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

项目摘要 嵌合抗原受体（CAR）T细胞是基于肿瘤嗜性细胞的疗法，其正在被研究作为一种治疗方法。 胶质母细胞瘤（GBM）的新型免疫疗法。早期的临床结果非常令人鼓舞， 已确定的安全性和已证实的抗肿瘤活性，并在至少一种情况下显示出完全消退 病人然而，CAR T疗法的效果在GBM患者中并不一致，我们对GBM患者的研究有限。 在治疗前了解什么可以预测疗效。预测性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数。 涉及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， 增强的间质液流（IFF）从肿瘤通过细胞外基质进入周围实质， 基质，与入侵细胞和周围胶质细胞相互作用。增加大量液体流动的疗法，例如 CAR T细胞的输注也将通过脑的细胞外空间增加IFF。因此，在整个 肿瘤进展和治疗干预期间，脑组织暴露于增强的IFF。IFF有 与改变细胞入侵有关在外周组织中，由于损伤或感染导致的间质液流量增加 触发了活化的树突状细胞向引流淋巴结的运输，并且是安装适当的 免疫反应这些影响在大脑中的研究很少，但对于理解T细胞如何在大脑中发挥作用至关重要。 在肿瘤生长和治疗过程中移动。然而，T细胞对流体剪切应力特别敏感， IFF对T细胞运动性的作用是未知的。脑肿瘤间质液流动的MRI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 将联合收割机MRI技术与预测建模相结合来测量IFF。我们的目标是描述障碍， CAR T细胞给药，并鉴定用于评价和预测临床应答的成像生物标志物 到CAR-T细胞治疗胶质母细胞瘤我们假设CAR T细胞疗法的有效性取决于 关键在于大脑和肿瘤中的流体动力学，这是患者特异性的。这一假设使我们 具体目标如下：具体目标1。确定间质液流动对T细胞迁移的影响， 在脑肿瘤微环境中的功效。具体目标2。调节临床相关的CAR T细胞递送 依赖IFF来提高治疗效果的策略。具体目标3。建立预测数学模型 模型来研究基于IFF和组织结构的CAR T细胞在肿瘤内的运输和分布。影响 和可交付成果。这项工作的影响是促进我们对影响因素的理解， CAR T细胞疗法在脑中的疗效，对其他实体瘤具有潜在意义。如果成功，我们将 建立易于实施的策略，以在CAR T细胞治疗中利用IFF，并将IFF作为潜在的 在脑肿瘤中对CAR T细胞疗法的反应的生物标志物，其可以在治疗前进行非侵入性评估。 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.