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

基本信息

批准号：
10698094
负责人：
Junzhong Xu
金额：
$ 45.68万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10698094
关键词：
Address Animal Model Cancer Patient Cell Fraction Cell Size Cells Clinic Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Complex Cytometry Data Development Diameter Diffusion Eligibility Determination Evaluation Histology Image Image Cytometry Imaging Device Immunohistochemistry Immunotherapy Infiltration Injections Label Lymphocyte Lymphocytic Infiltrate Magnetic Resonance Imaging Mainstreaming Malignant Neoplasms Measures Methods Modeling Patients Performance Positron-Emission Tomography Pre-Clinical Model Prediction of Response to Therapy Property Protocols documentation Radiation therapy Relaxation Reporting Risk Slide Spectrum Analysis T-Lymphocyte Testing Toxic effect Translating Tumor Volume Tumor-Infiltrating Lymphocytes Validation Water cancer cell cancer imaging castration resistant prostate cancer conventional therapy cost imaging approach imaging biomarker imaging modality immune checkpoint blockade improved in vivo meter 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

项目摘要

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.

项目概要该提案旨在进一步开发和验证一种基于细胞大小的 MR 成像方法，称为 MRI 细胞计数作为肿瘤浸润淋巴细胞 (TIL) 成像的一种新方法，并评估其作为替代成像生物标志物来预测对免疫检查点阻断（ICB）的治疗反应的潜力 ICB 是最广泛的免疫疗法，但它对评估提出了新的挑战。 ICB 诱导 TIL 浸润到肿瘤中以杀死癌症，但这种效果会增加。 TIL 的数量可能会导致短暂的肿瘤增大，这是当前肿瘤进展的指标，即因此，对 ICB 的有效反应可能会被误诊为肿瘤进展，即：验证假性进展的时间通常比传统治疗要长得多。肿瘤体积变化的持续存在，阻碍了治疗计划的及时调整，特别是在无反应患者，导致不必要的治疗延误、费用和毒性风险。成像方法需要外源试剂来标记 TIL，这显着增加了成本和风险为了克服这些限制，本申请提出了一种新颖的、无外源性试剂的方法。因为淋巴细胞（激活和未激活时直径为 5-10 μm）明显较小。与大多数癌细胞 (10-20 µm) 相比，细胞大小可用作内源性对比来区分“小”TIL 来自“大”癌细胞的显着增加的 TIL 预计会导致一些独特的微观结构。变化，例如，平均细胞大小减小和“小”细胞的细胞分数增加。我们最近开发了一种基于细胞大小的 MRI 方法，称为 MRI 细胞计数法，用于对细胞大小分布进行成像根据我们的初步数据，我们追求 MRI 细胞计数可以测量体内的细胞内体积分数。作为 TIL 的特异性成像生物标志物，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标：目标 1 [开发]：进一步开发 MRI 细胞计数术成像以克服潜在的混杂效应，从而准确估计微观结构参数。 [验证]：验证 MRI 细胞计数成像来表征 ICB 后淋巴细胞浸润的特征使用临床前动物模型进行免疫治疗目标 3 [评估]：评估 MRI 细胞术预测肿瘤的效果。 ICB 免疫疗法和放射疗法组合的反应将成功完成该项目。建立一种新的无外源性 MRI 工具，用于对肿瘤浸润淋巴细胞进行成像免疫检查点阻断免疫疗法可以作为临床 MRI 的“附加”，以降低成本和降低成本。与那些淋巴细胞标记方法相比，该方法存在毒性风险。预计可以轻松转化为临床，从而对有反应和无反应的患者进行分层尽早以个体化医疗的方式调整治疗方案。