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

• 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
• 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

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的联合临床研究资源 摘要 用于监测癌症治疗反应的定量成像（QI）方法的发展已经 对于新型癌症治疗方法的发展具有变革性意义。QI努力将成像定位为 癌症治疗反应评估临床试验设计的关键要素。因此，有 学术界和工业界对使用网上可访问的研究资源的兴趣增加， 开发共识方法，以验证下一代临床试验的QI方法。这是 与癌症免疫疗法的评估特别相关，因为免疫疗法不会导致癌症复发。 肿瘤尺寸减小，至少在治疗后即刻不减小。因此，我们迫切需要新的 QI工具可以监测肿瘤对新型免疫疗法的反应。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 相关巨噬细胞（TAM）在骨肉瘤。最近的证据表明，丰富的TAM 在骨肉瘤的微环境中的免疫应答可用于直接攻击癌细胞。 阻断肉瘤细胞表面表达的细胞表面分子CD 47导致吞噬细胞的激活。 TAM的抗癌活性，并有效地根除骨肉瘤小鼠模型中的肿瘤细胞。26 临床前研究已经完成，目前正在计划进行多中心I期临床试验， 预计2021年开始。为了解决QI工具监测对新TAM的反应的未满足的临床需求， 调节疗法，我们的团队开发了一种定量TAM成像测试，它依赖于静脉注射， 注射铁补充剂ferumoxytol。Ferumoxytol由氧化铁纳米颗粒组成， 被TAM吞噬，并且可以用T2* 加权MRI定量45。因为ferumoxytol是FDA批准的 并且可以作为TAM生物标志物“标签外”使用，因此它立即在临床上可用。我们发现 ferumoxytol-MRI可以检测小鼠模型21和患者25中骨肉瘤中的TAM。通过这个 项目，我们将（a）优化和验证TAM成像的临床前定量成像方法， 建立的骨肉瘤小鼠模型，（B）在共同临床试验中实施优化的方法， 在接受CD 47 mAb免疫治疗的骨肉瘤患者中进行的试验， (c)用收集到的所有数据、方法和结果填充一个网络可访问的研究资源 来自联合临床研究。开发拟议的成像测试可能代表一个重要的 作为治疗分层的新手段和新的金标准成像测试， 预测新型免疫疗法的治疗反应。我们的QI成像测试可以用来比较 不同免疫调节疗法在临床前环境中的疗效，并将最有效的 候选人到诊所。由于新的治疗药物的开发是昂贵的，并且需要数年才能 完成后，我们的QI工具的即时价值和医疗保健影响可能是巨大的。

项目成果

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: 10.3791/64773
• 发表时间: 2023
• 期刊: Journal of visualized experiments : JoVE
• 作者: Ramasamy,ShakthiKumaran;Roudi,Raheleh;Morakote,Wipawee;Adams,LisaC;Pisani,LauraJ;Moseley,Michael;Daldrup-Link,HeikeE
• 通讯作者: Daldrup-Link,HeikeE