Co-Clinical Research Resource for Imaging Tumor Associated Macrophages

肿瘤相关巨噬细胞成像联合临床研究资源

基本信息

批准号：
10688045
负责人：
Heike Elizabeth Daldrup-Link
金额：
$ 63.91万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688045
关键词：
Aftercare Animal Model Biological Markers Blocking Antibodies CD47 gene Cell physiology Cell surface Cells Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Communities Computer software Consensus Darkness Data Data Pooling Development Diagnosis Disease Eating Elements FDA approved Goals Growth Healthcare Histology Hour Image Imaging Device Imaging Techniques Immunotherapy Industry Injections Institution Integral Membrane Protein Intravenous Investigation Learning Magnetic Resonance Imaging Malignant Neoplasms Maps Methods Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Multi-Institutional Clinical Trial Necrosis Neoplasm Metastasis Operative Surgical Procedures Outcome Measure Patient-Focused Outcomes Patients Phagocytes Pharmaceutical Preparations Phase Phase I Clinical Trials Positioning Attribute Prediction of Response to Therapy Protocols documentation Reference Standards Reproducibility Research Research Personnel Resources SHPS-1 protein Signal Transduction Speed Standardization Testing Therapeutic Time Translating Tumor-associated macrophages Work anticancer activity cancer cell cancer clinical trial cancer imaging cancer immunotherapy cancer therapy chemotherapy clinical application clinical imaging clinical investigation clinical translation co-clinical trial comparative efficacy design efficacy study ferumoxytol first-in-human imaging approach imaging biomarker imaging modality imaging study immunomodulatory therapies improved improved outcome in vivo interest intravenous injection iron oxide nanoparticle iron supplement mouse model nanoparticle neoplastic cell next generation novel novel therapeutics off-label use osteosarcoma patient population pediatric patients pre-clinical preclinical imaging preclinical study predicting response quantitative imaging receptor response sarcoma treatment response treatment stratification tumor tumor eradication tumor growth tumor progression uptake web-accessible

项目摘要

Co-Clinical Research Resource for Imaging Tumor Associated Macrophages ABSTRACT The development of quantitative imaging (QI) methods for monitoring cancer therapy response has been transformative for the development of novel cancer therapeutics. QI efforts have positioned imaging as a key element in the design of clinical trials for cancer therapy response assessment. Hence, there is increased interest by the academic and industry sectors to use web accessible research resources and develop consensus approaches to validate QI methods for the next generation of clinical trials. This is particularly relevant for assessment of cancer immunotherapy, since immunotherapy does not lead to a decrease in tumor size, at least not in the immediate post-treatment phase. Therefore, we urgently need new QI tools that can monitor tumor response to novel immunotherapies. The overall goal of our project is to optimize and validate preclinical and clinical imaging techniques for in vivo quantification of tumor associated macrophages (TAM) in osteosarcomas. Recent evidence has shown that the abundant TAM response in the microenvironment of bone sarcomas can be employed to directly attack cancer cells. Blockade of the cell surface molecule CD47 expressed on sarcoma cells resulted in activation of phagocytic anti-cancer activity from TAM and efficiently eradicated tumor cells in mouse models of osteosarcoma. 26 Preclinical studies have been finalized and a multi-center phase I clinical trial is currently being planned, with expected start date in 2021. To solve the unmet clinical need for a QI tool to monitor response to new TAM- modulating therapies, our team developed a quantitative TAM imaging test, which relies on intravenous injection of the iron supplement ferumoxytol. Ferumoxytol is composed of iron oxide nanoparticles, which are phagocytosed by TAM and can be quantified with T2*-weighted MRI 45. Since ferumoxytol is FDA-approved and can be used “off label” as a TAM biomarker, it is immediately clinically available. We showed that ferumoxytol-MRI can detect TAM in osteosarcomas in mouse models 21 and patients 25. Through this project, we will (a) optimize and validate pre-clinical quantitative imaging methods for TAM imaging in an established mouse model of osteosarcoma, (b) implement the optimized methods in a co-clinical trial in patients with osteosarcoma who are undergoing immunotherapy with CD47 mAb, and finally (c) populate a web-accessible research resource with all the data, methods, and results collected from the co-clinical investigations. Developing the proposed imaging test could represent a significant breakthrough for clinicians as a new means for treatment stratification and new gold-standard imaging test for predicting treatment response of novel immunotherapies. Our QI imaging test could be utilized to compare the efficacy of different immune-modulating therapies in preclinical settings and translate the most primising candidates to the clinic. Since the development of new therapeutic drugs is expensive and take years to complete, the immediate value and heath care impact of our QI tool could be immense.

