Genetic basis for clinical response to CTLA-4 blockade in melanoma Journal Article


Authors: Snyder, A.; Makarov, V.; Merghoub, T.; Yuan, J.; Zaretsky, J. M.; Desrichard, A.; Walsh, L. A.; Postow, M. A.; Wong, P.; Ho, T. S. ; Hollmann, T. J.; Bruggeman, C.; Kannan, K.; Li, Y.; Elipenahli, C.; Liu, C.; Harbison, C. T.; Wang, L.; Ribas, A.; Wolchok, J. D.; Chan, T. A.
Article Title: Genetic basis for clinical response to CTLA-4 blockade in melanoma
Abstract: 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.).
Journal Title: New England Journal of Medicine
Volume: 371
Issue: 23
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2014-12-04
Start Page: 2189
End Page: 2199
Language: English
DOI: 10.1056/NEJMoa1406498
PROVIDER: scopus
PUBMED: 25409260
PMCID: PMC4315319
DOI/URL:
Notes: Export Date: 2 January 2015 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    295 Chan
  2. Jedd D Wolchok
    815 Wolchok
  3. Taha Merghoub
    293 Merghoub
  4. Michael Andrew Postow
    267 Postow
  5. Phillip Wong
    56 Wong
  6. Cailian Liu
    51 Liu
  7. Jianda Yuan
    105 Yuan
  8. Logan Alexander Walsh
    19 Walsh
  9. Kasthuri Srinivasan Kannan
    11 Kannan
  10. Yanyun Li
    28 Li
  11. Teresa Rasalan
    28 Rasalan
  12. Vladimir Makarov
    50 Makarov