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Genetic Basis forClinical Response toCTLA-4 Blockade inMelanoma Alexandra SnyderVladimir MakarovTaha Merghoub2014 год

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

Полный текстСтраница публикацииПубликация в OpenAlex
Аннотация: 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.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.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.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.).
Год издания: 2014
Авторы: Alexandra Snyder, Vladimir Makarov, Taha Merghoub, Jianda Yuan, Jesse M. Zaretsky, Alexis Desrichard, Logan A. Walsh, Michael A. Postow, Phillip Wong, Teresa Ho, Travis J. Hollmann, Cameron Bruggeman, Kasthuri Kannan, Yanyun Li, Ceyhan Elipenahli, Cailian Liu, Christopher Harbison, Lisu Wang, Antoni Ribas, Jedd D. Wolchok, Timothy A. Chan
Издательство: Massachusetts Medical Society
Источник: New England Journal of Medicine
Ключевые слова: Cancer Immunotherapy and Biomarkers, CAR-T cell therapy research, Immunotherapy and Immune Responses
Другие ссылки: New England Journal of Medicine (PDF)
New England Journal of Medicine (HTML)
eScholarship (California Digital Library) (PDF)
eScholarship (California Digital Library) (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)