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.

项目概要本研究的目的是设计一种能够呈现抗原特异性的人工 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 细胞的功能特征仿生环境捕获淋巴结 (LN) 的关键生化和生物物理特征。 LN 提供关键的微环境，协调抗原特异性信号的呈现格式和动态精确且受控的方式导致 T 细胞激活、扩增和成熟。目前可用的T细胞然而，在携带抗原呈递复合物和共刺激线索的同时刺激基质，缺乏 LN 中 T 细胞刺激微环境固有的足够的支持线索。我们将设计和表征集成了三个关键 T 细胞刺激信号的 aTM：抗原特异性（信号 1）、共刺激（信号 2）和细胞因子（信号 3），以及细胞外基质 (ECM) 分子和可调节的生物物理学其特性受到抗原呈递细胞 (APC) 和 LN 特性的启发。我们将检验假设在 T 细胞刺激期间，在这种仿生环境中共同呈现 APC 信号线索将导致功能性具有受控表型特征和效力的 T 细胞。以及揭示所有信号线索如何协同作用的机制激活并极化 T 细胞。在具体目标 1 中，我们将确定调节鲁棒性的 aTM 的关键矩阵属性使用透明质酸 (HA) 水凝胶和 HA-纳米纤维复合材料 (NHC) 制备的 aTM 激活 CD8+ T 细胞矩阵。在具体目标 2 中，我们将定义影响的最佳信号提示及其呈现配置 aTM 上 CD4+ T 细胞的激活和极化；并展示aTM刺激和的持久性和功能过继转移的抗原特异性 CD4+ T 细胞。在Specific Aim 3中，我们将使用aTM微粒来共同刺激 CD8+ 和 CD4+ T 细胞，并评估 CD4+ 和 CD8+ T 细胞联合治疗的治疗效果癌症免疫治疗小鼠模型。如果成功，这项研究将产生第一套工程 aTM 强烈刺激抗原特异性 CD8+ 和 CD4+ T 细胞，有望改善治疗效果；进一步丰富我们对刺激、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）

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

暴露于 SARS-CoV-2 的个体中 SARS-CoV-2 和甲型流感特异性 T 细胞的交叉反应。

DOI：
发表时间：
2022-09-22
期刊：
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

Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy.

基于纳米颗粒的 CD4 T 细胞效应和辅助功能调节可增强过继性免疫治疗。

DOI：
发表时间：
2022-10-14
期刊：
影响因子：
16.6
作者：
Isser, Ariel;Silver, Aliyah B;Pruitt, Hawley C;Mass, Michal;Elias, Emma H;Aihara, Gohta;Kang, Si;Bachmann, Niklas;Chen, Ying;Leonard, Elissa K;Bieler, Joan G;Chaisawangwong, Worarat;Choy, Joseph;Shannon, Sydney R;Gerecht, Sharon;Webe
通讯作者：
Webe

Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy.

设计用于免疫治疗的人工 T 细胞刺激基质。

DOI：
发表时间：
2019-06
期刊：
影响因子：
0
作者：
Hickey, John W;Dong, Yi;Chung, Jae Wook;Salathe, Sebastian F;Pruitt, Hawley C;Li, Xiaowei;Chang, Calvin;Fraser, Andrew K;Bessell, Catherine A;Ewald, Andrew J;Gerecht, Sharon;Mao, Hai;Schneck, Jonathan P
通讯作者：
Schneck, Jonathan P

Nanoparticles for generating antigen-specific T cells for immunotherapy.

用于生成用于免疫治疗的抗原特异性 T 细胞的纳米颗粒。

DOI：
10.1016/j.smim.2021.101541
发表时间：
2021-08
期刊：
Seminars in immunology
影响因子：
7.8
作者：
Est-Witte SE;Livingston NK;Omotoso MO;Green JJ;Schneck JP
通讯作者：
Schneck JP

In Vivo Stimulation of Therapeutic Antigen-Specific T Cells in an Artificial Lymph Node Matrix.

人工淋巴结基质中治疗性抗原特异性 T 细胞的体内刺激。

DOI：
发表时间：
2024-02-15
期刊：
影响因子：
0
作者：
Livingston, Natalie K;Hickey, John W;Sim, Hajin;Salathe, Sebastian F;Choy, Joseph;Kong, Jiayuan;Silver, Aliyah B;Stelzel, Jessica L;Omotoso, Mary O;Li, Shuyi;Chaisawangwong, Worarat;Roy, Sayantika;Ariail, Emily C;Lanis, Mara R;Pradeep, Prati
通讯作者：
Pradeep, Prati