How can we know when curing cancer causes myocarditis?

Treatments for cancer are continuously improving, but they can still cause debilitating, even fatal, side effects. Immune checkpoint inhibitors, or ICIs, have revolutionized cancer therapy, yet their use can trigger a rare but deadly side effect that affects the heart: myocarditis. ICI-related myocarditis has a mortality of up to 40%.

The adverse side effects caused by ICIs are immune-related. The immune system becomes hyperactive and attacks tissue that is healthy, not cancerous. In ICI-related myocarditis, immune cells such as white blood cells, infiltrate the heart. It is extremely important to diagnose ICI-related myocarditis early, so treatment can be adjusted, and the risk of mortality can be lowered. However, early diagnosis has been difficult. ICI-related myocarditis cannot be easily detected via imaging of the heart and taking heart tissue samples for biopsy comes with its own risks.

To address the challenge of diagnosing ICI-related myocarditis, a team of Stanford investigators led by Dr. Alireza Raissadati and Dr. Sean Wu developed a promising new tool: a liquid biopsy using cell-free mRNA. Their study was recently published in the Journal of Clinical Investigation. What is unique about cell-free mRNA as a biomarker is that, unlike other methods of liquid biopsy, it enables tissue- and even cell type-specific profiling of gene expression. This is not possible with other blood-draw based diagnostics such as protein markers, cfDNA, and miRNA.  By analyzing blood from a routine blood draw, it is possible to detect cell-free mRNA from immune cells that are attacking the heart, as well as cell-free mRNA from heart muscle tissue that has been released due to damage.Being able to assess heart and immune cell-specific changes in gene expression can allow the early identification of ICI-related myocarditis.

The investigators validated this new cell-free mRNA technique in a cohort of 22 patients with ICI therapy-related myocarditis. Not only were the investigators consistently able to retrieve sufficient mRNA from blood draws to perform the analysis, which demonstrates feasibility, but they were able to identify a panel of genes that were upregulated in patients with ICI-related myocarditis compared to controls. The investigators used machine learning approaches to further refine their ability to discriminate changes in gene expression due to ICI-related myocarditis. Many of these genes were, as predicted, related to the immune response.

By leveraging the power of cell-free mRNA and machine learning to identify the genes most affected by cancer treatment, the investigators were able to use a liquid biopsy to detect both a treatment-specific immune response and heart tissue damage. This study demonstrates the immense potential of mRNA-based liquid biopsies for diagnosis and earlier treatment of cancer therapy-related myocarditis.

Additional Stanford Cardiovascular Institute-affiliated investigators who contributed to this study include Xuanyu Zhou, Harrison Chou, Yuhsin Vivian Huang, Shaheen Khatua, Yin Sun, Anne Xu, Sharon Loa, Arturo Hernandez, and Han Zhu.