Prediction and Treatment for Cancer Immunotherapy Induced Myocarditis

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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.