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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘: