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Principal Investigator: Rizia Bardhan
Organization: IOWA STATE UNIVERSITY
Fiscal Year: 2024
Award: $266,335
Funding agency: National Institute of Biomedical Imaging and Bioengineering
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.
Terms: <Acceleration><Address><After Care><After-Treatment><Aftercare><Alternative Therapies><Alternative intervention><Antibodies><Antigens><Assay><Autoimmune Status><Autoimmunity><B7-H1><B7H1><Beta Cell><Binding><Bioassay><Biological Assay><Biological Markers><Breast Cancer><Breast Cancer Model><Breast Cancer Patient><Breast Cancer Treatment><Breast Implants><Breast Tumor Patient><Breast tumor model><Brittle Diabetes Mellitus><CD274><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Clinical Treatment Moab><Clinical Trials><Detection><Disease><Disorder><Dose><Early Diagnosis><Heterogeneity><Histopathology><Human><IDDM><IR/UV/Raman Spectroscopy><Image><Immune mediated therapy><Immuno-PET><ImmunoPET><Immunocompetent><Immunologically Directed Therapy><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Infection><Infiltration><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Internal Breast Prosthesis><Intracellular Communication and Signaling><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><LYT3><Label><Ligands><Light><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Maps><Measures><Methods><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monitor><Monoclonal Antibodies><Multimodal Imaging><Murine><Mus><Optics><Outcome><PBMC><PD 1><PD-1><PD-L1><PD-L1 blockade><PD-L1 therapy><PD-L1 treatment><PD1><PDL-1><PDL1><PDL1 blockade><PDL1 therapy><PDL1 treatment><PET><PET Scan><PET imaging><PETSCAN><PETT><Patients><Peripheral Blood Mononuclear Cell><Photoradiation><Play><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Rad.-PET><Radiation Chemistry><Radiation exposure><Radioactive Isotopes><Radiochemistry><Radioimmunoconjugate><Radioisotopes><Radiolabeled><Radiolabeled Antibodies><Radionuclides><Raman Spectroscopy><Raman Spectrum Analysis><Raman imaging><Raman spectrometry><Receptor Protein><Regimen><Reporter><Resolution><Retrieval><Role><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Spectroscopy><Spectrum Analyses><Spectrum Analysis><Subcellular Process><Sudden-Onset Diabetes Mellitus><Surface><T-Cell Activation><T1 DM><T1 diabetes><T1D><T1DM><T8 Cells><T8 Lymphocytes><Techniques><Therapeutic><Treatment Protocols><Treatment Regimen><Treatment Schedule><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Up-Regulation><Upregulation><Wait Time><aPD-L1><aPD-L1 therapy><aPD-L1 treatment><aPDL1><activate T cells><alternative treatment><anti programmed cell death ligand 1><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-PD-(L)1><anti-PD-L1><anti-PD-L1 blockade><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PDL-1><anti-PDL1><anti-PDL1 therapy><anti-PDL1 treatment><antiPD-L1><antiPDL1><bio-markers><biologic marker><biological signal transduction><biomarker><biomedical imaging><clinical relevance><clinical translation><clinically relevant><clinically translatable><diagnostic tool><disease model><disorder model><early detection><gold nano particle><gold nanoparticle><humanized mice><humanized mouse><imaging><imaging biomarker><imaging in vivo><imaging marker><imaging spectroscopy><imaging-based biological marker><imaging-based biomarker><imaging-based marker><immune competent><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-PET><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><improved><in vivo><in vivo imaging><inhibitor><innovate><innovation><innovative><insulin dependent diabetes><insulin dependent type 1><interest><intraperitoneal><islet><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><longitudinal positron emission tomography><mAbs><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><monoclonal Abs><mouse model><multi-modal imaging><multi-modality><multi-modality imaging><multidisciplinary><multimodality><multimodality imaging><multiplex detection><murine model><nano gold><nano particle><nano-sized particle><nanoGold><nanoparticle><nanoprobe><nanosized particle><neoplasm/cancer><non-invasive diagnosis><non-invasive diagnostic><noninvasive diagnosis><noninvasive diagnostic><novel><optical><orthotopic breast adenocarcinoma><orthotopic breast cancer><orthotopic breast carcinoma><orthotopic breast tumor><patient screening><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post treatment><pre-clinical><preclinical><predict responsiveness><predicting response><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><radiolabel><radiolabeling><radiolabels><radiologically labeled><radiotracer><receptor><resolutions><response><response to therapy><response to treatment><screening><screenings><sle2><social role><spatiotemporal><spectroscopic imaging><systemic lupus erythematosus susceptibility 2><therapeutic outcome><therapeutic response><therapy outcome><therapy response><tissue fixing><translational study><treatment response><treatment responsiveness><tumor><tumor immune microenvironment><tumor-immune system interactions><type I diabetes><type one diabetes><whole body imaging><whole body scanning><αPD-L1><αPD-L1 therapy><αPD-L1 treatment><αPDL1><β-cell><β-cells><βCell>