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.

项目摘要嵌合抗原受体（CAR）T细胞是基于肿瘤的基于肿瘤的细胞疗法，正在研究为一种新型免疫疗法治疗胶质母细胞瘤（GBM）。早期的临床发现令人鼓舞，并确定的安全性并展示了抗肿瘤活性，并在至少一个中显示了完全回归病人。但是，在GBM患者中，汽车T疗法的影响并不均匀，我们有限有关在治疗前可以预测功效的知识。鉴定预测生物标志物和优化治疗的方法可以使患者受益并提高疗效，但是有关在实体瘤和切除腔内的运输和分娩。在GBM中，随着肿瘤的生长，从肿瘤通过细胞外的实质从肿瘤进入周围的实质增强的间质流体流量（IFF）基质与入侵细胞和周围的神经胶质相互作用。增加散装流体流动的疗法，例如 IFF通过大脑的细胞外空间也会增加IFF。因此，始终肿瘤进展和治疗干预期间，脑组织暴露于IFF的增强。如果有与细胞浸润改变有关。在外围组织中，由于受伤或感染引起的间隙流体流量增加触发激活的树突状细胞运输以排干淋巴结，并且必须安装适当的免疫反应。这些效果在大脑中的研究很少，但对于了解T细胞的方式至关重要在肿瘤生长和治疗过程中移动。 T细胞对流体剪切应力特别敏感，但是 IFF对T细胞运动的作用尚不清楚。通过MRI在脑肿瘤中MRI的间隙流体流动的非侵入性成像可以帮助临床医生预测治疗期间和之后的T细胞定位模式。因此，我们建议结合MRI技术以测量IFF与预测建模。我们的目标是表征最佳的障碍汽车T细胞给药，并确定成像生物标志物以评估和预测临床反应用于用于胶质母细胞瘤的汽车T细胞疗法。我们假设汽车T细胞疗法的有效性取决于对大脑和肿瘤中患者特异性的液体动力学进行了严格的关键。这个假设使我们进入以下具体目的：特定目标1。确定间质流体流对T细胞迁移的影响脑肿瘤微环境的功效。特定的目标2。调节与临床相关的汽车T细胞输送依靠IFF增加治疗作用的策略。特定目标3。建立预测性数学根据IFF和组织结构研究肿瘤内汽车T细胞运输和分布的模型。影响和可交付成果。这项工作的影响是提高我们对因素的理解，这会影响 CAR T细胞疗法在大脑中的功效，对其他实体瘤有潜在的影响。如果成功，我们将建立易于实施的策略，以利用IFF在汽车T细胞疗法中，又是IFF作为潜力对脑肿瘤中对CAR T细胞疗法的反应的生物标志物，可以在此之前对此进行非侵入性评估治疗，在体内进行纵向延伸，并轻松地纳入正在进行的和将来的临床试验设计中。