Nanoparticles to Track T Cell Immunotherapy Using Magnetic Particle Imaging

使用磁粒子成像追踪 T 细胞免疫治疗的纳米粒子

基本信息

批准号：
10365339
负责人：
Carlos M Rinaldi-Ramos
金额：
$ 47.21万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365339
关键词：
Adoptive Cell Transfers Affect Animals Anisotropy Benchmarking Biodistribution Biological Assay Biomedical Engineering Blood Circulation Time Caliber Cancer Model Cell Count Cell Survival Cells Charge Coculture Techniques Computer Models Coupled Cytotoxic T-Lymphocytes Defect Disease Dose Electron Microscopy Environment Euthanasia Exocytosis Failure Flow Cytometry Fluorescence Microscopy Foundations Future Generations Glioblastoma Glioma Goals Image Imaging technology Immunotherapy Impact evaluation In Vitro Intracranial Neoplasms Ionizing radiation Label Life Longitudinal Studies Magnetic Resonance Imaging Magnetic nanoparticles Magnetism Malignant Neoplasms Measures Mediating Methods Modeling Modification Molecular Monitor Motivation Multimodal Imaging Mus Organ Oxygen Penetration Performance Phenotype Physics Polymers Preclinical Testing Property Quantitative Evaluations Research Research Project Grants Resolution Route Signal Transduction Site Solid Solid Neoplasm Specificity Stratification Surface T cell therapy T-Lymphocyte Therapeutic Tissues Toxic effect Tracer Validation Work biomaterial development cancer cell cancer immunotherapy cancer therapy clinical translation cytotoxic imaging approach imaging modality immune imaging improved in vivo insight instrumentation interest iron oxide nanoparticle magnetic field melanoma molecular imaging mouse model nanoparticle neoplastic cell nuclear imaging particle preclinical evaluation public health relevance quantitative imaging research and development responders and non-responders response success superparamagnetism tomography tool trafficking treatment response tumor uptake

Adoptive Cell Transfers Affect Animals Anisotropy Benchmarking Biodistribution Biological Assay Biomedical Engineering Blood Circulation Time Caliber Cancer Model Cell Count Cell Survival Cells Charge Coculture Techniques Computer Models Coupled Cytotoxic T-Lymphocytes Defect Disease Dose Electron Microscopy Environment Euthanasia Exocytosis Failure Flow Cytometry Fluorescence Microscopy Foundations Future Generations Glioblastoma Glioma Goals Image Imaging technology Immunotherapy Impact evaluation In Vitro Intracranial Neoplasms Ionizing radiation Label Life Longitudinal Studies Magnetic Resonance Imaging Magnetic nanoparticles Magnetism Malignant Neoplasms Measures Mediating Methods Modeling Modification Molecular Monitor Motivation Multimodal Imaging Mus Organ Oxygen Penetration Performance Phenotype Physics Polymers Preclinical Testing Property Quantitative Evaluations Research Research Project Grants Resolution Route Signal Transduction Site Solid Solid Neoplasm Specificity Stratification Surface T cell therapy T-Lymphocyte Therapeutic Tissues Toxic effect Tracer Validation Work biomaterial development cancer cell cancer immunotherapy cancer therapy clinical translation cytotoxic imaging approach imaging modality immune imaging improved in vivo insight instrumentation interest iron oxide nanoparticle magnetic field melanoma molecular imaging mouse model nanoparticle neoplastic cell nuclear imaging particle preclinical evaluation public health relevance quantitative imaging research and development responders and non-responders response success superparamagnetism tomography tool trafficking treatment response tumor uptake

