Kenneth Ford

 Introduction. Immune checkpoint inhibitors are some of the most exciting new therapies in the world of cancer treatment. These inhibitors of PD-1 and CTLA-4 have become first line therapy for metastatic melanoma, non-small cell lung cancer, and second line drugs for an increasing number of malignancies.¹ Immune checkpoint inhibitors function on the premise of disinhibition of the body’s immune system.² This enables the body to combat cancer through the inhibition of negative regulators of the immune system.² While these new drugs have proven to be highly efficacious in treating cancer, there has also been an increase in occurrence of immune related adverse events.^2,3  One of the most worrisome of these adverse outcomes is myocarditis. Myocarditis is inflammation of the myocardium and has an alarmingly high mortality rate.^2,4 Methods. To further understand the mechanism by which this occurs, data collection focused predominantly on autoreactive T cells and the protective role of PD-1. One study used experimentally created PD-1 deficient mice to evaluate the prevalence of both T cells and myocarditis.⁵ Another study examining the same mechanism used a combination of cardiac irradiation and immune checkpoint inhibition and then evaluated cardiac dysfunction and myocarditis.⁶ Autoreactive T cells were examined by a study that performed post mortem analysis on two patients who had died of myocarditis following treatment with immune checkpoint inhibitors.⁷ Results. A deficiency in PD-1 leads to a statistically significant increase in Cd4, Cd8 T cells, monocytes, and neutrophils in the myocardium of experimental mice.⁵ This increase in inflammatory cells in the myocardium was associated with cardiac damage and death.⁵ When cardiac irradiation was combined with immune checkpoint inhibitor therapy there was a statistically significant (p=.23) increase in mortality over either cardiac irradiation or immune checkpoint inhibition alone.⁶ There was also a significant decrease in mice ejection fraction, (p<.01) indicating cardiac dysfunction.⁶ Post mortem analysis of two patients who had died of myocarditis following immune checkpoint inhibitor therapy showed an increase T cell infiltration of the myocardium with T cell epitopes specific for straited muscle antigens.⁷ Conclusion. It is evident that Pd-1 is inherently protective to the myocardium. An environment deficient in PD-1, such as is created by this cancer therapy, is detrimental to the myocardium.^5,6 T cells are clearly responsible for some degree of the autoimmunity occurring, as the disinhibition of the immune system creates an environment in which these cells become autoreactive.⁷

1. Reuben A, Macedo MPD, Mcquade J, et al. Comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab. OncoImmunology. 2017;6(12). doi:10.1080/2162402x.2017.1361097.
2. Hu J-R, Florido R, Lipson EJ, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovascular Research. 2019. doi:10.1093/cvr/cvz026.
3. Asnani A. Cardiotoxicity of Immunotherapy: Incidence, Diagnosis, and Management. Current Oncology Reports. 2018;20(6). doi:10.1007/s11912-018-0690-1.
4. Salem J-E, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. The Lancet Oncology. 2018;19(12):1579-1589. doi:10.1016/s1470-2045(18)30608-9.
5. Tarrio ML, Grabie N, Bu D-X, Sharpe AH, Lichtman AH. PD-1 Protects against Inflammation and Myocyte Damage in T Cell-Mediated Myocarditis. The Journal of Immunology. 2012;188(10):4876-4884. doi:10.4049/jimmunol.1200389.
6. Du S, Zhou L, Alexander GS, et al. PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. Journal of Thoracic Oncology. 2018;13(4):510-520. doi:10.1016/j.jtho.2017.12.002.
7. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55.