An activity pattern in certain genes responsible for building proteins known as spleen tyrosine kinases may predict the occurrence of severe side effects from immunotherapy in patients with melanoma, according to a recent study published by Monson et al in Clinical Cancer Research.
Background
Immunotherapy drugs such as nivolumab and ipilimumab are designed to block checkpoints on the surface of immune T cells and make cancer cells more visible. Over the past decade, checkpoint inhibitors have become a mainstay in the treatment of melanoma.
However, more than 30% of patients with melanoma who receive checkpoint inhibitors develop severe side effects that can compromise their quality of life and ability to continue therapy. Side effects most often involve some type of inflammation—a sign of an overactive immune response—severe skin rashes, diarrhea, or hyperthyroidism. More severe side effects include liver toxicity, colitis, and rheumatoid arthritis.
Study Methods and Results
In the recent study, researchers analyzed immune system cell samples from 212 male and female patients with melanoma participating in the national multicenter CheckMate 915 trial. The trial was designed to test whether combined therapy with nivolumab and ipilimumab was more effective in preventing postsurgical recurrence of melanoma compared with single therapy with nivolumab. All immune system cell samples were taken prior to the start of immunotherapy.
After examining which genes were more active than others in patients who experienced side effects from immunotherapy, they found a specific pattern among 24 genes tied to the production of spleen tyrosine kinases. Further statistical analyses demonstrated that the increased or decreased activity of five of these genes—CD22, PAG1, CD33, HNRNPU, and FCGR2C—along with patients’ age and stage of melanoma served as the most accurate predictors of which patients may experience severe side effects from treatment.
The researchers discovered that even before treatment began, the activity of genes controlling the production of spleen tyrosine kinases predicted 83% of the patients who eventually developed severe side effects from combined immunotherapy with nivolumab and ipilimumab. Further, they found that this heightened gene signature, as evidenced by the production of spleen tyrosine kinases or the spleen tyrosine kinase (SYK) pathway, did not interfere with the effectiveness of therapies in preventing melanoma recurrence. The impact was connected to side effects alone.
The researchers noted that the SYK pathway has previously been linked to other autoimmune diseases such as lupus, rheumatoid arthritis, and colitis. The side effects from immunotherapy were most common in areas affected by these autoimmune diseases, including the skin, colon, and liver.
Conclusions
“Predictive information of this kind is critically important to oncologists and patients to help guide their immunotherapy decisions, to either minimize these side effects by taking additional precautions or to choose alternative immunotherapies,” indicated co–senior study author Tomas Kirchhoff, PhD, Associate Professor in the Department of Population Health at the New York University (NYU) Grossman School of Medicine and a member of the Perlmutter Cancer Center. “If our future research can explain how an activated (SYK) pathway leads to increased risk of side effects from immunotherapy, then it could also … help us to design better cancer immunotherapies and potentially other treatments for autoimmune diseases,” he underscored.
The researchers plan to investigate whether an activated SYK pathway is predictive of side effects in patients treated with ipilimumab alone or with other combination immunotherapies.
“Our study results show that increased gene activity in the [SYK] pathway could be the basis of a possible blood test that identifies those patients [with melanoma] most susceptible to having severe side effects from immunotherapy—and well before they start treatment,” concluded lead study author Kelsey Monson, PhD, of the NYU Langone Medical Center.
Disclosure: The research in this study was funded by the National Institutes of Health and the Melanoma Research Alliance. For full disclosures of the study authors, visit aacrjournals.org.
