Somatic Mutations Linked To CTLA-4 Blockade Treatment Response In Melanoma

A neoepitope signature is associated with improved immunotherapy outcomes in patients given anti-CTLA-4 therapy

medwireNews: Researchers have identified a neoepitope signature arising from tumour mutations that correlates with a prolonged beneficial response to cytotoxic T-lymphocyte Antigen 4 (CTLA-4) blockade therapy in patients with melanoma.

Timothy Chan, from the Memorial Sloan Kettering Cancer Center in New York, USA, and co-investigators hypothesised that the genetic landscape of melanoma, a type of tumour that has a “very high mutational burden” compared with other solid cancers, could explain the variation in response to CTLA-4 blocking agents, such as ipilimumab and tremelimumab.

Whole exome sequencing of tumour DNA showed that mutational burden was significantly higher in patients who derived a long-term clinical benefit from anti-CTLA-4 treatment, defined as freedom from disease or stable or reduced disease volume for at least 6 months (n=11 and 25 in the discovery and validation cohorts, respectively), than those who derived no or minimal benefit (n=14 and 14 in the discovery and validation cohorts, respectively).

The team observes that a high mutational load alone is not enough to ensure a clinical response to treatment as there were tumours with such a burden that did not respond to therapy.

“Rather, there are somatic neoepitopes that are shared by patients with a prolonged benefit and are absent in those without a prolonged benefit”, the researchers explain. One such set of neoepitopes consisting of tetrapeptide sequences and identified using a Bioinformatics algorithm defined a signature that was associated with a sustained beneficial response to CTLA-4 blockade.

Participants with the neoepitope signature also had a significantly extended overall survival than those without the signature, a finding that was observed in both the discovery and validation cohorts. Interestingly, this association was stronger than that between mutational burden and overall survival.

“Our use of whole-exome sequencing to identify a genetic basis associated with a benefit from CTLA-4 blockade provides proof of principle that tumor Genomics can inform responses to immunotherapy”, the researchers conclude in The New England Journal of Medicine.

In an accompanying comment, Vassiliki Boussiotis, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, USA, points out that “[s]trikingly, many neoepitopes that were common to patients who had a sustained clinical benefit were homologous to viral and bacterial antigens”, suggesting that the clinical benefit arises as a result of immune responses against epitopes that T cells are likely to recognise.

“It is tempting to speculate that development of these antitumor responses might also be mediated by memory T cells generated during prior exposure to such antigens that were foreign to the host and happened to be homologous to neoepitopes induced by somatic mutations in melanomas”, concludes the commentator.

References

Snyder A, Makarov V, Merghoub T,et al.Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. N Engl J Med 2014; Advance online publication 19 November. doi:10.1056/NEJMoa1406498

Boussiotis VA. Somatic Mutations and Immunotherapy Outcome with CTLA-4 Blockade in Melanoma. N Engl J Med 2014; Advance online publication 19 November. doi:10.1056/NEJMe1413061

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