438P - A novel treatment for immune checkpoint inhibitor-related myocarditis

Background

Immune checkpoint inhibitors (ICIs) demonstrate efficacy against various cancers by activating the immune response against neoplasia. On the other hand, ICI-related myocarditis, which has a high mortality rate, is known to occur as adverse event. Therefore, safe ICI therapy should be established worldwide. In the present study, we developed a mouse model of ICI-related myocarditis and evaluated the efficacy of vitamin D, which exerts therapeutic effects on autoimmune myocarditis.

Methods

PD-1 knockout (PD-1KO) mice were treated with the myocardial myosin peptide and pertussis toxin to create a mouse model of ICI-related myocarditis. After 21 days of myocardial myosin peptide administration, their hearts were dissected and evaluated for the development of myocarditis. In addition, vitamin D, a candidate drug, was administered to the model mice every other day to evaluate its effect on the severity of myocarditis.

Results

Administering the myocardial myosin peptide to PD-1KO mice resulted in infiltration of inflammatory cells into the myocardial tissue and progressive myocardial fibrosis. Fluorescent immunostaining showed infiltration of CD4⁺ and CD8⁺ T cells in the myocardial tissue. Inflammatory cell infiltration was significantly suppressed in the vitamin D-treated group than in the vehicle group, as was CD4⁺ and CD8⁺ T cell infiltration. There was a trend toward suppression of myocardial fibrosis with vitamin D administration, although without statistical significance.

Conclusions

By administering the myocardial myosin peptide to PD-1KO mice, we generated a simple and reproducible experimental model of ICI-related myocarditis. Furthermore, vitamin D attenuated the infiltration of inflammatory cells and prevented the onset of ICI-related myocarditis in the model mice. The application of vitamin D as a prophylactic agent for ICI-related myocarditis should be investigated in the future.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Japan Society for the Promotion of Science.

Disclosure

All authors have declared no conflicts of interest.