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: 10304651
• 负责人: Heike Elizabeth Daldrup-Link
• 金额: $ 65.26万
• 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/10304651
• 关键词: Aftercare; Animal Model; Biological Markers; Blocking Antibodies; CD47 gene; Caring; Cell physiology; Cell surface; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Communities; Computer software; Consensus; Data; Data Pooling; Development; Diagnosis; Disease; Eating; Elements; FDA approved; Goals; Gold; Growth; Histology; Hour; Image; Image Enhancement; 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; base; cancer cell; cancer clinical trial; cancer imaging; cancer immunotherapy; cancer therapy; chemotherapy; clinical application; clinical imaging; clinical investigation; clinically translatable; 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; predictive test; quantitative imaging; receptor; response; sarcoma; treatment stratification; tumor; 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.

用于成像肿瘤相关巨噬细胞的共同研究资源 抽象的 用于监测癌症治疗反应的定量成像（QI）方法的开发已有 对于开发新的癌症治疗是有变革性的。 Qi的努力将成像定位为 癌症治疗反应评估临床试验设计设计的关键要素。因此，有 学术和行业增加了使用可访问的研究资源的兴趣 开发共识方法来验证Qi方法以进行下一代临床试验。这是 与评估癌症免疫疗法特别相关，因为免疫疗法不会导致 肿瘤大小的减小，至少不在立即治疗阶段。因此，我们迫切需要新的 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 优化和验证用于体内定量肿瘤的临床前和临床成像技术 骨肉瘤中的相关巨噬细胞（TAM）。最近的证据表明，丰富的tam 可以聘请骨肉瘤微环境中的反应以直接攻击癌细胞。 在肉瘤细胞上表达的细胞表面分子CD47的阻断导致吞噬细胞的激活 骨肉瘤小鼠模型中TAM的抗癌活性和有效发射的肿瘤细胞。 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，并有 预期的开始日期在2021年。解决对QI工具的未满足临床需求，以监视对新TAM的反应 调节疗法，我们的团队开发了定量的TAM成像测试，该测试依赖于静脉 注入铁补充铁氧二醇。铁氧基二醇由氧化铁纳米颗粒组成， 通过TAM吞噬并可以用T2*加权的MRI 45定量。由于Ferumoxytol是FDA批准的 并且可以用作TAM生物标志物的“关闭标签”，它立即在临床上可用。我们表明了这一点 铁氧基-MRI可以在小鼠模型21和患者25中检测到骨肉瘤中的TAM。 项目，我们将（a）优化和验证用于TAM成像的临床前定量成像方法 已建立的骨肉瘤的鼠标模型，（b）在共同链接中实现优化方法 正在接受CD47 mAb免疫疗法的骨肉瘤患者的试验，最后 （c）用所有数据，方法和收集的结果填充可访问的研究资源 从共同研究。开发提出的成像测试可能代表着重要的 临床医生的突破是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成像测试可以用于比较 临床前环境中不同免疫调节疗法的效率，并翻译最原始的效率 候选人到诊所。由于新的治疗药物的开发非常昂贵，需要数年 完整，我们的Qi工具的直接价值和健康护理影响可能是巨大的。