Genetic basis for clinical response to CTLA-4 blockade in melanoma
- PMID: 25409260
- PMCID: PMC4315319
- DOI: 10.1056/NEJMoa1406498
Genetic basis for clinical response to CTLA-4 blockade in melanoma
Erratum in
-
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer; Nivolumab and Ipilimumab in Advanced Melanoma; Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma; Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy; Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma; Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma; Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma; Rapid Eradication of a Bulky Melanoma Mass with One Dose of Immunotherapy; Genetic Basis for Clinical Response to CTLA-4 Blockade; Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma; Nivolumab plus Ipilimumab in Advanced Melanoma; Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma; Hepatotoxicity with Combination of Vemurafenib and Ipilimumab.N Engl J Med. 2018 Nov 29;379(22):2185. doi: 10.1056/NEJMx180040. Epub 2018 Nov 9. N Engl J Med. 2018. PMID: 31442371 No abstract available.
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.).
Figures
Comment in
-
Somatic mutations and immunotherapy outcome with CTLA-4 blockade in melanoma.N Engl J Med. 2014 Dec 4;371(23):2230-2. doi: 10.1056/NEJMe1413061. Epub 2014 Nov 19. N Engl J Med. 2014. PMID: 25409261 Free PMC article. No abstract available.
-
Skin cancer. Benefiting from CTLA-4 blockade--a genetic rationale.Nat Rev Clin Oncol. 2015 Jan;12(1):4. doi: 10.1038/nrclinonc.2014.217. Epub 2014 Dec 9. Nat Rev Clin Oncol. 2015. PMID: 25488393 No abstract available.
-
Genetic basis for clinical response to CTLA-4 blockade.N Engl J Med. 2015 Feb 19;372(8):783. doi: 10.1056/NEJMc1415938. N Engl J Med. 2015. PMID: 25693024 No abstract available.
-
Genetic basis for clinical response to CTLA-4 blockade.N Engl J Med. 2015 Feb 19;372(8):783. doi: 10.1056/NEJMc1415938. N Engl J Med. 2015. PMID: 25693025 No abstract available.
-
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma.N Engl J Med. 2015 Nov 12;373(20):1984. doi: 10.1056/NEJMc1508163. N Engl J Med. 2015. PMID: 26559592 No abstract available.
Similar articles
-
Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.Science. 2015 Oct 9;350(6257):207-211. doi: 10.1126/science.aad0095. Epub 2015 Sep 10. Science. 2015. PMID: 26359337 Free PMC article.
-
Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition.Eur J Cancer. 2017 Sep;82:56-65. doi: 10.1016/j.ejca.2017.05.038. Epub 2017 Jun 22. Eur J Cancer. 2017. PMID: 28648699
-
Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials.Cancer Med. 2016 Jul;5(7):1481-91. doi: 10.1002/cam4.732. Epub 2016 May 11. Cancer Med. 2016. PMID: 27167347 Free PMC article. Review.
-
Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer.Pharmacol Res. 2012 Jan;65(1):9-22. doi: 10.1016/j.phrs.2011.09.002. Epub 2011 Sep 10. Pharmacol Res. 2012. PMID: 21930211 Review.
-
Immune checkpoint blockade.Hematol Oncol Clin North Am. 2014 Jun;28(3):585-600. doi: 10.1016/j.hoc.2014.02.002. Hematol Oncol Clin North Am. 2014. PMID: 24880949 Review.
Cited by
-
MHC class II genotypes are independent predictors of anti-PD1 immunotherapy response in melanoma.Commun Med (Lond). 2024 Sep 30;4(1):184. doi: 10.1038/s43856-024-00612-w. Commun Med (Lond). 2024. PMID: 39349759
-
Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab.Nat Med. 2024 Sep 30. doi: 10.1038/s41591-024-03240-y. Online ahead of print. Nat Med. 2024. PMID: 39349627
-
Fighting Pancreatic Cancer with a Vaccine-Based Winning Combination: Hope or Reality?Cells. 2024 Sep 16;13(18):1558. doi: 10.3390/cells13181558. Cells. 2024. PMID: 39329742 Free PMC article. Review.
-
Treatment resistance to melanoma therapeutics on a single cell level.Sci Rep. 2024 Sep 19;14(1):21915. doi: 10.1038/s41598-024-72255-9. Sci Rep. 2024. PMID: 39300183 Free PMC article.
-
Genomic and molecular alterations associated with primary resistance to immune checkpoint inhibitors.Cancer Immunol Immunother. 2024 Sep 13;73(11):234. doi: 10.1007/s00262-024-03825-z. Cancer Immunol Immunother. 2024. PMID: 39271499 Free PMC article. Review.
References
-
-
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. [Erratum, N Engl J Med 2010;363:1290.]
-
-
- Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 2010;16:399–403. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials