Close up of melanoma
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A genetic marker can identify patients at high risk of potentially serious side effects from immunotherapy used to treat melanoma skin cancer.

Researchers identified the first genetic risk factor for immunotherapy toxicity in the IL-7 gene, which codes for an important factor in lymphocyte survival.

Carriers had up to a six-fold increase in the risk of toxicities after immunotherapy using checkpoint inhibitors, according to the findings published in Nature Medicine.

Approximately eight per cent of white Europeans, who are the group most commonly affected by melanoma—one of the most common skin cancers—carry the risk allele.

“The risk allele seems to function to regulate expression of IL7 in B cells—these cells have had little attention in the response to immunotherapy beforehand and the work identifies an important role for them,” explained lead researcher Ben Fairfax, an associate professor at the MRC Weatherall Institute of Molecular Medicine at the University of Oxford.

He told Inside Precision Medicine: “Patients with melanoma carrying this risk allele appear to have a better prognosis when untreated—in essence, it appears to ’supercharge’ their immune response to melanoma.”

Fairfax’s study is co-published with another from the Dana Faber Cancer Institute, which together identify and confirm the genetic variant and reveal its immunological consequences.

Autoimmune side effects are frequent issue from cancer treatment using immunotherapy and can potentially be life threatening.

They typically include severe diarrhea, arthritis, dermatitis, and endocrine dysfunction such as thyroid problems and diabetes.

Currently there is no way to predict who will develop these toxicities and only limited insight into its underlying immunological mechanisms.

A parallel, genome-wide association study identified a non-coding polymorphism at IL7 that was associated with an increased risk of autoimmune complications following immune checkpoint blockade.

Fairfax and co-workers confirmed this association in 214 patients receiving this immunotherapy for melanoma and found the risk allele predisposed them to toxicities requiring corticosteroid treatment.

The impact of the genetic variant was detectable in B cells prior to immunotherapy, indicating these cells played an important role in the immune response to untreated skin cancer.

Further studies of historical samples from patients with melanoma indicated that the genetic change may be naturally protective against its recurrence.

“The results of this study are important as they may permit us to help stratify immunotherapies going forward, as well as providing insights into the mechanisms of toxicity,” said Fairfax.

“Finally, the work suggests IL7 is a potential target for future treatments in patients whose cancers are insensitive to standard treatment.”

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