Scientists at NYU Langone Health, its Perlmutter Cancer Center, and collaborators report that an activity pattern in certain genes responsible for building spleen tyrosine kinases can predict which melanoma patients are likely to have severe side effects from immunotherapy designed to treat the deadliest skin cancer, which kills almost 10,000 annually.
The team, which published its study, “Tyrosine-protein kinase SYK-related gene signature in baseline immune cells associated with adjuvant immunotherapy-induced immune-related adverse events in melanoma,” in Clinical Cancer Research, focused on checkpoint inhibitors, drugs that have in the last decade critical in the treatment of melanoma.
The drugs work by blocking molecules that sit on the surface of immune T cells and stop them from attacking cancer cells as they would invading viruses or bacteria. While the immune system normally uses checkpoints to recognize and protect healthy cells, cancer cells can hijack and turn off immune cell surveillance, evading detection. Immunotherapy drugs like nivolumab and ipilimumab are designed to block checkpoints, making cancer cells more visible again to T cells.
However, more than a third of melanoma patients given checkpoint inhibitors develop side effects so severe that they compromise their quality of life and ability to continue therapy, according to the researchers. Side effects most often involve some form of inflammation, a sign of an overactive immune response. Patients can experience severe skin rashes, diarrhea, or hyperthyroidism. More severe side effects can include liver toxicity, colitis, and rheumatoid arthritis.
In the new study, scientists found that even before treatment began in their test subjects, the activity of genes controlling the production of spleen tyrosine kinases predicted 83% of melanoma patients who eventually developed severe side effects from combined immunotherapy with nivolumab and ipilimumab.
In addition, the researchers discovered that this heightened gene signature, as evidenced by the production of spleen tyrosine kinases, or the SYK pathway, did not interfere with the effectiveness of therapies in preventing recurrence of melanoma. The impact was connected only to side effects.
“The analysis of predicted protein-protein interactions among differentially expressed genes (DEGs) in peripheral CD4+ cells revealed significant enrichment of the spleen tyrosine kinase (SYK) pathway, associated with severe irAEs in COMBO-treated patients. This gene-expression signature predicted severe-irAE COMBO patients (chi-square p-value=0.001) with 73% accuracy and was independent of disease recurrence (p=0.79). The irAE-predictive model incorporating this gene-expression signature demonstrated 82% accuracy (chi-square p-value=8.91E-06).
“We identified baseline gene-expression differences in key immune pathways of peripheral blood T cells from COMBO-treated patients with grade 3-5 irAEs and defined a SYK-related gene signature correctly identifying ~60% of COMBO-treated patients with grade 3-5 irAE. This finding aligns with our previous work linking anti-CTLA-4 irAEs with a germline variant associated with high SYK expression. This gene signature may serve as a baseline biomarker of severe grade 3-5 irAE risk, which is especially important in AT.”
“Our study results show that increased gene activity in the spleen tyrosine kinase pathway could be the basis of a possible blood test that identifies melanoma patients most susceptible to having severe side effects from immunotherapy, and well before they start treatment,” said study co-senior investigator Tomas Kirchhoff, PhD, associate professor in the department of population health at NYU Grossman School of Medicine and a member of Perlmutter Cancer Center.
“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 choose alternative immunotherapies,” said study co-lead investigator Kelsey Monson, PhD.
Analyzed immune system cell samples
For the study, researchers analyzed immune system cell samples from 212 men and women with melanoma participating in a national multicenter trial called CheckMate-915. The trial was designed to test whether combined therapy with nivolumab and ipilimumab worked better than single therapy with nivolumab in preventing postsurgical recurrence of melanoma. All immune cell samples were taken prior to the start of immunotherapy. Both drugs are manufactured by Bristol Myers Squibb, which sponsored the CheckMate-915 trial, and provided the patient specimens and data used in the analysis.
When researchers looked at what genes were more active than others in patients who experienced side effects from their immunotherapy, they found a specific pattern among 24 genes tied to the production of spleen tyrosine kinases. Further statistical analyses showed that increased or decreased transcription of only five of these genes—CD22, PAG1, CD33, HNRNPU, and FCGR2C—along with age and stage severity of their melanoma served as the best predictors of who would experience immunotherapy side effects.
Study co-senior investigator Jeffrey Weber, MD, PhD, noted that the SYK pathway has previously been linked to other autoimmune diseases, including lupus, rheumatoid arthritis, and colitis, disorders marked by immune system attacks on healthy cells. He also pointed out that immunotherapy side effects were also most common in areas affected by these autoimmune diseases, including the skin, colon, and liver.
Weber, the Laura and Isaac Perlmutter Professor of Oncology in the department of medicine at NYU Grossman School of Medicine, said the team next plans to investigate if an activated SYK pathway is predictive of side effects in patients treated with ipilimumab alone or with other combination immunotherapies. Weber also serves as deputy director of NYU Langone’s Perlmutter Cancer Center.
“If our future research can explain how an activated spleen tyrosine kinase pathway leads to increased risk of side effects from immunotherapy, then it could also potentially help us to design better cancer immunotherapies and potentially other treatments for autoimmune diseases,” added Kirchhoff.
