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Principal Investigator: Saraswati Pokharel
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2020
Award: $258,790
Funding agency: National Heart Lung and Blood Institute
Early Detection and Immunomodulation of PD-1 Inhibitor-Induced Cardiotoxicity
Abstract
The recent discovery of immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockers, has
revolutionized the management of advanced stage malignancies including lung cancers, melanoma, head and
neck, and breast cancers. The anti-cancer effects of ICIs are mediated by amplified T-cell-mediated immune
response. However, ICI therapy results in unwanted off-target effects presenting as immune related adverse
events (irAEs). Cardiotoxic effects of the immunomodulatory therapies can be serious and rapidly fatal,
particularly myocarditis, heart failure and sudden cardiac death. As a result, up to 42% patients presenting with
symptomatic cardiovascular adverse events die. Therefore, there is an urgent need to i) develop accurate and
sensitive diagnostic modalities for the early detection of this condition, and ii) advance our knowledge on the
mechanisms contributing to ICI related cardiotoxicity, so that specific therapies can be developed.
Prior studies have postulated that fragments of cardiac contractile protein, troponin I (cTnI), released
from the damaged cardiomyocytes could trigger autoimmune response leading to irAEs. Using advanced
bioinformatics tools that screened over 100,000 antigenic sequences, we have identified a 13-amino acid linear
sequence of cTnI (cTnI AA 146-158) with an exceptionally high antigenic index. We have also developed solid-
phase epitope detection platform using cTnI AA 146-158-avidin-biotin conjugation in a polystyrene flat-bottom
system. Our hypothesis is that ICI-induced cardiotoxicity can be detected early by cardiac MRI and that
the immune activation to cardiomyocyte-derived cTnI AA 14-158 antigens can be prevented by
preformed anti-cTnI AA 146-158 neutralizing antibodies. To test this hypothesis, we will perform the
following experiments: a) vaccinate normal mice with cTnI AA 146-158 primary epitope to develop circulating
anti- cTnI AA 146-158 neutralizing antibodies in vivo, b) administer a PD-1 inhibitor in vaccinated mice and
biological controls, and compare the incidence and severity of IrAEs. We will utilize high field cardiac magnetic
resonance imaging with comprehensive tissue characterization protocols to objectively monitor cardiac
inflammation, fibrosis and loss of function. Our long-term goal is to precisely identify linear, conformational or
3D spatial cTnI epitopes and develop novel therapeutic agent(s) to counteract ICI-associated myocardial
immune toxicity.
Significance: If the neutralizing vaccine targeted against linear cTnI epitopes (cTnI AA 146-158) is
found to be effective to mitigate ICI-induced myocardial immune toxicity in a pre-clinical model, this will
facilitate further translational studies with important therapeutic implications. This discovery will benefit patients
with aggressive cancers that are treated with ICI-therapy. Lack of new knowledge and approaches for the early
detection and therapeutic modulation of ICI-related irAEs will either curtail these life-saving cancer therapies
due to their side effects, or lead to high mortality from cardiac immune toxicity.
Terms: <3-D><3-Dimensional><3D><Acceleration><Address><Adverse Experience><Adverse event><Affect><Amino Acid Sequence><Amino Acids><Antibodies><Antigenic Determinants><Antigens><Autoimmune><Autoimmune Process><Autoimmune Responses><Automobile Driving><Avidin><B7-H1><B7H1><Binding Determinants><Biological><Biological Markers><Biomedical Engineering><Biotin><Blood Serum><Body Tissues><Breast Cancer><CD152><CD152 Antigen><CD152 Gene><CD274><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Treatment><Cancers><Cardiac><Cardiac Block><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Toxicity><Cardiocyte><Cardiomyopathies><Cardiotoxic><Cardiotoxicity><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Characteristics><Checkpoint inhibitor><Chest><Clinical><Cobalt><Complication><Contractile Proteins><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Detection><Development><Diagnostic><Dynein><Dynein ATPase><Dynein Adenosine Triphosphatase><Dynein Adenosinetriphosphatase><Early Diagnosis><Epitopes><Exposure to><Fibrosis><Future><Goals><Gold><Head Cancer><Heart Block><Heart Injuries><Heart Muscle Cells><Heart Muscle tissue><Heart Vascular><Heart failure><Heart myocyte><Histology><Human><I-antigen><Immobilization><Immune><Immune Cell Activation><Immune Globulins><Immune Modulation