Personalized, antigen-directed immunotherapy delivered to lymph nodes

递送至淋巴结的个性化抗原导向免疫疗法

基本信息

批准号：
10744599
负责人：
Mona Mohsen
金额：
$ 60.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744599
关键词：
4T1 Affect Age Animals Antigen Presentation Antigens Antitumor Response Autoantigens Autoimmune Diseases Bacteriophages Binding Bioinformatics Breast Cancer Patient Breast Carcinoma Cancer Center Cancer Detection Cancer Patient Cancer Vaccines Cells Clinical Clinical Research Clonal Expansion Collaborations Combination immunotherapy Combined Modality Therapy Communicable Diseases Cross Presentation Cucumber mosaic virus Data Dendritic Cells Development Disease Dose Drug Delivery Systems Educational process of instructing Effectiveness Environment Growth Health Sciences Imaging technology Immune response Immunity Immunofluorescence Immunologic Immunologic Tests Immunologics Immunology Immunotherapy Infiltration Intervention Intravenous Ligands Link Lymphatic Malignant Neoplasms Mass Spectrum Analysis Metastatic Neoplasm to Lymph Nodes Modeling Mus Neoplasm Circulating Cells Normal tissue morphology Pathology Patients Phenotype Plants Predisposition Privatization Regulatory T-Lymphocyte Relapse Research Research Proposals Signal Transduction Site Switzerland T cell response T-Lymphocyte T-cell receptor repertoire TLR9 gene Technology Texas Time Transgenic Mice Translating Tumor Antigens Tumor Escape Tumor-Infiltrating Lymphocytes Universities Vaccinated Vaccination Vaccine Design Vaccine Production Vaccines Virus-like particle Woman Work anti-tumor immune response cancer immunotherapy cancer therapy cancer type cancer vaccination cell assembly cell type central tolerance clinical translation combat draining lymph node exhaust exome sequencing experience image guided immune checkpoint blockade immune-related adverse events immunoregulation improved intravenous administration lymph nodes lymphatic imaging man mouse model multidisciplinary neoantigen vaccination neoantigens peripheral tolerance permissiveness prevent response safety testing single cell analysis single-cell RNA sequencing transcriptomics triple-negative invasive breast carcinoma tumor tumor growth

4T1 Affect Age Animals Antigen Presentation Antigens Antitumor Response Autoantigens Autoimmune Diseases Bacteriophages Binding Bioinformatics Breast Cancer Patient Breast Carcinoma Cancer Center Cancer Detection Cancer Patient Cancer Vaccines Cells Clinical Clinical Research Clonal Expansion Collaborations Combination immunotherapy Combined Modality Therapy Communicable Diseases Cross Presentation Cucumber mosaic virus Data Dendritic Cells Development Disease Dose Drug Delivery Systems Educational process of instructing Effectiveness Environment Growth Health Sciences Imaging technology Immune response Immunity Immunofluorescence Immunologic Immunologic Tests Immunologics Immunology Immunotherapy Infiltration Intervention Intravenous Ligands Link Lymphatic Malignant Neoplasms Mass Spectrum Analysis Metastatic Neoplasm to Lymph Nodes Modeling Mus Neoplasm Circulating Cells Normal tissue morphology Pathology Patients Phenotype Plants Predisposition Privatization Regulatory T-Lymphocyte Relapse Research Research Proposals Signal Transduction Site Switzerland T cell response T-Lymphocyte T-cell receptor repertoire TLR9 gene Technology Texas Time Transgenic Mice Translating Tumor Antigens Tumor Escape Tumor-Infiltrating Lymphocytes Universities Vaccinated Vaccination Vaccine Design Vaccine Production Vaccines Virus-like particle Woman Work anti-tumor immune response cancer immunotherapy cancer therapy cancer type cancer vaccination cell assembly cell type central tolerance clinical translation combat draining lymph node exhaust exome sequencing experience image guided immune checkpoint blockade immune-related adverse events immunoregulation improved intravenous administration lymph nodes lymphatic imaging man mouse model multidisciplinary neoantigen vaccination neoantigens peripheral tolerance permissiveness prevent response safety testing single cell analysis single-cell RNA sequencing transcriptomics triple-negative invasive breast carcinoma tumor tumor growth

