Developing Multimodal Multiplexed ImmunoPET-Raman Probes to Guide Immunotherapies

开发多模式多重免疫 PET-拉曼探针来指导免疫治疗

• 批准号: 10447750
• 负责人: Rizia Bardhan
• 金额: $ 29.61万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447750
• 关键词: Acceleration; Address; Aftercare; Alternative Therapies; Antibodies; Antigens; Autoimmunity; Beta Cell; Binding; Biological Assay; Biological Markers; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Clinical; Clinical Trials; Detection; Disease; Disease model; Dose; Early Diagnosis; Heterogeneity; Histopathology; Human; Image; ImmunoPET; Immunocompetent; Immunosuppression; Immunotherapy; Infection; Infiltration; Insulin-Dependent Diabetes Mellitus; Internal Breast Prosthesis; Label; Ligands; Light; Malignant Neoplasms; Maps; Measures; Methods; Monitor; Monoclonal Antibodies; Multimodal Imaging; Mus; Optics; Outcome; PD-L1 blockade; Patients; Peripheral Blood Mononuclear Cell; Play; Positron-Emission Tomography; Radiation exposure; Radiochemistry; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Raman Spectrum Analysis; Regimen; Reporter; Resolution; Retrieval; Role; Signal Transduction; Specificity; Spectrum Analysis; Surface; T-Cell Activation; Techniques; Therapeutic; Treatment Protocols; Up-Regulation; Wait Time; alternative treatment; anti-PD-L1; anti-PD-L1 therapy; biomedical imaging; clinical translation; clinically relevant; diagnostic tool; humanized mouse; imaging biomarker; immunoregulation; improved; in vivo; in vivo imaging; inhibitor; innovation; interest; intraperitoneal; islet; longitudinal positron emission tomography; malignant breast neoplasm; mouse model; multidisciplinary; multimodality; multiplex detection; nanoGold; nanoparticle; nanoprobe; noninvasive diagnosis; novel; orthotopic breast cancer; patient screening; patient subsets; pre-clinical; predicting response; programmed cell death ligand 1; programmed cell death protein 1; radiotracer; receptor; response; screening; spatiotemporal; spectroscopic imaging; therapy outcome; tissue fixing; translational study; treatment response; tumor; tumor-immune system interactions; whole body imaging

Project Summary/Abstract: Inhibitors of the PD-1/PD-L1 axis has been successful across multiple diseases. However, only a small subset of patients respond to these regimen and identifying patients likely to benefit from these therapies remains challenging. Current clinical standard relies on histopathology that fail to accurately predict PD-L1 due to spatial and temporal heterogeneities among patients. Further, screening patients for PD-L1 alone is not predictive of treatment response due to significant variabilities in PD-L1 assays across labs necessitating simultaneous detection of multiple immunomarkers. This establishes our scientific premise that an urgent need exists for accurate noninvasive diagnostic tools that enables detection of both PD-L1 and other markers involved in immune modulation directly in vivo. Whereas ImmunoPET (positron emission tomography) imaging has transformed our ability to detect single immunomarkers in vivo, multiplexing cannot be achieved with PET as signal between radionuclides cannot be distinguished. Without the ability to multiplex, patients would undergo multiple radiotracer dosing and repeated radiation exposure. Further, dynamic changes in immunomarkers during treatment would be missed as sequential dosing of different radiotracers would require >1 week wait time between doses to allow for decay of the radiotracers. Our objective is to address the limitations of current approaches and enable multiplexed detection of both PD-L1 and CD8+ T cells in vivo with an innovative nanoprobe, immunoactive gold nanoparticles (IGNs). IGNs labeled with antibodies, Raman reporters, and 89Zr radiotracers synergistically integrates the merits of immunoPET with surface-enhanced Raman spectroscopy (SERS). SERS, an optical technique, uses near-infrared light to enhance the vibrational signal of Raman reporters enabling narrow spectral features amenable for multiplexing. Our approach is unique because clinically-translatable IGNs seamlessly combine the depth-resolved whole body imaging of PET with the high resolution and multiplexing ability of SERS enabling simultaneous detection of both immunomarkers in vivo with high specificity. Detection of both immunomarkers in vivo is important because dynamic changes occur in both PD-L1 and CD8 during and after treatment that are not captured by static measure of receptors or by single biomarker imaging. Whereas immunomarker detection with IGNs is relevant to many diseases, we will use mouse models of breast cancer (BC) since PD-L1 and CD8 immunomarkers play a critical role in BC treatment response. IGNs will detect both PD-L1 and CD8 in orthotopic BC mouse models (Aim 1), monitor response to immunotherapies (Aim 2), and validate in clinically-relevant humanized mice (Aim 3). IGNs is a generalizable platform and ultimately our strategy can be mapped onto other diseases including infection and autoimmunity where PD-L1 and CD8 biomarkers also play a key role. Further, IGNs can also be targeted to a number of other biomarkers via antibodies facilitating treatment response in multiple disorders with unprecedented accuracy not achievable with current clinicopathological approaches.

项目概要/摘要： PD-1/PD-L1轴的抑制剂在多种疾病中取得了成功。然而，只有一小部分 的患者对这些治疗方案有反应， 挑战性目前的临床标准依赖于组织病理学，由于组织病理学不能准确预测PD-L1， 患者之间的时空异质性。此外，单独筛查患者的PD-L1并不 由于实验室间PD-L1测定的显著变异性， 同时检测多种免疫标志物。这就确立了我们的科学前提， 需要能够检测PD-L1和其他标志物的精确的非侵入性诊断工具 直接参与体内免疫调节。而免疫PET（正电子发射断层扫描）成像 已经改变了我们在体内检测单一免疫标记物的能力，但PET无法实现多重检测 因为放射性核素之间的信号不能被区分。如果没有多重感染的能力， 进行多次放射性示踪剂给药和重复辐射暴露。此外， 治疗期间的免疫标记物将被遗漏，因为不同放射性示踪剂的顺序给药将需要 剂量之间的等待时间>1周，以允许放射性示踪剂的衰变。我们的目标是解决 并且能够在体内多重检测PD-L1和CD 8 + T细胞， 一种创新的纳米探针，免疫活性金纳米颗粒（IGN）。用抗体标记的IGNs，拉曼 报道分子和89 Zr放射性示踪剂协同整合了免疫PET与表面增强的 拉曼光谱（Sers）。Sers是一种光学技术，使用近红外光来增强振动 拉曼报告子信号使窄光谱特征适合于多路复用。我们的做法是 独特之处在于，临床上可翻译的IGN无缝联合收割机结合了深度分辨全身成像， PET具有Sers的高分辨率和多路复用能力，可同时检测 具有高特异性的体内免疫标记物。在体内检测两种免疫标记物是重要的，因为 在治疗期间和治疗后，PD-L1和CD 8都发生了动态变化，而静态变化无法捕获。 受体的测量或通过单一生物标志物成像。而免疫标记物检测与IGNs相关 由于PD-L1和CD 8免疫标记物的存在， 在BC治疗反应中发挥关键作用。IGN将检测原位BC小鼠中的PD-L1和CD 8 模型（目标1），监测对免疫疗法的反应（目标2），并在临床相关的人源化 小鼠（Aim 3）。IGNs是一个可推广的平台，最终我们的策略可以映射到其他疾病 包括感染和自身免疫，其中PD-L1和CD 8生物标志物也发挥关键作用。此外，IGN 也可以通过抗体靶向许多其他生物标志物，促进多种疾病的治疗反应。 目前临床病理学方法无法达到的前所未有的准确性。