[HTML][HTML] Genetic basis for clinical response to CTLA-4 blockade in melanoma

A Snyder, V Makarov, T Merghoub… - … England Journal of …, 2014 - Mass Medical Soc
New England Journal of Medicine, 2014Mass Medical Soc
Background Immune checkpoint inhibitors are effective cancer treatments, but molecular
determinants of clinical benefit are unknown. Ipilimumab 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. Methods We obtained tumor tissue from patients with melanoma who
were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed …
Background
Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab 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.
Methods
We 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.
Results
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, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature 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.
Conclusions
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. (Funded by the Frederick Adler Fund and others.)
The New England Journal Of Medicine