A high-throughput nanoparticle assay to characterize cancer neoepitope-specific T cells

用于表征癌症新表位特异性 T 细胞的高通量纳米颗粒测定

基本信息

批准号：
9916739
负责人：
JONATHAN P SCHNECK
金额：
$ 40.05万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916739
关键词：
Address Adoptive Cell Transfers Affect Alleles Antigen-Presenting Cells Antigens Avidity Biological Assay Blood Cells Blood specimen CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical Clinical Trials Dendritic Cells Detection Development Engineering Epitopes Goals HLA Antigens Histocompatibility Antigens Class I Histology Human Immune Immune Targeting Immune response Immune system Immunologics Immunotherapy Knowledge Laboratories Ligands MHC Class II Genes Magnetic nanoparticles Magnetism Malignant Neoplasms Measures Methods Modeling Mus Mutate Mutation Output PD-1 blockade Patients Peptide/MHC Complex Peptides Peripheral Blood Mononuclear Cell Population Process Proteins Regimen Reproducibility Research Personnel Resected Role Shapes Specificity Splenocyte Surface System T cell response T cell therapy T-Lymphocyte Techniques Technology Testing Therapeutic Time Translating Tumor Antigens Viral Antigens Work anti-CTLA-4 therapy anti-CTLA4 anti-PD-1 antigen-specific T cells base burden of illness cancer cell cancer diagnosis cancer therapy checkpoint inhibition cost density exhaust high risk high throughput screening immune checkpoint blockade immunogenic improved innovation interest melanoma mouse model nanoparticle neoantigens neoplastic cell new technology next generation novel particle patient response patient subsets peripheral blood programmed cell death protein 1 response screening success technology validation therapy development tumor vaccine development

项目摘要

ABSTRACT The application of immunotherapy to cancer has yielded impressive and inspiring results. However, these results seem to only apply to a subset of patients. Many practitioners and researchers are aiming to discover why there are differential responses from patients. Yet existing techniques to characterize cancer do not focus on the immune response itself. Therefore, we aim to fill this gap with a technology that directly characterizes the cancer in terms of its immune response. To do this, we will use a core technology, developed in our labs, that utilizes magnetic nanoparticles to enrich and activate cancer targeting CD8+ T cells to detectable and, potentially even, therapeutic levels. Specifically, we will look for neoepitopes—epitopes generated by the mutations of the cancer itself that can generate an immune response. We have demonstrated feasibility of this approach within both murine and human contexts; however, we have yet to develop the assay into a high- throughput approach that covers a broad heterogenous human population. To do so, we will first engineer the magnetic nanoparticles, called artificial antigen-presenting cells (aAPCs) because they have both an antigen- loaded human leukocyte antigen (HLA) and co-stimulatory molecules on their surface. Engineering parameters will include size, ligand density, and ligand choice. Furthermore, we will extend output by developing a 96-well plate high-throughput version of the assay. We will also broaden the reach of this technology by developing aAPCs for additional class I HLA alleles and also for an aAPC for CD4+ T cell stimulation. Finally, through our collaborative efforts with Dr. Jeff Weber at NYU, we will validate the technology by measuring and detecting neoepitopes from stage IV melanoma patients. We will assess how treatment affects the immune response to the tumor by probing before and after checkpoint blockade therapy. This technology will fill the gap of providing an immunological characterization of cancer in both murine models and critically in patients with cancer. This representation will shape both how therapy is delivered and how the next generation of therapies are developed.

抽象的免疫疗法在癌症中的应用带来了令人印象深刻且令人鼓舞的结果。但是，这些结果似乎仅适用于一部分患者。许多从业者和研究人员的目标是发现为什么患者有不同的反应。然而，现有的特征癌症的技术并不集中关于免疫反应本身。因此，我们旨在用直接表征的技术填补这一空白癌症就其免疫反应而言。为此，我们将使用在实验室中开发的核心技术，这利用磁性纳米颗粒来富集和激活靶向CD8+ T细胞的癌症，以检测到，并且，甚至可能是治疗水平。具体而言，我们将寻找neoeppitopes，这是由可以产生免疫反应的癌症本身的突变。我们已经证明了这一点的可行性在鼠和人类环境中的接近；但是，我们尚未将测定法开发为高涵盖广泛异体人口的吞吐量方法。为此，我们首先要设计磁性纳米颗粒，称为人造抗原呈递细胞（AAPC），因为它们既有抗原在其表面上加载的人白细胞抗原（HLA）和共刺激分子。工程参数将包括尺寸，配体密度和配体选择。此外，我们将通过开发96孔来扩展输出板高通量版本的测定版。我们还将通过开发该技术扩大该技术的影响力 AAPC用于其他I类HLA等位基因以及用于CD4+ T细胞刺激的AAPC。最后，通过我们的与纽约大学Jeff Weber博士的合作努力，我们将通过衡量和检测来验证该技术 IV期黑色素瘤患者的毒药。我们将评估治疗如何影响对通过在检查点阻滞治疗前后探测肿瘤。这项技术将填补提供的空白在鼠模型和癌症患者中，癌症的免疫学表征。这表示既可以塑造治疗的分娩方式以及下一代治疗方式发达。