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Genetic basis for benefit from CTLA-4 blockade in melanoma


Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab ( Yervoy ) and Tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 ( CTLA-4 ).
Anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.

Researchers obtained tumor tissue from patients with melanoma who were treated with Ipilimumab or Tremelimumab.
Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized.
Neoantigen peptides were tested for the ability to activate lymphocytes from Ipilimumab-treated patients.

Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing.

A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit.

Mutational load was associated with the degree of clinical benefit ( P=0.01 ) but alone was not sufficient to predict benefit.

Using genomewide somatic neoepitope analysis and patient-specific HLA typing, candidate tumor neoantigens for each patient were identified.
Researchers elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade.

This signature was validated in a second set of 39 patients with melanoma who were treated with anti–CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with Ipilimumab.

In conclusion, these findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti–CTLA-4 agents are being considered. ( Xagena )

Snyder A et al, N Engl J Med 2014; 371:2189-2199

XagenaMedicine_2014



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