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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.

抽象的过去10年，FDA批准了6种检查点抑制剂，并迅速扩大适应症黑色素瘤、非小细胞肺癌、霍奇金淋巴瘤、肾癌和膀胱癌。而且，还有超过 150 项正在进行的仅针对 PD-1 抑制剂治疗的临床试验。尽管有抗癌功效，免疫治疗相关的免疫相关不良事件影响广泛的器官，包括心脏。目前临床实践中的诊断方法是肌钙蛋白测试和心电图，但缺乏对心肌炎有必要的敏感性和特异性。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 (RNAseq/MirSeq) 生物标志物诱发心肌炎。在这个具体目标中，我们将重点关注患有自身免疫性疾病的患者接受检查点抑制剂治疗并储存血液样本后出现心肌炎。此类患者提供了一个机会来识别新的关联和预测生物标志物，这些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。为了免疫检查点抑制剂相关心肌炎的医疗管理，当前订阅实践类固醇会使患者遭受全身免疫抑制。在具体目标 2 中，我们将评估一种新的抗基于炎症肽的纳米粒子系统，用于递送针对 NF-κB 的 siRNA 来治疗心肌炎由免疫检查点抑制剂诱导。与目前现有的方法不同，新技术具体目标 2 中提出的方案将能够仅向心脏发炎区域提供抗炎治疗。此外，该测试剂具有已知的抗癌作用。因此，具体目标 2 的成功可以提供精准的治疗并最大限度地减少系统性脱靶副作用。