Gene signature predicts severe adverse events from ICI therapy for melanoma

Key takeaways:

• The spleen tyrosine kinase pathway was upregulated in patients that had severe toxicities from immune checkpoint inhibitor therapy.
• This signature accurately identified 60% of patients with toxicities.

Researchers identified a gene signature that can predict which group of patients with melanoma will experience severe immune-related adverse events when treated with immune checkpoint inhibitor therapy, according to a study.

“Immune checkpoint inhibition (ICI) therapies, combining the two antibodies anti-PD-1 and anti-CTLA-4, is an approved frontline therapy with the highest clinical efficacy for treating melanoma,” Tomas Kirchhoff, PhD, associate professor in the department of population health at NYU Langone Health, researcher at Perlmutter Cancer Center and an investigator of this study, told Healio. “However, they are associated with significant immune-related toxicities, which may be a major clinical problem.”

For patients with advanced melanoma, the risk for toxicity, also known as immune-related adverse events (irAE), may be outweighed by the benefits. In fact, recent studies have shown that in an adjuvant and neoadjuvant setting, ICI therapy improves outcomes compared with surgery alone. On the other hand, it is estimated that many patients in these treatments will be cured by surgery and such ICI may not add on additional benefit to the outcome. As such, the unnecessary risk of possible toxicities for these patients, represents a clinical burden. But how can clinicians know which patients will develop toxicities or not?

“If we could be able to identify these patients before they even start treatment by a particular host immune signature in their blood, we can improve clinical surveillance or decide on other less toxic treatment options,” Kirchhoff said.

As a result, Kirchhoff and colleagues set out to identify the biomarkers that signal which group of patients will develop severe toxicities before even starting treatment. The researchers assessed post-surgical, pre-ICI treatment peripheral CD4 and CD8 T cells from patients that were treated with adjuvant therapy nivolumab (n = 130) or a combination treatment of ipilimumab and nivolumab (n = 82) during the clinical trial CheckMate-915.

Results showed that a subset of differentially expressed genes in peripheral CD4 cells operating in the biological pathway of spleen tyrosine kinase (SYK), an established biological hub in autoimmunity, is more prevalent in patients that experience severe toxicities from ICI treatment. In fact, this signature predicted approximately 60% of the combination-treated patients that experienced grade 3 to 5, or severe, irAEs.

The prediction ability of this gene-expression signature exhibited 73% accuracy (chi-square P = 0.001) and proved to be independent of disease recurrence. Incorporating this gene-expression signature into an irAE-predictive model allowed for 82% accuracy in predicting if a patient is at risk for irAEs from ICI treatment (chi-square P = 8.91E-06).

“While the obvious clinical impact, upon further validation, is in its potential as a toxicity-predicting biomarker, this signature points to the novel biological targets that could be used for possible toxicity-reducing therapies,” Kirchhoff explained. “Moving forward, we can potentially pre-treat patients to suppress the effects of these toxicities instead of taking them off the treatment.”

According to Kirchhoff, this study is one of the very first to relate an established biological pathway in autoimmunity as a novel host-immune factor that impacts ICI toxicity.

“This intersection needs to be biologically studied,” he told Healio. “The major novelty of this particular study is raising a concrete link between the host biology of autoimmunity and ICI, with a possible relevance in immuno-oncology-based therapies of other cancer.”