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Biomimetic Matrix for Ex Vivo and In Vivo Activation of T Cells

用于 T 细胞离体和体内激活的仿生基质

基本信息

批准号：
10608176
负责人：
Hai-Quan Mao
金额：
$ 47.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608176
关键词：
3-Dimensional Adoptive Transfer Animal Model Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Autoimmune Binding Binding Sites Biochemical Biomechanics Biomimetics Biophysics CD4 Positive T Lymphocytes CD44 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Adhesion Cells Cellular biology Combined Modality Therapy Complex Cues Data Development Engineering Extracellular Matrix Gel Human Hyaluronic Acid Hydrogels Immunotherapy In Vitro Injectable Interleukin-2 Malignant Neoplasms Mediating Modeling Mus Outcome Study Pathogenicity Phenotype Population Proliferating Property Proteins Publishing Research Personnel Role Signal Transduction T cell therapy T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Therapeutic Effect Treatment Cost Treatment Efficacy Work adaptive immunity anti-cancer biophysical properties cancer immunotherapy cell killing cytokine density design effector T cell engineering design exhaustion experience fighting improved in vivo innovation invention lymph node microenvironment lymph nodes mouse model nanofiber nanoparticle nanopolymer novel novel strategies particle response subcutaneous synergism therapy outcome

项目摘要

PROJECT SUMMARY The objective of this study is to engineer an artificial T cell-stimulating matrix (aTM) that presents antigen-specific and cell-specific biochemical and biophysical cues to control phenotype and improve functional profiles of T cells in a biomimetic context that captures key biochemical and biophysical features of the lymph node (LN). LN provides the critical microenvironment that orchestrates the presentation format and dynamics of the antigen-specific signals in a precise and controlled manner that leads to T cell activation, expansion, and maturation. Currently available T cell stimulating matrices while carrying the antigen-presentation complexes and co-stimulating cues, however, lacks adequate supporting cues inherent to the T cell stimulating microenvironment in the LN. We will design and characterize an aTM that integrates the three key T-cell stimulating signals: antigen-specific (Signal 1), co-stimulatory (Signal 2), and cytokines (Signal 3), together with extracellular matrix (ECM) molecules and tunable biophysical properties inspired by the properties of both antigen-presenting cells (APCs) and the LN. We will test the hypothesis that co-presenting the APC signal cues in such a biomimetic context during T cell stimulation will result in functional T cells with controlled phenotypic profiles and potency. and mechanism revealing how all signaling cues synergize to active and polarize T cells. In Specific Aim 1, we will determine key matrix properties of the aTM that mediate robust CD8+ T cell activation using aTMs prepared from hyaluronic acid (HA) hydrogel and HA-nanofiber composite (NHC) matrix. In Specific Aim 2, we will define optimal signaling cues and their presentation configuration that influence CD4+ T cell activation and polarization on aTM; and demonstrate persistence and functions of aTM-stimulated and adoptively transferred antigen-specific CD4+ T cells. In Specific Aim 3, we will use aTM microparticles to co-stimulate CD8+ and CD4+ T cells and evaluate therapeutic benefits of a combination treatment with CD4+ and CD8+ T cells in a cancer immunotherapy mouse model. If successful, this study will result in the first set of engineered aTM that delivers robust stimulation of antigen-specific CD8+ and CD4+ T cells that promise improved therapeutic outcomes; and further enrich our understandings of design principles and mechanism of signaling cues in stimulation, polarization, and activation of T cells.

项目摘要本研究的目的是设计一种人工T细胞刺激基质（aTM），以及细胞特异性生化和生物物理线索，以控制表型并改善T细胞的功能概况，仿生背景，其捕获淋巴结（LN）的关键生物化学和生物物理特征。LN提供了关键的微环境，其协调抗原特异性信号的呈现格式和动力学，精确和受控的方式，导致T细胞活化，扩增和成熟。目前可用的T细胞然而，携带抗原呈递复合物和共刺激因子的刺激基质缺乏 LN中T细胞刺激微环境固有的足够的支持线索。我们将设计和表征整合了三种关键T细胞刺激信号的aTM：抗原特异性（信号1）、共刺激性（信号2）、免疫调节性（信号3）和免疫调节性（信号4）。细胞因子（信号2）和细胞因子（信号3），连同细胞外基质（ECM）分子和可调生物物理活性分子，受抗原呈递细胞（APC）和LN的性质启发的性质。我们将检验这个假设在T细胞刺激过程中，在这种仿生环境中共同呈递APC信号提示将导致功能性具有受控表型特征和效力的T细胞。揭示了所有信号线索如何协同作用，活化和活化T细胞。在具体目标1中，我们将确定aTM的关键矩阵属性，使用由透明质酸（HA）水凝胶和HA-HA复合物（NHC）制备的aTM的CD 8 + T细胞活化矩阵在具体目标2中，我们将定义最佳信号提示及其呈现配置， aTM上的CD 4 + T细胞活化和极化;并证明aTM刺激的CD 4 + T细胞活化和极化的持续性和功能。过继转移的抗原特异性CD 4 + T细胞。在特定目标3中，我们将使用aTM微粒来共刺激 CD 8+和CD 4 + T细胞的联合治疗，并评估CD 4+和CD 8 + T细胞在癌症免疫治疗小鼠模型。如果成功的话，这项研究将产生第一组工程化的aTM， - 提供对抗原特异性CD 8+和CD 4 + T细胞的强刺激，这有望改善治疗结果; 进一步丰富了我们对信号线索在刺激，极化，和T细胞的激活。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy.

DOI：
10.1002/adma.201807359
发表时间：
2019-06
期刊：
Advanced materials (Deerfield Beach, Fla.)
影响因子：
0
作者：
Hickey JW;Dong Y;Chung JW;Salathe SF;Pruitt HC;Li X;Chang C;Fraser AK;Bessell CA;Ewald AJ;Gerecht S;Mao HQ;Schneck JP
通讯作者：
Schneck JP

Biomaterials to enhance antigen-specific T cell expansion for cancer immunotherapy.

生物材料可增强抗原特异性T细胞扩张以进行癌症免疫疗法。

DOI：
10.1016/j.biomaterials.2020.120584
发表时间：
2021-01
期刊：
Biomaterials
影响因子：
14
作者：
Isser A;Livingston NK;Schneck JP
通讯作者：
Schneck JP

Cross-reactivity of SARS-CoV-2- and influenza A-specific T cells in individuals exposed to SARS-CoV-2.

DOI：
10.1172/jci.insight.158308
发表时间：
2022-09-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Chaisawangwong, Worarat;Wang, Hanzhi;Kouo, Theodore;Salathe, Sebastian F.;Isser, Ariel;Bieler, Joan Glick;Zhang, Maya L.;Livingston, Natalie K.;Li, Shuyi;Horowitz, Joseph J.;Samet, Ron E.;Zyskind, Israel;Rosenberg, Avi Z.;Schneck, Jonathan P.
通讯作者：
Schneck, Jonathan P.

Nanoparticles for generating antigen-specific T cells for immunotherapy.