肿瘤相关巨噬细胞成像联合临床研究资源抽象的用于监测癌症治疗反应的定量成像（QI）方法的发展已经 QI 的努力对新型癌症疗法的发展具有变革性，将成像定位为因此，这是癌症治疗反应评估临床试验设计的关键要素。学术界和工业界对使用可通过网络访问的研究资源的兴趣日益浓厚制定共识方法来验证下一代临床试验的 QI 方法。对于癌症免疫治疗的评估特别相关，因为免疫治疗不会导致肿瘤尺寸的减小，至少在治疗后阶段不会减小，因此，我们迫切需要新的治疗方法。可以监测肿瘤对新型免疫疗法的反应的 QI 工具我们项目的总体目标是优化和验证用于肿瘤体内定量的临床前和临床成像技术最近的证据表明，骨肉瘤中存在丰富的 TAM。骨肉瘤微环境中的反应可用于直接攻击癌细胞。阻断肉瘤细胞上表达的细胞表面分子 CD47 导致吞噬细胞的激活 TAM 具有抗癌活性，并能有效根除骨肉瘤小鼠模型中的肿瘤细胞 26。临床前研究已完成，目前正在计划进行多中心I期临床试验，预计开始日期为 2021 年。为了解决对 QI 工具的未满足的临床需求，以监测对新 TAM 的反应为了调节治疗，我们的团队开发了一种 TAM 成像测试，该测试定量依赖于静脉注射注射铁补充剂 Ferumoxytol 由氧化铁纳米粒子组成，其成分是被 TAM 吞噬，并可通过 T2* 加权 MRI 45 进行量化。由于 ferumoxytol 已获得 FDA 批准并且可以“标签外”用作 TAM 生物标志物，我们证明它可以立即投入临床使用。 ferumoxytol-MRI 可检测小鼠模型 21 和患者 25 骨肉瘤中的 TAM。项目中，我们将 (a) 优化和验证 TAM 成像的临床前定量成像方法建立骨肉瘤小鼠模型，（b）在联合临床中实施优化方法在接受 CD47 mAb 免疫治疗的骨肉瘤患者中进行试验，最后 (c) 用收集到的所有数据、方法和结果填充可通过网络访问的研究资源从联合临床研究来看，开发所提议的成像测试可能具有重要意义。作为治疗分层的新手段和新的金标准成像测试，参议员们取得了突破我们的 QI 成像测试可用于预测新型免疫疗法的治疗反应。不同免疫调节疗法在临床前环境中的功效，并转化为最令人兴奋的结果由于新治疗药物的开发成本高昂且需要数年时间才能进入临床。完成后，我们的 QI 工具的直接价值和健康保健影响可能是巨大的。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Measurement of Tumor T2* Relaxation Times after Iron Oxide Nanoparticle Administration.

氧化铁纳米颗粒给药后肿瘤 T2* 弛豫时间的测量。

DOI：
发表时间：
2023-05-19
期刊：
影响因子：
0
作者：
Ramasamy, Shakthi Kumaran;Roudi, Raheleh;Morakote, Wipawee;Adams, Lisa C;Pisani, Laura J;Moseley, Michael;Daldrup
通讯作者：
Daldrup