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

• 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
• 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

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，如过去出现的免疫检查点阻断 十年来，为转移性癌症患者带来了巨大的希望。事实上，PD-1/PD-L1阻断已经享受了 对于免疫原性“热”肿瘤如黑色素瘤和非小细胞肺癌的亚群， 肺癌患者;然而，对于免疫学上“冷”肿瘤的患者，例如最晚期的肺癌患者， 对于结直肠癌，患者反应率可低至5%。随着全基因组测序的出现 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， 为临床前和临床开发中的许多治疗性疫苗提供了基础。基于新抗原 癌症疫苗可以通过鉴定其独特的新抗原来适应个体患者。 我们率先开发了纳米配位聚合物（NCP），这是一类 通过金属离子和多齿桥接配体的自组装形成的混合纳米颗粒。NCPs 通过利用增强的渗透性和保留， 影响并具有优于现有纳米载体的几个优点。我们合作的长期目标 研究的目的是建立一个新的治疗转移性结直肠癌的范例，通过开发 和表征可以全身递送的有效NCP。 拟议研究的总体目标是为系统性疾病开发稳健的NCP，即ZnCDN。 递送新抗原和亲水性环状二核苷酸（CDN）STING激动剂，包括CDA，ADU-S100， 和MK-1454，以增强抗PD-L1免疫疗法的抗肿瘤免疫作用， MCRC的治疗增加对这种联合治疗机制的理解将有助于 为提高mCRC免疫疗法的应答率和持久性提供重要见解。 我们设计了具有CDA和Zn 2+离子的核和PEG 2000的亲水壳的ZnCDN NCP， 抵抗单核细胞吞噬系统对血浆蛋白的吸收和清除。因此，ZnCDN可以 通过静脉内注射给予小鼠，以在TME中显著积累。我们将研究三个 使用CDA、ADU-S100和MK-1454对ZnCDN制剂进行了比较，以获得最佳ZnCDN并评估其对 肿瘤脉管系统和肿瘤内滞留。我们将评估mCRC小鼠模型中的免疫激活， 并阐明肿瘤微环境中ZnCDN介导的STING激活机制。为了 为了评估肿瘤特异性抗原的递送，我们将肿瘤抗原肽掺入NCP中， 促进CD 8 + T细胞的交叉致敏并增强抗肿瘤功效。最后，我们将阐明 用ZnCDN-抗原激活STING以克服对PD-1/PD-L1阻断的抗性的机制。 我们的实验室一直在路德维希转移研究中心合作这个项目， 过去十年中的最大变化这种跨学科的奋进可能会导致mCRC治疗的转变。