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: 10256611
• 负责人: Rizia Bardhan
• 金额: $ 31.12万
• 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/10256611
• 关键词: Address; Aftercare; Alternative Therapies; Antibodies; 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; ImmunoPET; Immunocompetent; Immunosuppression; Immunotherapy; Infection; Infiltration; Insulin-Dependent Diabetes Mellitus; Internal Breast Prosthesis; Label; Leukocyte L1 Antigen Complex; 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; Surface; T-Lymphocyte; Techniques; Therapeutic; Tissues; Treatment Protocols; Up-Regulation; Wait Time; alternative treatment; anti-PD-L1; anti-PD-L1 therapy; bioimaging; clinically relevant; clinically translatable; humanized mouse; imaging biomarker; immunoregulation; improved; in vivo; in vivo imaging; in vivo monitoring; inhibitor/antagonist; 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; tool; translational study; treatment response; tumor; tumor-immune system interactions; vibration; 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.

项目摘要/摘要： PD-1/PD-L1轴的抑制剂在多种疾病之间已经成功。但是，只有一个小子集 患者对这些治疗方案的反应，并确定可能从这些疗法中受益的患者仍然存在 具有挑战性的。当前的临床标准依赖于由于无法准确预测PD-L1的组织病理学 患者之间的空间和时间异质性。此外，仅对PD-L1筛查患者不是 预测由于需要的PD-L1分析的显着变化而导致的治疗反应 同时检测多个免疫标志物。这确立了我们的科学前提 存在需要准确的非侵入性诊断工具，可以检测PD-L1和其他标记 直接在体内参与免疫调节。而免疫集（正电子发射断层扫描）成像 已经改变了我们在体内检测单个免疫标记物的能力，宠物无法实现多重。 由于无法区分放射性核素之间的信号。没有多重能力，患者将 经历多种放射性剂量的剂量和重复的辐射暴露。此外，动态变化 由于不同的放射性示例的顺序剂量将需要 > 1周的等待时间之间的剂量允许放射性示踪剂衰减。我们的目标是解决 当前方法的局限性并能够在体内对PD-L1和CD8+ T细胞的多路复用检测与 创新的纳米探针，免疫活性金纳米颗粒（IGNS）。用抗体标记的IGNS，拉曼 记者和89ZR radiotracers协同整合了免疫集的优点与表面增强 拉曼光谱法（SERS）。 SERS是一种光学技术，使用近红外光来增强振动 拉曼记者的信号使狭窄的光谱特征适合多重。我们的方法是 唯一的，因为临床上可转移的IGN无缝地结合了深度分辨的全身成像 具有高分辨率和多路复用能力的PET，可以同时检测两者 具有高特异性的体内免疫标记物。在体内检测两个免疫标记物很重要，因为 在处理期间和之后的PD-L1和CD8中都发生动态变化，这些变化未被静态捕获 受体的度量或单个生物标志物成像。而IGN的免疫标志物检测是相关的 对于许多疾病，我们将使用乳腺癌的小鼠模型（BC），因为PD-L1和CD8免疫标志物 在卑诗省治疗反应中起关键作用。 IGNS将在原位BC小鼠中检测PD-L1和CD8 模型（AIM 1），监测对免疫疗法的反应（AIM 2），并在临床上验证人性化的验证 小鼠（目标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上 PD-L1和CD8生物标志物的感染和自身免疫也起着关键作用。此外，IGNS 还可以通过抗体促进多个治疗反应的抗体来针对许多其他生物标志物 目前的临床病理方法无法实现具有前所未有的准确性的疾病。