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 对新的癌症疗法的发展起到了革命性的作用。齐的努力将成像定位为 癌症治疗反应评估临床试验设计中的一个关键因素。因此，有 学术界和工业界对使用网上可访问的研究资源和 为下一代临床试验制定一致的方法来验证QI方法。这是 尤其与癌症免疫疗法的评估有关，因为免疫疗法不会导致 肿瘤体积缩小，至少不是在治疗后的即刻阶段。因此，我们迫切需要新的 QI工具，可以监测肿瘤对新的免疫疗法的反应。我们项目的总体目标是 优化和验证用于体内肿瘤量化的临床前和临床成像技术 骨肉瘤中的相关巨噬细胞()。最近的证据表明，丰厚的 骨肉瘤微环境中的反应可用于直接攻击癌细胞。 封闭肉瘤细胞表达的细胞表面分子CD47导致吞噬细胞激活 的抗癌活性和有效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，目前正在规划多中心I期临床试验， 预计开始日期为2021年。为了解决临床上对QI工具的未得到满足的需求，以监测对新的的反应- 为了调整治疗方法，我们团队开发了一种定量成像测试，它依赖于静脉注射 注射补充铁剂阿魏酸甘油。阿魏酸甲酯是由氧化铁纳米颗粒组成的， 可被吞噬，可用T2加权磁共振45进行定量。由于阿魏酸甲酯是FDA批准的 并可作为的生物标志物，立即投入临床使用。我们向大家展示了 在21只小鼠模型和25名患者中，阿魏酸甘油酯核磁共振可以检测到骨肉瘤中的。通过这件事 项目，我们将(A)优化和验证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单抗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、方法和结果填充网上可访问的研究资源 从联合临床调查中。开发拟议的成像测试可能代表着一个重要的 临床医生作为治疗分层的新手段和新的金标准影像检查的突破 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和翻译最令人满意的 把候选人送到诊所。因为开发新的治疗药物是昂贵的，而且需要数年时间才能 完整，我们的QI工具的直接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