Novel Strategies for Precision T-cell Therapies

精准 T 细胞治疗的新策略

基本信息

批准号：
10003466
负责人：
STEVEN C. ALMO
金额：
$ 11.63万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10003466
关键词：
Address Affinity Alleles Animal Model Antigens Autoantigens Autoimmune Diseases Automobile Driving Avidity Biological Biological Models Biological Response Modifier Therapy CAR T cell therapy CD28 gene CD8-Positive T-Lymphocytes CD8B1 gene CTAG1 gene Cancer Burden Cell Separation Cell Surface Receptors Cell Therapy Cell surface Chimeric Proteins Clinical Trials Clone Cells Communicable Diseases Cross Presentation Data Development Devices Disease Disease regression Dissociation Dose Epitopes Evaluation Exhibits Family G6PC2 gene Genetically Engineered Mouse Goals HLA-A2 Antigen HLA-A2.1 Immunoglobulin A Immunoglobulin G Immunoglobulin M Immunotherapeutic agent Immunotherapy In Vitro Inbred NOD Mice Knowledge Life Link Lymphocyte Malignant Neoplasms Malignant neoplasm of pancreas Microarray Analysis Modeling Molecular Mus Mutate Ovum Pancreas Pancreatic Ductal Adenocarcinoma Patients Peptide/MHC Complex Peptides Peripheral Blood Mononuclear Cell Population Positioning Attribute Process Proteins Protocols documentation Reagent Receptor Signaling Series Signal Pathway Signal Transduction Specificity System T cell therapy T-Cell Activation T-Cell Proliferation T-Lymphocyte Technology Therapeutic Transgenic Mice Transgenic Organisms Translating Variant Work base biophysical properties cancer regression cancer therapy cell injury clinical application design experience flexibility immune function immunological synapse immunoregulation in vivo in vivo evaluation information model insight melanoma mouse model novel novel strategies programs public health relevance receptor scaffold side effect stoichiometry success targeted treatment therapeutic protein therapeutic target treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Immunotherapies, including biologics and cell-based therapies, are emerging as highly promising and effective strategies for the treatment of cancer. Accompanying the great potential of these approaches are continuing challenges, including 1) untargeted global immune modulation associated with biologics, resulting in serious side effects; 2) challenges in scalability of cell-based therapies (e.g., adoptive/CAR-T therapies) and bispecifics, 3) lack of differentiation, as most efforts are focused on relatively few therapeutic targets and mechanisms; and 4) the lack of flexible platforms to rapidly and efficiently target new indications and mechanisms. To address these challenges, we describe a novel class of soluble precision biologics for the treatment of cancer. Our approach manipulates antigen-specific (i.e., clonal) lymphocyte populations by covalently linking single chain peptide-MHC (sc-pMHC) and costimulatory molecules in a manner that recapitulates the proximity, orientation and overall organization experienced at the immunological synapse. The sc-pMHC unit serves to selectively target distinct T cell clones for the delivery of a modulatory domain that can represent any potential costimulatory function. These constructs are generated as Fc-fusion proteins (i.e., IgG) for enhanced avidity and stability. This combined targeting:modulation construct is referred to as synTac (artificial immunological Synapse for T-cell Activation). Using this strategy we have already demonstrated clonal-specific T cell proliferation and activation in vitro, and clonal T cell expansion in vivo. The extreme specificity associated with these reagents eliminates the extensive side effects associated with currently used immunotherapeutics and the highly modular design supports a wide range of indications and therapeutic mechanisms via substitution of the disease relevant peptide epitope and comodulatory modules, respectively. The proposed work focuses on the continued development of the synTac platform for the selective in vivo expansion of CTLs that specifically target malignancies. Our Specific Aims are: AIM 1: Continued development of the synTac fusion protein platform, including the exploration of new presentation platforms with altered stoichiometries and new comodualory domains. AIM 2: Assessment of affinity and overall molecular organization on synTac efficacy to realize new insights into cell surface receptor signaling and new strategies for controlling synTac therapeutic activity. AIM 3: Application of synTacs to specific disease regression models to investigate synTac function in melanoma and pancreatic cancer, using disease and tumor regression models, including HLA-A2 transgenics. The continued success of this program promises to deliver a unique and highly flexible platform for the rapid development, evaluation and implementation of a novel family of biologics to treat a range of indications via a number of distinct mechanisms, and position us to initiate clinical trials for pancreatic ductal adenocarcinoma.

描述（由适用提供）：包括生物制剂和基于细胞的疗法在内的免疫疗法正在成为癌症治疗的高度有希望和有效的策略。伴随着这些方法的巨大潜力是持续的挑战，包括1）与生物制剂相关的非靶向全球免疫调节，从而产生严重的副作用； 2）基于细胞的疗法（例如自适应/CAR-T疗法）和双特异性的挑战，3）缺乏分化，因为大多数努力都集中在相对较少的治疗靶标和机制上； 4）缺乏灵活的平台来快速有效地针对新的指示和机制。为了应对这些挑战，我们描述了一类新型的固体精确生物制剂来治疗癌症。我们的方法通过共价连接单链肽-MHC（SC-PMHC）和共刺激分子来操纵抗原特异性（即克隆）淋巴细胞群体，以缩减接近，方向和整体组织在免疫学突触中经历的方式。 SC-PMHC单元用于选择性地靶向不同的T细胞克隆，用于传递可以代表任何潜在共刺激功能的调节域。这些构建体是作为FC融合蛋白（即IgG）生成的，以增强亲和稳定性。该组合的靶向：调制构建体称为Santac（用于T细胞激活的人工免疫突触）。使用这种策略，我们已经证明了克隆特异性的T细胞增殖和体外激活，以及在体内克隆T细胞的扩张。与这些试剂相关的极为特异性消除了与当前使用的免疫治疗药有关的广泛副作用，并且高度模块化的设计通过替代疾病相关的肽表位和商品模块来支持广泛的适应症和治疗机制。拟议的工作着重于持续开发特定针对Malignancys的CTL的选择性在体内扩展的Santtac平台的持续开发。我们的具体目的是：目标1：持续开发Syntac Fusion蛋白平台，包括探索具有改变石化的新演示平台和新的商品域。 AIM 2：评估亲和力和整体分子组织对Santac效率的评估，以实现对细胞表面受体信号传导的新见解和控制Santtac治疗的新策略活动。 AIM 3：使用疾病和肿瘤回归模型（包括HLA-A2 Transformics），应用于特定疾病回归模型在特定疾病回归模型中的应用在黑色素瘤和胰腺癌中的征态功能。该计划的持续成功有望提供一个独特而高度灵活的平台，用于快速开发，评估和实施新型生物制剂家族，以通过多种不同的机制来治疗一系列适应症，并定位我们启动胰腺导管腺癌的临床试验。