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.

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