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

• 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
• 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

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.

摘要 免疫疗法在癌症中的应用已经取得了令人印象深刻和鼓舞人心的结果。但这些 结果似乎只适用于一部分患者。许多从业者和研究人员的目标是发现 为什么病人的反应不同然而，现有的描述癌症的技术并没有关注 免疫反应本身。因此，我们的目标是用一种直接表征 癌症的免疫反应。为了做到这一点，我们将使用一项核心技术，在我们的实验室开发， 利用磁性纳米颗粒富集和激活癌症靶向CD 8 + T细胞， 甚至可能达到治疗水平具体地说，我们将寻找新表位--由蛋白质产生的表位。 癌症本身的突变可以产生免疫反应。我们已经证明了这一点的可行性 方法在鼠和人的情况下;然而，我们还没有发展到一个高， 这是一种涵盖广泛异质人群的通量方法。为此，我们将首先设计 磁性纳米颗粒，称为人工抗原呈递细胞（aAPC），因为它们既有抗原， 在它们的表面上装载人类白细胞抗原（HLA）和共刺激分子。工程参数 将包括大小、配体密度和配体选择。此外，我们将通过开发一个96井， 平板高通量版本的测定。我们还将通过开发 用于额外的I类HLA等位基因的aAPC以及用于CD 4 + T细胞刺激的aAPC。最后，通过我们的 与纽约大学的杰夫·韦伯博士合作，我们将通过测量和检测来验证这项技术。 来自IV期黑素瘤患者的新表位。我们将评估治疗如何影响免疫反应， 在检查点阻断治疗之前和之后探测肿瘤。这项技术将填补差距提供 在小鼠模型和严重的癌症患者中的癌症的免疫学表征。这 代表性将塑造如何提供治疗以及下一代治疗如何 开发