Cell-free DNA Could Detect Adverse Events from Immunotherapy

A noninvasive blood test to detect genetic material shed by tumors may help clinicians identify adverse events related to treatment with immune checkpoint inhibitor drugs, investigators at the Johns Hopkins Kimmel Cancer Center have found.

In a Dec. 11 letter to the editor of the New England Journal of Medicine, the researchers described how they measured cell-free DNA to identify tissue damage to nine organs in a study involving 14 patients with solid tumors who received immune checkpoint inhibitor therapy, a treatment that helps boost the immune system’s ability to attack cancer. The test determined that the six patients in the cohort who had immune-related adverse events (irAEs) — such as inflammation in the lung or gastrointestinal tract — had evidence of tissue damage in multiple organs at the time of, or prior to, their irAE diagnoses, based on symptoms.

“To our surprise, our findings suggest the tissue damage was more systemic, and not restricted to single organs,” says lead co-author Yuxuan Wang, M.D., Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine. “We saw evidence of multiorgan injury in all six patients with irAEs, along with roughly six times more tissue-specific cell-free DNA in their blood. This pattern suggests that the clinical syndromes we diagnose may represent only a small fraction of the underlying organ damage these patients experience.”

About half of patients who receive contemporary immunotherapies develop serious immune-related adverse events, and these can be life-threatening, particularly if not identified early, explains Mark Yarchoan, M.D., an associate professor of oncology at the Johns Hopkins University School of Medicine. “Unfortunately, we still lack reliable tools to identify which patients are developing these toxicities. Our results suggest that cell-free DNA could offer a new way to detect these complications earlier.”

The small study population included six patients with irAEs and eight patients who did not experience an irAE. Blood samples were collected prior to the start of treatment and between weeks four and eight of therapy. Because each tissue in the body has unique DNA methylation patterns (epigenetic modifications of DNA), the cell-free DNA test can be used to detect damage to individual organs.

The tissue damage was determined to precede the clinical diagnosis of irAE in three of the six patients by a range of four to 236 days. By contrast, none of the eight patients without clinically documented irAEs had evidence of multiorgan damage.

Further validation of the test in a larger trial would be needed to determine how causes of multiorgan damage affect the release of cell-free DNA, and how this test could be used to inform patient care, says Bert Vogelstein, M.D., the Clayton Professor of Oncology and co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center. The test could potentially provide information not only about immune response to treatment, but also help identify patients at risk for irAEs in need of additional treatment to prevent these toxicities, he says.

Co-writers of the letter were Howard L. Li, Chetan Bettegowda, Kenneth W. Kinzler and Nickolas Papadopoulos of Johns Hopkins. 

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