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

项目总结 嵌合抗原受体(CAR)T细胞是一种基于肿瘤的细胞疗法，正在作为一种 胶质母细胞瘤(GBM)的新免疫疗法。早期临床发现非常令人鼓舞， 已确定的安全性和显示的抗肿瘤活性，并至少有一例显示完全消退 有耐心的。然而，CAR T疗法在GBM患者中的效果并不一致，我们的研究有限 在治疗前了解什么可以预测疗效。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，但仍有许多未知之处。 到它们在实体瘤和切除腔内的运输和输送。在GBM中，随着肿瘤的生长，有 间质液体流量(IFF)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，如 CAR T细胞的输注也会通过大脑的细胞外间隙增加IFF。因此，自始至终 在肿瘤进展和治疗干预期间，脑组织暴露在高强度的IFF中。IFF有 与改变的细胞入侵有关。在外周组织中，由于损伤或感染导致间质液体流量增加 触发激活的树突状细胞向引流淋巴结的运输，并且是安装适当的 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 在肿瘤生长和治疗期间都会移动。然而，T细胞对流体剪切力特别敏感， IFF在T细胞运动中的作用尚不清楚。脑肿瘤间质液体流动的MRI无创性成像 可以帮助临床医生预测治疗过程中和治疗后T细胞定位的模式。因此，我们建议 将MRI技术与预测建模相结合来测量IFF。我们的目标是描述达到最佳状态的障碍 CAR T细胞给药，并确定用于评估和预测临床反应的成像生物标记物 为治疗胶质母细胞瘤提供T细胞疗法。我们假设CAR T细胞疗法的有效性取决于 关键是大脑和肿瘤中的液体动力学，这是患者特有的。这一假设将我们引向 以下具体目标：具体目标1.确定间质液体流动对T细胞迁移和 在脑肿瘤微环境中的疗效。特定目标2.调节与临床相关的CAR T细胞的传递 依靠IFF提高治疗效果的策略。具体目标3.建立预测数学 基于IFF和组织结构研究CAR T细胞在肿瘤内的运输和分布的模型。影响 和交付成果。这项工作的影响是增进我们对影响经济增长的因素的理解 CAR T细胞治疗在大脑中的有效性，以及对其他实体肿瘤的潜在影响。如果成功，我们将 建立两个易于实施的战略，以利用IFF在CAR T细胞治疗中的作用，并将IFF作为潜在的 脑肿瘤对CAR T细胞治疗反应的生物标志物，可在治疗前进行无创评估 治疗，在体内纵向跟踪，并很容易纳入正在进行的和未来的临床试验设计。

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.