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Early Detection and Immunomodulation of PD-1 Inhibitor Induced Cardiotoxicity

PD-1 抑制剂引起的心脏毒性的早期检测和免疫调节

基本信息

批准号：
10042197
负责人：
Saraswati Pokharel
金额：
$ 25.88万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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：
2020-08-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042197
关键词：
3-Dimensional Acceleration Address Adverse event Affect Amino Acid Sequence Amino Acids Antibodies Antigens Autoimmune Process Autoimmune Responses Automobile Driving Avidin Biological Biological Markers Biomedical Engineering Biotin CD8-Positive T-Lymphocytes CTLA4 gene Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular system Cells Characteristics Chest Clinical Cobalt Complication Contractile Proteins Data Detection Development Diagnostic Dynein ATPase Early Diagnosis Epitopes Exposure to Fibrosis Future Goals Gold Head Cancer Heart Block Heart Injuries Heart failure Histology Human I-antigen Immobilization Immune Immune checkpoint inhibitor Immunoglobulins Immunotherapeutic agent Incidence Incubated Inflammation Inflammatory Intestines Knowledge Lead Life Liposomes Lung Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Mediating Modality Molecular Conformation Monitor Mus Myocardial Myocardial tissue Myocarditis Neck Cancer Organ PD-1 blockade PD-1 inhibitors PD-1/PD-L1 Pathologist Patients Peptides Phase Polystyrenes Pre-Clinical Model Primary Ciliary Dyskinesias Process Proteins Protocols documentation Radial Relaxation Renal carcinoma Savings Screening procedure Serum Severities Skin Solid System T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic antibodies Thyroid Gland Time Tissues Toxic effect Troponin I Tumor-infiltrating immune cells Vaccinated Vaccination anti-PD1 antibodies anti-cancer base bioinformatics tool cancer therapy cell mediated immune response checkpoint therapy cross reactivity cytotoxic effectiveness testing experience experimental study heart function high reward high risk immune activation immune checkpoint blockade immune self tolerance immune-related adverse events immunogenic immunomodulatory therapies immunoreaction immunoregulation in vivo indexing loss of function malignant breast neoplasm melanoma mortality mouse model neutralizing antibody neutralizing vaccine novel novel strategies novel therapeutics novel vaccines polyhistidine preclinical study prevent programmed cell death ligand 1 programmed cell death protein 1 prototype side effect sudden cardiac death translational study vaccine effectiveness

项目摘要

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.

PD-1抑制剂诱导的心脏毒性的早期检测和免疫调节