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Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

Alexandra Snyder, M.D., Vladimir Makarov, M.D., Taha Merghoub, Ph.D., et al.

Editorial comment by Dr. J. Larkin:
Whole-exome sequencing was undertaken on tumours and matched blood samples of 64 patients with melanoma treated with the anti-CTLA4 agents ipilimumab or tremelimumab. Somatic mutations and candidate neoantigens were characterised. Neoantigen peptides were tested for their ability to activate lymphocytes from ipilimumab-treated patients.

 

A discovery set consisted of 11 patients with long-term clinical benefit and 14 patients without such benefit. Mutational load was associated with the degree of clinical benefit but was insufficient alone to predict this whereas a neoantigen signature specifically present in tumours with a good response to CTLA-4 blockade was reported and validated in a second set of 39 patients. Furthermore predicted neoantigens activated T cells from patients treated with ipilimumab.

 

These findings provide a genetic basis for efficacy from CTLA-4 blockade in melanoma and whilst confirmation in other datasets is required, suggest a potential means of prospectively defining patients most likely to benefit from this treatment.

N Engl J Med 2014; 371:2189-2199December 4, 2014DOI: 10.1056/NEJMoa1406498

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.)