权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Prediction and Treatment for Cancer Immunotherapy Induced Myocarditis

癌症免疫治疗引起的心肌炎的预测和治疗

基本信息

批准号：
10217416
负责人：
Hua Pan
金额：
$ 18.69万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217416
关键词：
Address Affect Animal Model Anti-Inflammatory Agents Autoimmune Back Biological Markers Bladder Blood Chemical Analysis Blood Circulation Blood specimen Bortezomib Breast CTLA4 gene Cancer Patient Cardiac Cardiotoxicity Cardiovascular system Cells Clinical Clinical Trials Diagnosis Disseminated Malignant Neoplasm Electrocardiogram Enrollment Evaluation Exhibits FDA approved Female Genomic approach Goals Heart Histology Hodgkin Disease Immune Immune checkpoint inhibitor Immune system Immunologic Markers Immunosuppression Immunotherapy Impairment Infiltration Inflammation Inflammatory Intravenous Investigation Kidney Kinetics Life Liver Lung Lymph Node of Head, Face and Neck Malignant Neoplasms Malignant neoplasm of urinary bladder Medical Messenger RNA Metastatic Neoplasm to the Lung Mus Myocarditis NF-kappa B Nivolumab Non-Small-Cell Lung Carcinoma Normal tissue morphology Organ Ovary PD-1 inhibitors Pathogenesis Pathway Analysis Patients Peptides Precision therapeutics Predictive Value Prevalence Production Publishing RNA Renal Cell Carcinoma Renal carcinoma Reporting Research Safety Sensitivity and Specificity Signal Pathway Signal Transduction Skin Small Interfering RNA Small RNA Steroids System T-Lymphocyte Testing Therapeutic Effect Tissues Toxin Treatment Efficacy Troponin Tumor Immunity anti-PD-L1 anti-PD1 therapy anti-cancer anticancer treatment autoimmune arthritis base body system cancer cell cancer immunotherapy cancer therapy clinical practice cohort cytokine design early detection biomarkers exosome experience heart function immune checkpoint immune-related adverse events improved ipilimumab knock-down macrophage male melanoma mouse model nano nanoparticle nanoparticle delivery nanotherapeutic new technology novel novel strategies novel therapeutic intervention p65 pembrolizumab potential biomarker predictive marker programmed cell death ligand 1 programmed cell death protein 1 siRNA delivery side effect success transcriptome sequencing transcriptomics tumor microenvironment

项目摘要

Abstract In the past 10 years, the FDA has approved 6 checkpoint inhibitors and quickly expanded indications from melanoma and non-small cell lung cancer to Hodgkin lymphoma, kidney, and bladder cancer. Moreover, there are more than 150 ongoing clinical trials on PD-1 inhibitors treatment alone. Despite the anti-cancer benefits, immunotherapy associated immune related adverse events affect a broad spectrum of organs, including heart. Current diagnosis in clinical practices are troponin test and electrocardiograms, which, however, lack of necessary sensitivity and specificity to myocarditis. Accordingly, in Specific Aim 1, we seek to identify transcriptomic (RNAseq/MirSeq) biomarkers that may have predictive value for checkpoint inhibitor treatment induced myocarditis. In this specific aim, we will be focused on patients who have developed autoimmune myocarditis after receiving checkpoint inhibitor treatments and have blood samples banked. Such patients provided an opportunity to identify new associative and predictive biomarkers that can serve as guideposts for the implementation of new therapeutic approaches to suppress the inflammatory drivers of cardiotoxicity. For medical management of immune Checkpoint Inhibitors associated myocarditis, current practices of subscribing steroids expose patients to immune suppression systemically. In Specific Aim 2, we will evaluate a new anti- inflammatory peptide-based nanoparticle system for delivering siRNA against NF-κB to manage myocarditis induced by immune checkpoint inhibitors. Different from currently existing approaches, the new technology proposed in Specific Aim 2 would enable anti-inflammation treatment delivery only to inflamed region in the heart. Moreover, the testing agent has known anti-cancer effects. Therefore, the success of Specific Aim 2 could provide precision treatment delivery and minimize systemic off-target side effects.

摘要在过去的10年里，FDA已经批准了6种检查点抑制剂，并迅速扩大了适应症，黑色素瘤和非小细胞肺癌到霍奇金淋巴瘤、肾癌和膀胱癌。而且目前有超过150项关于PD-1抑制剂治疗的临床试验正在进行中。尽管有抗癌的好处，免疫治疗相关免疫相关不良事件影响包括心脏在内的广泛器官。目前临床实践中的诊断是肌钙蛋白测试和心电图，然而，缺乏对心肌炎的敏感性和特异性。因此，在具体目标1中，我们寻求确定可能对检查点抑制剂治疗具有预测价值的转录组学（RNAseq/MirSeq）生物标志物诱发心肌炎。在这一特定目标中，我们将重点关注患有自身免疫性疾病的患者，心肌炎后接受检查点抑制剂治疗，并有血液样本库。此类患者提供了一个机会，以确定新的关联和预测生物标志物，可以作为路标，实施新的治疗方法来抑制心脏毒性的炎症驱动因素。为免疫检查点抑制剂相关性心肌炎的医疗管理，类固醇使患者全身性地受到免疫抑制。在具体目标2中，我们将评估一种新的抗- 用于递送针对NF-κB siRNA以控制心肌炎的基于炎性肽的纳米颗粒系统由免疫检查点抑制剂诱导。与现有的方法不同，新技术具体目标2中提出的方法将使抗炎治疗仅针对心脏的炎症区域进行。此外，测试剂具有已知的抗癌作用。因此，《特定目标2》的成功可能会提供精确的治疗输送，并最大限度地减少全身脱靶副作用。