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.
Although major advances have been made in halting the progression of most aggressive cancers with immune checkpoint inhibitors (ICIs), therapy-related cardiac complications pose serious clinical challenges. This proposal aims to test novel approaches for timely detection and therapeutic immune modulation of ICI- induced cardiotoxicity, with a goal of preventing life threatening cardiovascular complications.
