥配体的自组装形成的杂化纳米颗粒。 NCP 通过利用增强的渗透性和保留率优先积聚在肿瘤组织中与现有纳米载体相比，效果和潜在的几个优势。我们合作的长期目标研究是通过开发建立用于转移性结直肠癌的新治疗范式以及可以系统地交付的有效NCP的表征。拟议研究的总体目标是为系统性开发强大的NCP，即ZnCDN 提供新抗原和亲水性环状二核苷酸（CDN）刺痛激动剂，包括CDA，ADU-S100，和MK-1454，潜在抗PD-L1免疫疗法的抗肿瘤免疫疗法以有效 MCRC的治疗。对这种组合疗法所涉及的机制的了解将增加提供关键的见解，以提高MCRC免疫疗法的反应率和耐用性。我们已经设计了具有CDA和Zn2+离子核心的ZnCDN NCP以及PEG2000的亲水性壳抵抗单核细胞囊肿系统的血浆蛋白吸收和清除。结果，zncdn可以通过静脉注射将小鼠施用，以显着积聚在TME中。我们将研究三个带有CDA，ADU-S100和MK-1454的ZnCDN公式以获得最佳的ZnCDN，并评估其对其对肿瘤脉管系统和肿瘤内保留。我们将评估MCRC小鼠模型中的免疫激活，并阐明了肿瘤微环境中ZnCDN介导的刺激激活的机制。为了为了评估肿瘤特异性抗原的递送，我们将肿瘤抗原纳入NCP 促进CD8+ T细胞的交叉染色并提高抗肿瘤效率。最后，我们将阐明用ZnCDN-抗原激活刺激的机理，以克服对PD-1/PD-L1阻滞的抗性。我们的实验室一直在大多数人的路德维希转移研究中心共同努力。过去十年。这项跨学科的努力可能导致MCRC治疗的转变。