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项目摘要

Project Summary T-cell priming is orchestrated in the sequestered environment of lymph nodes (LNs) where a cascade of co- inhibitory and co-stimulatory signals from an assembly of cell types determines systemic, immunodominant responses to regionally presented antigens (Ag). Yet tumor draining LNs (tdLNs) are often tolerized against tumor Ags (tAgs), rendering an otherwise inhospitable environment permissive to regional LN metastases and eventual dissemination throughout the body. While checkpoint blockade immunotherapy (CBI) cancer therapy is meant to re-invigorate T-cell priming and effector function against tAgs, these therapies are administered i.v. without regard to all the other non-tAgs that are present in the body. As a result of this Ag-indiscriminate activity, CBI can cause immune related adverse events (irAEs) that limit the use of current and emerging CBI. In addition, because tdLNs are already tolerized to tAgs by the time of cancer detection, the effectiveness of CBI to potently prime tAg-specific T-cell responses may be limited. While CBI does result in durable cancer cures, most cancer types are non-responsive and the majority of patients with cancers known to be responsive either do not benefit from CBI treatment or experience relapse and irAEs. In this application, multi-disciplinary teams from the University of Texas and University of Bern collaborate to deliver both tAg and CBI to non-tdLNs in order to mount efficient, tAg-directed CBI without the irAEs that impact other CBI combinational therapies. Specifically, the team proposes to develop and use a translatable, plant-based, virus-like-particle (VLP) platform presenting private tumor neoantigens (tNeoAgs) and to combine it with CBI delivered to lymphatic watersheds in syngeneic mouse models of triple negative breast cancer (TNBC). Effectiveness of the approach is evidenced by strong preliminary data showing enhanced anti-tumor responses accompanied by clonal expansion of cytolytic, tAg-specific tumor infiltrating lymphocytes from bioinformatic analyses of single cell RNA sequencing. The team further proposes to separately dose different VLP-tNeoAgs with CBI to discrete lymphatic watersheds to mount multiple, immunodominant responses to combat tumor immune escape and regrowth. The team will also test safety of the approach in a transgenic mouse susceptible to induced lymphatic infiltration in normal tissues as a clinical readout of irAEs following CBI dosing. Because the teams have translated their respective technologies into clinical studies, the developments made herein could be rapidly implemented to improve the efficacy of current and emerging CBI, establish the concept of personalized cancer vaccines, and expand the use of CBI in TNBC patients who have limited treatment options.

项目摘要 T细胞启动在淋巴结（LNS）的隔离环境中进行了策划来自细胞类型组装的抑制性和联合刺激信号决定了系统性的免疫主导作用对区域呈现抗原的反应（AG）。然而，肿瘤排出LN（TDLN）通常被耐受地耐受性肿瘤AGS（标签），使原本不可避免的环境允许区域LN转移和最终在整个身体中传播。同时检查点封锁免疫疗法（CBI）癌症治疗旨在重新侵害T细胞启动和针对标签的效应子功能，这些疗法被施用。不考虑体内存在的所有其他非标签。由于这种Ag-indiscriminate 活性，CBI会导致限制使用电流和新兴CBI的免疫相关的不良事件（IRAE）。另外，由于TDLN在癌症检测时已经耐受性标签，所以 CBI可以限制CBI对特定于TAG的T特异性T细胞响应。虽然CBI确实会导致耐用的癌症治疗方法，大多数癌症类型无反应性，大多数癌症患者已知反应迅速要么不从CBI治疗中受益，要么经验复发和伊拉斯。在此应用中，得克萨斯大学和伯尔尼大学的多学科团队合作将标签和CBI交付到非TDLN，以安装有效的，标签的CBI，而无需IRAE 影响其他CBI组合疗法。具体而言，团队建议开发和使用可翻译的，植物性的，类病毒样粒子（VLP）平台呈现私人肿瘤新抗原（tneoags）并结合在三重阴性乳腺癌的合成小鼠模型中，它将CBI传递到淋巴流域（TNBC）。强大的初步数据表明了该方法的有效性，显示了抗肿瘤伴随着细胞溶解的克隆膨胀的反应，从单细胞RNA测序的生物信息学分析。团队进一步建议分别剂量不同带有CBI的VLP-TNEOAGS，可离散的淋巴流域，以安装多个免疫力反应战斗肿瘤免疫逃生和再生。团队还将在转基因中测试该方法的安全性小鼠在正常组织中容易受到诱导的淋巴浸润，作为CBI后伊拉斯的临床读数给药。由于团队已经将各自的技术转化为临床研究可以迅速实施此处的发展，以提高当前和新兴CBI的功效，建立个性化癌症疫苗的概念，并扩大在具有的TNBC患者中使用CBI的概念有限的治疗选择。