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抽象的最近发现免疫检查点抑制剂（ICI），尤其是PD-1/PD-L1阻滞剂，具有彻底改变了高级舞台恶性肿瘤的管理，包括肺癌，黑色素瘤，头部和脖子和乳腺癌。 ICI的抗癌作用是通过扩增的T细胞介导的免疫介导的回复。但是，ICI疗法会导致不必要的脱靶效应，以呈现为免疫相关的不良事件（伊拉斯）。免疫调节疗法的心脏毒性作用可能是严重且迅速致命的，特别是心肌炎，心力衰竭和心脏猝死。结果，多达42％的患者出现有症状的心血管不良事件死亡。因此，迫切需要i）发展准确和敏感的诊断方式，用于早期检测到这种情况，ii）提高我们对有助于ICI相关心脏毒性的机制，因此可以开发特定的疗法。先前的研究假设心脏收缩蛋白肌钙蛋白I（CTNI）的碎片释放从受损的心肌细胞受损可能会触发自身免疫反应，导致伊拉斯。使用高级生物信息学工具筛选了100,000多个抗原序列，我们已经确定了13个氨基酸线性具有异常高的抗原指数的CTNI序列（CTNI AA 146-158）。我们还开发了固体使用CTNI AA 146-158-亚avidin-biotin结合的相位表位检测平台系统。我们的假设是，ICI诱导的心脏毒性可以通过心脏MRI早期检测到，并且对心肌细胞衍生的CTNI AA 14-158抗原的免疫激活可以通过预先形成的抗CTNI AA 146-158中和抗体。为了检验这一假设，我们将执行以下实验：a）用CTNI AA接种正常小鼠AA 146-158主要表位以发展循环抗CTNI AA 146-158中和体内中和抗体，b）在接种的小鼠和生物控制，并比较伊拉斯的发病率和严重性。我们将利用高场磁具有全面组织表征协议的共振成像，以客观监控心脏炎症，纤维化和功能丧失。我们的长期目标是精确识别线性，构象或 3D空间CTNI表位并发展出新颖的治疗剂以抵消ICI相关的心肌免疫毒性。意义：如果针对线性CTNI表位的中和疫苗（CTNI AA 146-158）为发现在临床前模型中减轻ICI诱导的心肌毒性有效，这将促进具有重要治疗意义的进一步翻译研究。这一发现将使患者受益伴有接受ICI疗法治疗的侵略性癌症。早期缺乏新知识和方法与ICI相关的IRAE的检测和治疗调节将削弱这些挽救生命的癌症疗法由于其副作用，或导致心脏免疫毒性高死亡率。