Cytokines Could Predict Risk of Side Effects From Immunotherapy

Blood-based cytokine markers may help identify cancer patients at greatest risk of developing side effects from immunotherapy treatment, according to a pilot study published Oct. 31 in the British Journal of Cancer. Patients with lower pretreatment cytokine levels experienced greater increases in immune-related adverse events (irAEs), as did patients with greater post-treatment increases in some cytokine levels. The authors say these findings suggest that underlying immune dysregulation may be associated with higher risk for irAEs.

“Identifying these cytokines and other biomarkers for the prediction and tracking of autoimmune toxicity could help us customize immunotherapy, tailor monitoring and increase patient safety, and possibly even expand the use of immunotherapy to populations that are currently excluded,” said senior author David Gerber, M.D., in a statement.

The need to identify patients at risk of AEs is great, given recent reports that side effects from certain immunotherapies may be more common than reported in the initial trials that led to the approval of these therapies. According to a study presented at the annual Palliative and Supportive Care in Oncology Symposium (Nov. 16-17; San Diego), analysis of real-world claims data from nearly 2,800 people with non-small cell lung cancer treated with immune checkpoint inhibitors experienced irAEs at rates substantially higher than in clinical trials.

Estimates are that between 40 and 80% of cancer patients on immune checkpoint inhibitors develop immune-related adverse events (irAEs), some of which can be severe or permanent. Diagnosis is challenged by the fact that irAEs can occur at any point in therapy and lack a specific diagnostic test.

In the pilot study, 65 patients receiving immune checkpoint inhibitors and 13 healthy controls were evaluated for 40 cytokines, markers of systemic immune status. Blood samples were collected from cancer patients at baseline, after one treatment cycle (either 2 weeks or 3 weeks), and at 6 weeks. Two samples were collected from healthy controls approximately two to three weeks apart.

The researchers found that irAEs occurred in 35 percent of cases overall. Specifically, irAEs occurred in 34 percent of patients treated with anti-PD1/PDL1 therapy and in 60 percent of patients treated with a combination of anti-PD1/PDL1 and anti-CTLA4 therapy. An irAE also occurred in the single patient treated with anti-CTLA4 monotherapy.

Cytokine levels were stable over time among healthy controls and lower than those in cancer patients at baseline. Patients who developed irAEs had lower levels of

CXCL9, CXCL10, CXCL11 and CXCL19 at baseline and exhibited greater increases in CXCL9 and CXCL10 levels at post-treatment versus patients without irAEs.

“The incorporation of data from pre-treatment baseline and after 1 to 2 doses of checkpoint inhibitor therapy (before the onset of most irAEs) means that these or the related biomarkers could serve to guide patient management in real time,” write the authors led by Shaheen Khan, from University of Texas Southwestern Medical Center in Dallas.

The authors say that their next steps include a forthcoming multicenter clinical trial that will enroll 600 patients and include evaluations of 130 autoantibodies, genetic tests for genes associated with autoimmune and inflammatory diseases, and functional tests, including cytokines.

Takeaway: Cytokines may be effective as biomarkers for predicting the development of irAEs in cancer patients undergoing immunotherapy treatment.