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项目摘要

Project Summary A critical step in the success of adoptive cell transfer (ACT) T cell immunotherapy in solid cancers is achieving trafficking and persistence of T cells at tumor sites, while avoiding toxicities due to T cell attack of off-target tissues and organs. Non-invasive quantitative imaging would be a powerful tool to understand mechanisms of action and failure of T cell immunotherapies, evaluate the impact of T cell modifications and delivery routes, monitor off-target T cell accumulation, and stratify response to therapy on the basis of measures of T cell tumor accumulation. This Bioengineering Research Grant project will pioneer non-invasive and quantitative tracking of adoptive T cell cancer immunotherapy using magnetic particle imaging (MPI), a new molecular imaging modality that enables non-invasive, unambiguous, and tomographic analysis of the whole-body distribution of superparamagnetic iron oxide nanoparticles (SPIONs). Preliminary results demonstrate non-invasive quantitative tracking of ACT T cells in solid intracranial tumors, synthesis of tracers with enhanced MPI sensitivity, and current sensitivity of 5x103 T cells. The proposed work aims to improve sensitivity to 5x102 T cells and demonstrate the accuracy of MPI in quantifying T cell biodistribution in mouse models of cancer. Modeling of MPI physics by the PI demonstrates that tracers optimal for MPI must have uniform physical and magnetic properties and low magnetocrystalline anisotropy, to enable fast dipole switching at large SPION diameters. The PI has developed a new synthesis that yields defect-free SPIONs with uniform magnetic properties and low magnetocrystalline anisotropy. The proposed work (Aim 1) will couple this new synthesis with modeling of MPI physics and comprehensive physical and magnetic characterization to gain fundamental understanding of the relation between SPION properties and MPI performance and to obtain SPIONs with superior sensitivity. Imaging approaches to track T cells must not compromise their viability or function and T cells pose unique challenges for nanoparticle labeling. The proposed work (Aim 2) will define an upper limit for labeling primary T cells with MPI tracers without compromising viability or function using tracers that associate with T cells through charge interactions. Preliminary studies demonstrate non-invasive tracking of T cell biodistribution in mice using MPI, and that SPION-labeled T cells reach solid tumors after systemic administration in murine models. The proposed work (Aim 3) will validate in vivo tracking of ACT T cell therapy using MPI against T cell counting using flow cytometry and will evaluate dynamics of T cell accumulation in tumors longitudinally using MPI. The proposed biomaterials-development research plan is enabled by the complementary expertise of the PI (SPIONs and MPI physics) and Co-I (ACT T cell therapies) and access to state-of-the-art instrumentation to characterize SPION MPI performance ex vivo and in vivo. Achieving the target sensitivity of 5x102 T cells will provide an order-of- magnitude improvement in quantitative cell tracking sensitivity over other whole body quantitative imaging technologies, establishing MPI as a powerful tool in the immunoimaging toolbox.

项目摘要固体癌症中收养细胞转移（ACT）T细胞免疫疗法成功的关键步骤正在实现 T细胞在肿瘤部位的贩运和持久性，同时避免因靶靶的T细胞攻击引起的毒性组织和器官。非侵入性定量成像将是了解理解机制的强大工具 T细胞免疫疗法的作用和失败，评估T细胞修饰和输送途径的影响，监测靶向脱靶T细胞的积累，并根据T细胞肿瘤的措施对治疗的反应进行分层积累。这个生物工程研究赠款项目将开创非侵入性和定量跟踪使用磁性颗粒成像（MPI），采用T细胞癌免疫疗法，一种新的分子成像方式这使得无创，明确和断层扫描分析对整体分布超磁铁氧化铁纳米颗粒（SPIONS）。初步结果表明非侵入性固体颅内肿瘤中ACT T细胞的定量跟踪，合成具有增强MPI敏感性的示踪剂， 5x103 T细胞的电流灵敏度。提出的工作旨在提高对5x102 T细胞的敏感性，并证明了MPI在量化T细胞生物分布中的准确性。建模 PI的MPI物理学表明，MPI最佳的示踪剂必须具有均匀的物理和磁性性质和低磁晶的各向异性，以在大SPION直径下快速偶极子开关。这 PI开发了一种新的合成，该合成产生具有均匀磁性和低磁性特性的无缺陷SPION 磁晶的各向异性。拟议的工作（AIM 1）将将这种新合成与MPI建模相结合物理和全面的物理和磁性表征，以获得对 SPION性质与MPI性能之间的关系，并获得具有较高灵敏度的SPION。成像跟踪T细胞的方法不得损害其生存能力或功能，T细胞构成了独特的挑战用于纳米颗粒标记。拟议的工作（AIM 2）将定义将原代T细胞标记的上限 MPI示踪剂而不损害可生存能力或功能，使用通过电荷与T细胞相关联的示踪剂互动。初步研究表明，使用MPI的小鼠中T细胞生物分布的无创追踪，在鼠模型中，全身给药后，该标记的T细胞进入实体瘤。提议工作（AIM 3）将使用MPI使用MPI对T细胞计数进行使用流量来验证TACT T细胞疗法的体内跟踪细胞仪并将使用MPI纵向评估肿瘤中T细胞积累的动力学。提议生物材料开发研究计划由PI的互补专业知识（SPIONS和MPI）启用物理学）和Co-I（ACT T细胞疗法），并获得最先进的仪器以表征SPION MPI性能离体和体内。达到5x102 T细胞的目标灵敏度将提供与其他全身定量成像相比，定量细胞跟踪敏感性的幅度改善技术，将MPI建立为免疫影像工具箱中的强大工具。