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.