Therapy><Immune checkpoint inhibitor><Immune infiltrates><Immune reaction><Immunes><Immunoglobulins><Immunomodulation><Immunotherapeutic agent><Incidence><Incubated><Inflammation><Inflammatory><Intestinal><Intestines><Kartagener Syndrome><Kartagener Triad><Kidney Cancer><Kidney Carcinoma><Knowledge><Lead><Life><Liposomal><Liposomes><Lung><Lung Respiratory System><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Malignant Melanoma><Malignant Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mice><Mice Mammals><Modality><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Monitor><Murine><Mus><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardial tissue><Myocardiopathies><Myocarditis><NMR Imaging><NMR Tomography><Neck Cancer><Nuclear Magnetic Resonance Imaging><Organ><PD 1><PD-1><PD-1 antibody><PD-1 blockade><PD-1 inhibitors><PD-1/PD-L1><PD-1/PDL1><PD-L1><PD1><PD1 antibody><PD1 blockade><PD1 inhibitors><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL-1><PDL1><Pathologist><Patients><Pb element><Peptides><Phase><Polynesian bronchiectasis><Polystyrenes><Polystyrol><Pre-Clinical Model><Preclinical Models><Primary Ciliary Dyskinesias><Primary Protein Structure><Process><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><Protocol><Protocols documentation><Pulmonary Cancer><Pulmonary malignant Neoplasm><Radial><Radius><Relaxation><Renal Cancer><Renal carcinoma><Savings><Screening procedure><Serum><Severities><Skin><Solid><System><T cell infiltration><T cell tumor trafficking><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Technology><Testing><Therapeutic><Therapeutic Agents><Therapeutic Effect><Therapeutic antibodies><Thorace><Thoracic><Thorax><Thyroid><Thyroid Gland><Thyroid Head and Neck><Time><Tissues><TnI><Toxic effect><Toxicities><Troponin I><Tumor-infiltrating immune cells><Vaccinated><Vaccination><Vitamin H><Zeugmatography><aminoacid><anti programmed cell death protein 1 inhibitor><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 blockade><anti-PD-1 inhibitors><anti-PD-1 monoclonal antibodies><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 blockade><anti-PD1 inhibitors><anti-PD1 monoclonal antibodies><anti-cancer><anti-cancer therapy><anti-programmed cell death protein 1 antibodies><anticancer><anticancer therapy><base><bio-engineered><bio-engineers><bio-informatics tool><bio-markers><bioengineering><bioinformatics tool><biologic marker><biomarker><bowel><cancer therapy><cardiac failure><cardiac function><cardiac inflammation><cardiac injury><cardiomyocyte><cell mediated immune response><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><circulatory system><coenzyme R><conformation><conformational state><cross reactivity><cytotoxic><cytotoxic T-lymphocyte antigen 4><developmental><driving><early detection><effectiveness testing><experience><experiment><experimental research><experimental study><function of the heart><heart function><heavy metal Pb><heavy metal lead><high reward><high risk><immune activation><immune cell infiltrate><immune check point blockade><immune check point inhibitor><immune check point therapy><immune checkpoint blockade><immune checkpoint therapy><immune drugs><immune infiltration><immune modulating therapies><immune modulation><immune modulatory therapies><immune regulation><immune regulator><immune self tolerance><immune-based therapeutics><immune-mediated adverse events><immune-modulation treatment><immune-related adverse events><immunogen><immunogenic><immunologic preparation><immunologic reactivity control><immunologic therapeutics><immunomodulation therapy><immunomodulation treatment><immunomodulatory><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoreaction><immunoregulation><immunoregulatory><immunotherapeutics><immunotherapy agent><in vivo><indexing><inhibitory troponin I><intratumoral immune cell><loss of function><lung cancer><malignancy><malignant breast neoplasm><malignant breast tumor><malignant neck tumor><melanoma><mortality><mouse model><murine model><myocardium disease><myocardium disorder><neoplasm/cancer><neutralizing antibody><neutralizing vaccine><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><new vaccines><next generation therapeutics><next generation vaccines><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><novel vaccines><orthopedic freezing><polyhistidine><pre-clinical study><preclinical study><prevent><preventing><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein sequence><prototype><pulmonary><screening tools><side effect><sle2><sudden cardiac death><systemic lupus erythematosus susceptibility 2><three dimensional><thymus derived lymphocyte><translational study><tumor immune cell><vaccine effectiveness>