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:
- 金额:$ 44.61万
- 依托单位:
- 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:
- 关键词:AffectAgonistAntigen PresentationAntigensBiodistributionBioinformaticsCD8-Positive T-LymphocytesCancer EtiologyCancer ModelCancer PatientCancer VaccinesCellsCessation of lifeChemicalsClinicalClinical ResearchColorectal CancerCombined Modality TherapyCross-PrimingCytotoxic T-LymphocytesDNADendritic CellsDevelopmentDiagnosisDinucleoside PhosphatesDiseaseDisseminated Malignant NeoplasmDistantDrug KineticsEpithelial CellsFormulationGene ActivationGoalsHumanHybridsImmuneImmune systemImmunologicsImmunomodulatorsImmunotherapyInjectionsInterferon Type IInterferon-betaIonsLigandsMC38MediatingMemoryMetalsMetastatic Neoplasm to the LiverMethodsMicrosatellite InstabilityMicrosatellite RepeatsMismatch RepairMismatch Repair DeficiencyModelingMorbidity - disease rateMusNeoplasm MetastasisNon-Small-Cell Lung CarcinomaOrganPD-1/PD-L1PD-L1 blockadePatientsPeptidesPeriodicityPermeabilityPhagocytesPlasma ProteinsPolymersProgression-Free SurvivalsProliferatingProteinsPublic HealthRenal clearance functionResearchResistanceSecond Messenger SystemsSignal TransductionStable DiseaseStimulator of Interferon GenesSurvival RateSystemT cell infiltrationT cell responseT-Cell ActivationTechniquesTestingTimeTreatment EfficacyTumor AntigensTumor ExpansionTumor TissueTumor-associated macrophagesabsorptionanti-PD-L1anti-PD-L1 antibodiesanti-PD1 antibodiesanti-canceranti-tumor immune responsebiomaterial compatibilitycheckpoint therapyclinical applicationclinical candidateclinical developmentcolon cancer patientsdesigndrug candidateeffective therapygenome sequencinghydrophilicityimmune activationimmune checkpointimmune checkpoint blockadeimmunogenicimprovedin vivoindividual patientinsightintravenous injectionmelanomametastatic colorectalmonocytemortalitymouse modelnanocarriernanoparticlenanoscalenanotherapeuticneoantigensnovelnovel strategiesnovel therapeuticsparticlepatient responsepatient subsetsphosphoric diester hydrolasepreclinical developmentresponseself assemblysubcutaneoussuccesssynergismtherapeutic vaccinetooltreatment effecttumortumor growthtumor microenvironmentwhole 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,潜在有效的抗肿瘤免疫疗法
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
通过单核细胞吞噬系统抵抗血浆蛋白抽象和清除。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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Wenbin Lin其他文献
Wenbin Lin的其他文献
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{{ truncateString('Wenbin Lin', 18)}}的其他基金
Tumor-Targeted Multimodality Nanoscale Coordination Polymers for Chemo-Immunotherapy of Metastatic Colorectal Cancer
用于转移性结直肠癌化疗免疫治疗的肿瘤靶向多模态纳米配位聚合物
- 批准号:
10639649 - 财政年份:2023
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10450090 - 财政年份:2020
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10684142 - 财政年份:2020
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10203892 - 财政年份:2020
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers
纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗
- 批准号:
10060188 - 财政年份:2020
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Coordination Polymers Co-deliver Chemotherapeutics and siRNAs for Efficacious Treatment of Resistant Ovarian Cancer
纳米级配位聚合物共同提供化疗药物和 siRNA,有效治疗耐药性卵巢癌
- 批准号:
10329991 - 财政年份:2018
- 资助金额:
$ 44.61万 - 项目类别:
Targeted Nanomedicines with Synergistic Chemotherapeutics to Enhance Immunotherapy of Metastatic Colorectal Cancer
靶向纳米药物与协同化疗增强转移性结直肠癌的免疫治疗
- 批准号:
10208813 - 财政年份:2018
- 资助金额:
$ 44.61万 - 项目类别:
Targeted Nanomedicines with Synergistic Chemotherapeutics to Enhance Immunotherapy of Metastatic Colorectal Cancer
靶向纳米药物与协同化疗增强转移性结直肠癌的免疫治疗
- 批准号:
10436331 - 财政年份:2018
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Metal-organic Frameworks for Light Triggered and X-ray Induced Photodynamic Therapy of Head and Neck Cancers
用于光触发和 X 射线诱导光动力治疗头颈癌的纳米级金属有机框架
- 批准号:
9150514 - 财政年份:2015
- 资助金额:
$ 44.61万 - 项目类别:
Nanoscale Metal-organic Frameworks for Light Triggered and X-ray Induced Photodynamic Therapy of Head and Neck Cancers
用于光触发和 X 射线诱导光动力治疗头颈癌的纳米级金属有机框架
- 批准号:
8959832 - 财政年份:2015
- 资助金额:
$ 44.61万 - 项目类别:
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