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

• 批准号: 10685954
• 负责人: CHRISTINE BROWN
• 金额: $ 66.48万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 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/10685954
• 关键词: Address; Adoptive Transfer; Brain; Brain Neoplasms; CAR T cell therapy; Cell Communication; Cell Therapy; Cells; Central Nervous System; 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; Neuroglia; Patients; Pattern; Peripheral; Role; Route; Safety; Solid Neoplasm; Structure; Surgically-Created Resection Cavity; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissue Engineering; Tissues; Translating; Treatment Efficacy; Work; biomarker evaluation; brain tissue; cell motility; cell type; chimeric antigen receptor; chimeric antigen receptor T cells; clinical biomarkers; clinical imaging; clinical predictors; clinical translation; clinically relevant; 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

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.

项目概要 嵌合抗原受体 (CAR) T 细胞是一种基于肿瘤细胞的疗法，目前正在研究作为一种 胶质母细胞瘤（GBM）的新型免疫疗法。早期临床发现非常令人鼓舞， 确定了安全性并证明了抗肿瘤活性，并且至少在一项研究中显示出完全消退 病人。然而，CAR T 疗法在 GBM 患者中的效果并不统一，而且我们的研究有限 了解治疗前可预测疗效的因素。预测生物标志物的鉴定和 优化治疗的方法可以使患者受益并提高疗效，但在这方面仍有很多未知之处 它们在实体瘤和切除腔内的运输和递送。在 GBM 中，随着肿瘤的生长， 间质液流（IFF）增加，从肿瘤通过细胞外进入周围实质 基质，与入侵细胞和周围的神经胶质细胞相互作用。增加体液流量的疗法，例如 CAR T 细胞的输注还将增加通过大脑细胞外空间的 IFF。因此，自始至终 肿瘤进展和治疗干预期间，脑组织暴露于增强的 IFF 下。国际金融论坛有 与细胞侵袭的改变有关。在外周组织中，由于损伤或感染，间质液流量增加 触发激活的树突状细胞向引流淋巴结的运输，并且有必要安装适当的 免疫反应。这些效应在大脑中的研究很少，但对于理解 T 细胞如何发挥作用至关重要 在肿瘤生长和治疗过程中都会移动。 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 对脑肿瘤间质液流动进行无创成像 可以帮助临床医生预测治疗期间和治疗后 T 细胞定位的模式。因此我们建议 将 MRI 技术与预测模型结合起来测量 IFF。我们的目标是描述实现最佳目标的障碍 CAR T 细胞管理，并识别成像生物标志物以评估和预测临床反应 胶质母细胞瘤的 CAR T 细胞疗法。我们假设 CAR T 细胞疗法的有效性取决于 关键是针对患者特定的大脑和肿瘤中的流体动力学。这个假设引导我们 具体目标如下： 具体目标 1. 确定间质液流动对 T 细胞迁移和 在脑肿瘤微环境中的功效。具体目标 2. 调节临床相关 CAR T 细胞递送 依赖 IFF 来提高治疗效果的策略。具体目标 3. 建立预测数学 基于 IFF 和组织结构来研究肿瘤内 CAR T 细胞运输和分布的模型。影响 和可交付成果。这项工作的影响是增进我们对影响因素的理解 CAR T 细胞疗法在大脑中的功效，对其他实体瘤具有潜在影响。如果成功的话，我们将 建立易于实施的策略，在 CAR T 细胞治疗中利用 IFF 并将 IFF 作为潜在的治疗方法 脑肿瘤 CAR T 细胞治疗反应的生物标志物，可以在治疗前进行非侵入性评估 治疗，在体内进行纵向跟踪，并轻松纳入正在进行和未来的临床试验设计中。