MRI of tumor-infiltrating lymphocytes using MRI-cytometry

使用 MRI 细胞计数法对肿瘤浸润淋巴细胞进行 MRI 检查

• 批准号: 10419101
• 负责人: Junzhong Xu
• 金额: $ 46.61万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419101
• 关键词: Address; Animal Model; Caliber; Cancer Patient; Cell Fraction; Cell Size; Cells; Clinic; Clinical; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complex; Cytometry; Data; Development; Diffusion; Evaluation; Histology; Image; Image Cytometry; Imaging Device; Immunohistochemistry; Immunotherapy; Infiltration; Injections; Label; Lead; Lymphocyte; Magnetic Resonance Imaging; Mainstreaming; Malignant Neoplasms; Measures; Methods; Modeling; Patients; Performance; Positron-Emission Tomography; Pre-Clinical Model; Prediction of Response to Therapy; Problem Solving; Property; Protocols documentation; Radiation therapy; Relaxation; Reporting; Risk; Slide; Spectrum Analysis; T-Lymphocyte; Testing; Time; Toxic effect; Translating; Tumor Volume; Tumor-Infiltrating Lymphocytes; Validation; Water; base; cancer cell; cancer imaging; castration resistant prostate cancer; conventional therapy; cost; imaging approach; imaging biomarker; imaging modality; immune checkpoint blockade; improved; in vivo; nanoparticle; novel; novel strategies; personalized medicine; pre-clinical; prevent; responders and non-responders; response; single photon emission computed tomography; treatment planning; treatment response; tumor; tumor progression

PROJECT SUMMARY This proposal seeks to further develop and validate a cell-size-based MR imaging method dubbed MRI-cytometry as a novel approach for imaging tumor-infiltrating lymphocytes (TILs), and to evaluate its potential as a surrogate imaging biomarker to predict treatment response to immune-checkpoint blockade (ICB) immunotherapy. ICB is the most widespread class of immunotherapies but it poses a new challenge to assess tumor therapeutic response. ICB induces infiltrations of TILs into tumors to kill cancer, but such increased numbers of TILs may lead to transient tumor enlargement, which is the current indicator of tumor progression i.e., non-responders. Therefore, effective response to ICB could be misdiagnosed as tumor progression i.e., pseudo-progression. There is often a much longer waiting period than conventional treatments to verify the persistence of tumor volume changes, which prevents timely adjustments of treatment plans particularly in non-responder patients, causing unwanted treatment delays, costs, and risks of toxicity. Current mainstream imaging methods require exogenous agents for labeling TILs, which significantly increases cost and risks of toxicity. To overcome these limitations, this application proposes a novel, exogenous-agent-free approach for imaging TILs. Because lymphocytes (5-10 μm in diameter with and without activation) are significantly smaller than most cancer cells (10-20 µm), cell size could be used as an endogenous contrast to distinguish “small” TILs from “large” cancer cells. The significantly increased TILs are expected to cause some unique microstructural changes e.g., decreased mean cell sizes and increased cell fractions of “small” cells. To detect these changes, we recently developed a cell-size-based MRI method dubbed MRI-cytometry for imaging cell size distribution and intracellular volume fractions in vivo. Based on our preliminary data, we hypothesize that MRI-cytometry can serve as a specific imaging biomarker of TILs, and hence can predict treatment response to ICB immunotherapy. To test our hypothesis, we propose three specific aims: Aim 1 [development]: To further develop MRI-cytometry imaging to overcome potentially confounding effects for accurate estimation of microstructural parameters. Aim 2 [validation]: To validate MRI-cytometry imaging to characterize lymphocyte infiltration following ICB immunotherapy using preclinical animal models. Aim 3 [evaluation]: To evaluate MRI-cytometry to predict tumor response to combinations of ICB immunotherapy and radiotherapy. Successful completion of this project will establish a new exogenous-agent-free MRI tool for imaging tumor-infiltrating lymphocytes following immune-checkpoint blockade immunotherapy. It can be used as an “add-on” to clinical MRI to reduce cost and risks of toxicity compared with those lymphocyte labeling methods. Moreover, the proposed approach is expected to be translated to the clinic easily, allowing clinicians to stratify responder and non-responder patients early to adjust treatment plans in the manner of personalized medicine.

项目摘要 该提案旨在进一步开发和验证一种名为单元大小的MR成像方法 MRI - 循环仪是一种新型方法，用于成像肿瘤浸润淋巴细胞（TILS），并评估其 作为替代成像生物标志物的潜力，可以预测对免疫检查封锁（ICB）的治疗反应 ICB是最广泛的免疫疗法类别，但它提出了一个新的挑战。 肿瘤治疗反应。 ICB诱导TIL浸润到肿瘤中杀死癌症，但这种增加 TIL的数量可能导致瞬时肿瘤膨胀，这是肿瘤进展的当前指标，即 非响应者。因此，对ICB的有效反应可能被诊断为肿瘤进展，即 伪发展。等待期通常比常规治疗时间更长 肿瘤体积的持久性变化，这阻止了及时调整治疗计划 无反应的患者，导致不良治疗的延迟，成本和毒性风险。当前主流 成像方法需要外源剂来标记tils，这显着增加了成本和风险 毒性。为了克服这些局限 成像tils。因为淋巴细胞（直径为5-10μm，有和无激活）明显较小 比大多数癌细胞（10-20 µm），细胞大小可用作内源性对比度，以区分“小” tils 来自“大”癌细胞。明显增加的TIL预计会引起一些独特的微观结构 变化，例如，平均细胞大小减少，“小”细胞的细胞部分增加。要检测这些变化， 我们最近开发了一种基于细胞大小的MRI方法，称为MRI - 周期仪，用于成像细胞尺寸分布 和细胞内体积分数在体内。基于我们的初步数据，我们假设MRI - 循环仪可以 用作特定的tils成像生物标志物，因此可以预测对ICB免疫疗法的治疗反应。 为了检验我们的假设，我们提出了三个具体目的：目标1 [开发]：进一步发展MRI - 循环仪 成像以克服潜在的混淆效果，以准确估计微结构参数。目标2 [验证]：验证MRI - 循环仪成像以表征ICB后淋巴细胞浸润 使用临床前动物模型的免疫疗法。 AIM 3 [评估]：评估MRI - 整合仪以预测肿瘤 对ICB免疫疗法和放疗的组合的反应。成功完成该项目将 建立一个新的无代理MRI工具，用于成像肿瘤浸入淋巴细胞之后 免疫检查封锁免疫疗法。它可以用作临床MRI的“附加”，以降低成本和 与这些淋巴细胞标记方法相比，毒性的风险。而且，拟议的方法是 预计将容易转化为诊所，从而使临床医生能够对响应者和无反应患者进行分层 尽早以个性化医学的方式调整治疗计划。