Gene activity predicts severe side effects from melanoma immunotherapy

Adverse effects from immunotherapy treatment in melanoma patients are associated with a distinct pattern of gene expression, offering the possibility for improved therapeutic strategies.

Researchers from NYU Langone Health, New York, analysed immune samples from over 200 melanoma patients treated with immunotherapy as part of the CheckMate-915 clinical trial. They found that the expression of 24 genes involved in the spleen tyrosine kinase signalling pathway was associated with severe immune-linked side effects, including skin rashes, liver toxicity and colitis. This pathway has previously been linked with autoimmune conditions, thus, a better understanding of this link may enable the development of better cancer treatments.

'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 those melanoma patients most susceptible to having severe side effects from immunotherapy, and well before they start treatment' said Dr Kelsey Monson, the co-lead author of the study.

Immunotherapies refer to a novel class of treatments which leverage the immune system to prevent cancer. Cancer cells are often able to evade surveillance by the immune system by establishing connections with immune cells. Immunotherapies can therefore make cancer cells visible to the immune system by inhibiting these connections.

Recently, immunotherapy has revolutionised the treatment of skin cancers such as melanoma. However, more than a third of melanoma patients experience severe side effects, which can prevent them from completing their cancer treatment.

This research, published in the journal Clinical Cancer Research, found that a small subset of genes linked with the spleen tyrosine kinase pathway could predict whether patients would experience adverse side effects with over 80 percent accuracy. While the authors suggest that the link between pathway expression and immune-related side effects is biologically plausible, further research is required to extract the exact mechanism of action.

'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' said Dr Tomas Kirchhoff, the co-senior lead of the study.

Further analysis found that accuracy could be increased using just five of the original 24 genes identified. However, while the ability to correctly classify patients without severe toxicity was very high, the sensitivity for identifying patients with high toxicity remained fairly low at around 50 percent.

Dr Kirchhoff added, 'Predictive information of this kind is critically important to oncologists and patients to help guide their immunotherapy decisions, to either minimise these side effects by taking additional precautions or to choose alternative immunotherapies'.