权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The impact of interstitial fluid flow on CAR T cell trafficking, distribution, and efficacy

间质液流动对 CAR T 细胞运输、分布和功效的影响

基本信息

批准号：
10427253
负责人：
CHRISTINE BROWN
金额：
$ 67.18万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427253
关键词：
Address Adoptive Transfer Brain Brain Neoplasms CAR T cell therapy Cell Communication Cell Therapy Cells Cerebrospinal Fluid Cities Clinical Clinical Treatment Clinical Trials Design Computer Models Data Dendritic Cells Disease ERBB2 gene Effectiveness Exposure to Extracellular Matrix Extracellular Space Future Glioblastoma Goals Imaging Techniques Immune Immune response Immunotherapy In Vitro Infection Infiltration Infusion procedures Injury Intercellular Fluid Invaded Knowledge Link Liquid substance Location Magnetic Resonance Imaging Malignant Neoplasms Measures Mediating Modeling Monitor Mus Neuraxis Neuroglia Patients Pattern Peripheral Role Route Safety Solid Neoplasm Structure Surgically-Created Resection Cavity T-Lymphocyte Therapeutic Therapeutic Effect Therapeutic Intervention Tissue Engineering Tissues Translating Treatment Efficacy Tumor-Derived Work base biomarker evaluation brain tissue cell motility cell type chimeric antigen receptor chimeric antigen receptor T cells clinical biomarkers clinical imaging clinical predictors clinically relevant clinically translatable draining lymph node early phase clinical trial effective therapy fluid flow imaging biomarker improved in vivo innovation mathematical model migration multidisciplinary neoplastic cell non-invasive imaging novel potential biomarker predictive marker predictive modeling programs receptor response response biomarker shear stress trafficking treatment optimization tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Chimeric Antigen Receptor (CAR) T-cells are tumor-tropic cell-based therapies that are being investigated as a novel immunotherapy treatment for glioblastoma (GBM). Early clinical findings are highly encouraging, with established safety and demonstrated antitumor activity, and have shown complete regression in at least one patient. However, the effects of CAR T therapies are not uniform across GBM patients, and we have limited knowledge about what may predict efficacy prior to treatment. Identification of predictive biomarkers and approaches to optimize therapy could benefit patients and increase efficacy, yet much is still unknown in regards to their transport and delivery within solid tumors and resection cavities. In GBM, as the tumor grows, there is heightened interstitial fluid flow (IFF) from the tumor into the surrounding parenchyma through the extracellular matrix, interacting with invading cells and surrounding glia. Therapies that increase bulk fluid flow such as infusion of CAR T-cells will also increase IFF through the extracellular spaces of the brain. Thus, throughout tumor progression and during therapeutic intervention, the brain tissue is exposed to heightened IFF. IFF has been linked to altered cell invasion. In peripheral tissues, increased interstitial fluid flow due to injury or infection triggers trafficking of activated dendritic cells to draining lymph nodes, and is necessary to mount an appropriate immune response. These effects are poorly studied in the brain but are critical to understanding how T-cells move both during tumor growth and therapy. T-cells are particularly responsive to fluid shear stress, however, the role of IFF on T-cell motility is unknown. Non-invasive imaging of interstitial fluid flow via MRI in brain tumors could help clinicians predict patterns of T-cell localization during and after therapy. We therefore propose to combine MRI techniques to measure IFF with predictive modeling. Our goal is to characterize barriers to optimal CAR T-cell administration, and to identify imaging biomarkers for evaluation and prediction of clinical response to CAR T-cell therapies for glioblastoma. We hypothesize that the effectiveness of CAR T-cell therapy depends critically on fluid dynamics in the brain and in the tumor, which are patient-specific. This hypothesis leads us to the following specific aims: Specific Aim 1. Identify the impact of interstitial fluid flow on T-cell migration and efficacy in the brain tumor microenvironment. Specific Aim 2. Modulate clinically-relevant CAR T-cell delivery strategies that depend on IFF to increase therapeutic effect. Specific Aim 3. Build predictive mathematical models to study CAR T-cell trafficking and distribution within the tumor based on IFF and tissue structure. Impact and deliverables. The impact of this work is to advance our understanding of factors, which influence the efficacy of CAR T-cell therapy in the brain, with potential implications for other solid tumors. If successful, we will establish both readily implementable strategies to leverage IFF in CAR T-cell therapy and IFF as a potential biomarker of response to CAR T-cell therapy in brain tumors, which can be evaluated non-invasively prior to treatment, followed longitudinally in vivo, and easily incorporated into ongoing and future clinical trial designs.

项目总结