Abstract 461: Use of Cardiac Magnetic Resonance Imaging for the Early Detection of Programmed Cell Death-1 Blockade-induced Cardiotoxicity in a Mouse Model

Abstract

Introduction: Immunotherapy has revolutionized the treatment of advanced stage lung cancers and melanoma. However, serious cardiotoxic side effects such as acute myocarditis, heart block, and sudden cardiac arrest have been reported. There is an urgent need to develop accurate diagnostic modalities for the early detection of this condition, such that toxic therapies can be adjudicated based on the anticipated risks vs. benefits. Hypothesis: Programmed cell death-1 (PD-1) blockade-induced cardiotoxicity, presenting as myocarditis or contractile dysfunction, can be detected at an early stage by cardiac magnetic resonance imaging (MRI). Methods: To develop a murine model of PD-1 blockade-induced cardiotoxicity, we intraperitoneally administered 200 μg (10 mg/kg) of PD-1 antibody (Ab) or IgG isotype control every 3 days for a total of 14 doses. Cardiac function was monitored by MRI with gadolinium infusion. Serum was collected at 27 days and at the time of sacrifice. Immunohistochemical stains were performed on formalin-fixed paraffin embedded tissues. Results: Blockade in mice trended towards reduced myocardial signal intensity (SI) after the gadolinium injection, one month after the last dose of PD-1 antibody (myocardial SI: control 2.55 ± 0.168, PD-1 Ab 2.02 ± 0.164, p=0.063, n=4-7). Three months after the last injection, late gadolinium myocardial SI was significantly reduced in treated mice (myocardial SI: control 2.84 ± 0.352, PD-1 Ab 1.50 ± 0.308, p=0.024, n=4-5). There were also significant decreases in stroke volume (mL: control 10.4 ± 0.355, PD-1 Ab 8.36 ± 0.599, p=0.030, n=4-5), radial strain (%: control 49.9 ± 3.91, PD-1 Ab 33.5 ± 3.00, p=0.012, n=4-5), peak acceleration (cm/s 2 : control 7.24 ± 1.03, PD-1 Ab 3.51 ± 1.08, p=0.044, n=4-5), and peak deceleration (cm/s 2 : control -8.03 ± 0.78, PD-1 Ab -4.64 ± 1.04, p=0.042, n=4-5) times. Interestingly, a subset of animals also had serum antibodies directed against cardiac troponin I peptide sequence. Conclusions: Our study showed that cardiac MRI with gadolinium can identify abnormal myocardial perfusion and reduced contractile function in mice treated with a PD-1 blocker. The presence of serum antibodies against cardiac troponin I may have a mechanistic value, which warrants further investigation.