Prediction and Treatment for Cancer Immunotherapy Induced Myocarditis

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。此外，还有 仅PD-1抑制剂治疗就有150多项正在进行的临床试验。尽管有抗癌的好处， 免疫治疗与免疫相关的不良事件影响广泛的器官，包括心脏。 目前临床上的诊断是肌钙蛋白试验和心电图，但缺乏 对心肌炎的必要敏感性和特异性。因此，在具体目标1中，我们试图确定 可能对检查点抑制剂治疗有预测价值的转录(RNAseq/MirSeq)生物标记物 诱发性心肌炎。在这个特定的目标中，我们将重点关注已发展为自身免疫的患者。 接受检查点抑制剂治疗后的心肌炎，并将血样存入银行。这样的病人 提供了一个机会来确定新的联合和预测性生物标记物，这些标记物可以作为 实施新的治疗方法以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，目前的订阅做法 类固醇使患者全身暴露在免疫抑制之下。在具体目标2中，我们将评估一种新的反 以炎性多肽为基础的纳米系统携带针对NF-κB的小干扰RNA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 在特定目标2中提出的将使抗炎治疗仅能输送到心脏发炎的区域。 此外，该测试剂具有已知的抗癌作用。因此，《特定目标2》的成功可能 提供精确的治疗交付，并最大限度地减少系统性偏离目标的副作用。

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.