NIH Administrative Supplement to Promote Diversity in Health Related Research

NIH 促进健康相关研究多样性的行政补充

基本信息

批准号：
10876754
负责人：
Carlos M Rinaldi-Ramos
金额：
$ 3.62万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10876754
关键词：
Administrative Supplement Adoptive Cell Transfers Affect Animals Anisotropy Benchmarking Biodistribution Biological Assay Biomedical Engineering Blood Circulation Time Cancer Model Cell Count Cell Survival Cell Therapy Cells Charge Coculture Techniques Computer Models Coupled Cytotoxic T-Lymphocytes Defect Diameter Disease Dose Electron Microscopy Elements Environment Euthanasia Exocytosis Failure Flow Cytometry Fluorescence Microscopy Foundations Future Generations Glioblastoma Glioma Goals Health 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 Qualifying 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 United States National Institutes of Health 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

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.

项目概要实体癌过继细胞移植 (ACT) T 细胞免疫疗法成功的关键一步是实现 T 细胞在肿瘤部位的运输和持续存在，同时避免由于 T 细胞攻击脱靶而产生的毒性组织和器官。非侵入性定量成像将是理解机制的有力工具 T 细胞免疫疗法的作用和失败，评估 T 细胞修饰和递送途径的影响，监测脱靶 T 细胞积累，并根据 T 细胞肿瘤的测量对治疗反应进行分层积累。该生物工程研究资助项目将开创非侵入性和定量跟踪使用磁性粒子成像 (MPI)（一种新的分子成像方式）进行过继性 T 细胞癌症免疫治疗能够对全身分布进行非侵入性、明确的断层扫描分析超顺磁性氧化铁纳米颗粒（SPION）。初步结果表明非侵入性定量追踪颅内实体瘤中的 ACT T 细胞，合成具有增强 MPI 敏感性的示踪剂，和 5x103 T 细胞的当前敏感性。拟议的工作旨在提高对 5x102 T 细胞的敏感性证明 MPI 在量化小鼠癌症模型中 T 细胞生物分布方面的准确性。建模 PI 的 MPI 物理学表明，最适合 MPI 的示踪剂必须具有均匀的物理和磁性特性和低磁晶各向异性，可在大 SPION 直径下实现快速偶极子切换。这 PI 开发了一种新的合成方法，可产生无缺陷的 SPION，具有均匀的磁性能和低磁晶各向异性。拟议的工作（目标 1）将把这种新的综合与 MPI 建模结合起来物理和全面的物理和磁性表征，以获得对 SPION 特性和 MPI 性能之间的关系，并获得具有优异灵敏度的 SPION。影像学追踪 T 细胞的方法不得损害其活力或功能，并且 T 细胞面临独特的挑战用于纳米颗粒标记。拟议的工作（目标 2）将定义标记原代 T 细胞的上限 MPI 示踪剂使用通过电荷与 T 细胞关联的示踪剂，不会影响活力或功能互动。初步研究表明使用 MPI 对小鼠 T 细胞生物分布进行非侵入性追踪， SPION 标记的 T 细胞在小鼠模型中全身给药后到达实体瘤。拟议的工作（目标 3）将验证使用 MPI 对使用流式细胞计数的 ACT T 细胞治疗进行体内跟踪细胞计数，并将使用 MPI 纵向评估肿瘤中 T 细胞积累的动态。拟议的生物材料开发研究计划是通过 PI（SPION 和 MPI）的互补专业知识来实现的物理学）和 Co-I（ACT T 细胞疗法），并使用最先进的仪器来表征 SPION MPI 体外和体内性能。实现 5x102 T 细胞的目标灵敏度将提供以下数量级：与其他全身定量成像相比，定量细胞追踪灵敏度大幅提高技术，使 MPI 成为免疫成像工具箱中的强大工具。