Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

Genetic Basis For Clinical Response To CTLA-4 Blockade In Melanoma.

A. Snyder, Vladimir Makarov, T. Merghoub, J. Yuan, J. Zaretsky, A. Desrichard, L. Walsh, M. Postow, P. Wong, Teresa S. Ho, Travis J Hollmann, Cameron Bruggeman, K. Kannan, Y. Li, Ceyhan Elipenahli, C. Liu, C. Harbison, L. Wang, A. Ribas, J. Wolchok, T. Chan
Published 2014 · Medicine
Referenced 1 time by Citationsy Users

Save to my Library
Download PDF
Analyze on Scholarcy
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.).
This paper references
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies
K. Peggs (2009)
Improved Survival with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients
E. Cha (2014)
Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials.
J. Wolchok (2010)
Development and Validation of a Prognostic Gene-Expression Signature for Lung Adenocarcinoma
Yun Yong Park (2012)
A unique tumor antigen produced by a single amino acid substitution.
P. Monach (1995)
Epitope landscape in breast and colorectal cancer.
N. Segal (2008)
Deconstructing the peptideMHC specificity of T cell recognition
JL Mendoza (2014)
A comprehensive vertebrate phylogeny using vector representations of protein sequences from whole genomes.
G. Stuart (2002)
Cancer Exome Analysis Reveals a T Cell Dependent Mechanism of Cancer Immunoediting
H. Matsushita (2012)
proved survival with T cell clonotype stability after anti - CTLA - 4 treatment in cancer patients
E Cha (2014)
Exploiting the mutanome for tumor vaccination.
J. Castle (2012)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Crystal Structures of Two Closely Related but Antigenically Distinct HLA-A2/Melanocyte-Melanoma Tumor-Antigen Peptide Complexes1
P. Sliz (2001)
Anti–CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response
P. Kvistborg (2014)
Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time
M. Aleksić (2010)
Melanoma genome sequencing reveals frequent PREX2 mutations
M. Berger (2012)
Loss of T Cell Antigen Recognition Arising from Changes in Peptide and Major Histocompatibility Complex Protein Flexibility
Francis Insaidoo (2011)
The Immunodominant Antigen of an Ultraviolet-induced Regressor Tumor Is Generated by a Somatic Point Mutation in the DEAD Box Helicase p68
P. Dubey (1997)
Identification of the T-cell and Ia contact residues of a T-cell antigenic epitope
P. Allen (1987)
Deconstructing the Peptide-MHC Specificity of T Cell Recognition
Michael E. Birnbaum (2014)
Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.
Y. Li (2010)
The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation The New England Journal of Medicine Downloaded from at WELCH MED LIB JHU-MCAULEY
P Dubey (2014)
Modeling the Repertoire of True Tumor-Specific MHC I Epitopes in a Human Tumor
N. Srivastava (2009)
A mouse mutant p53 product recognized by CD4+ and CD8+ T cells.
Y. Noguchi (1994)
Gene Signature in Melanoma Associated With Clinical Activity: A Potential Clue to Unlock Cancer Immunotherapy
T. Gajewski (2010)
Exome sequencing identifies GRIN2A as frequently mutated in melanoma
X. Wei (2011)
Harnessing the antigenic fingerprint of each individual cancer for immunotherapy of human cancer: genomics shows a new way and its challenges
P. Srivastava (2013)
A Landscape of Driver Mutations in Melanoma
Eran Hodis (2012)
Cutting Edge: TCR Contacts as Anchors: Effects on Affinity and HLA-DM Stability 1
M. Anderson (2003)
Nivolumab plus ipilimumab in advanced melanoma.
J. Wolchok (2013)
Immune response to synthetic peptides of hepatitis delta antigen.
F. Poisson (1993)
An immune-active tumor microenvironment favors clinical response to ipilimumab
R. Ji (2011)
Identification of HLA-A*2402-restricted HCMV immediate early-1 (IE-1) epitopes as targets for CD8+ HCMV-specific cytotoxic T lymphocytes
Jong-Baeck Lim (2009)
Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting
G. Ku (2010)
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma.
T. Chan (2015)
Molecular Requirements for T Cell Recognition of N-Myristoylated Peptides Derived from the Simian Immunodeficiency Virus Nef Protein
Daisuke Morita (2012)
Immune Responses to a Class II Helper Peptide Epitope in Patients with Stage III/IV Resected Melanoma
R. Wong (2004)
Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma.
Nienke van Rooij (2013)
Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer
E. Tran (2014)
Signatures of mutational processes in human cancer
L. Alexandrov (2013)

This paper is referenced by
Targeting the immune system in head and neck cancer.
Gilberto de Castro (2015)
Toward the Identification of Genetic Determinants of Responsiveness to Cancer Immunotherapy
D. Bedognetti (2015)
Systems Biology Approach for Cancer Vaccine Development and Evaluation
L. Circelli (2015)
Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma
M. Löffler (2019)
Genomic characterization of six virus-associated cancers identifies changes in the tumor microenvironment and altered genetic programming
F. S. Varn (2018)
Releasing the Immune System Brakes Using siRNAs Enhances Cancer Immunotherapy
M. Sioud (2019)
Comparison of the molecular and cellular phenotypes of common mouse syngeneic models with human tumors
Wenyan Zhong (2020)
Gut microbiota: a new player in regulating immune- and chemo-therapy efficacy
S. Anfossi (2020)
Personalized peptide vaccines for cancer therapy: current progress and state of the art
Satoshi Wada (2017)
Emerging role of mutations in epigenetic regulators including MLL2 derived from The Cancer Genome Atlas for cervical cancer
Xia Li (2017)
Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma
K. Kiyotani (2017)
It’s a long way to the top (if you want to personalize immunotherapy)
S. Haebe (2017)
The expression of class II major histocompatibility molecules on breast tumors delays T cell exhaustion, expands the T cell repertoire and slows tumor growth
Tyler R McCaw (2018)
MicroRNA MIR21 and T Cells in Colorectal Cancer
K. Mima (2015)
Targeted Therapy for Cancer in the Genomic Era.
Anosheh Afghahi (2015)
The current state of molecular testing in the treatment of patients with solid tumors, 2019
W. El-Deiry (2019)
CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival
P. Zeiner (2018)
Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group.
T. Eder (2019)
MHC class I presented antigens from malignancies: A perspective on analytical characterization & immunogenicity.
M. Schmidt (2019)
Cancer stem cell immunology and immunotherapy: Harnessing the immune system against cancer's source.
R. Ruiu (2019)
Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option
M. Rohaan (2018)
Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma
Y. Chae (2019)
Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge 2018” (28–29 November, 2018, Naples, Italy)
P. Ascierto (2019)
The incidence and risk of cutaneous toxicities associated with dabrafenib in melanoma patients: a systematic review and meta-analysis.
Chen Peng (2020)
Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence.
S. Klempner (2019)
Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy
Rachael M. Zemek (2020)
Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non–Small Cell Lung Cancer
K. Arbour (2017)
The immunocheckpoints in modern oncology: the next 15 years
F. Massari (2015)
'Genotype/immunotype' correlations in resected NSCLC.
P. Paik (2017)
Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies
K. Komatsubara (2017)
Population-level distribution and putative immunogenicity of cancer neoepitopes
M. Wood (2018)
Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies.
Shetal A Patel (2018)
See more
Semantic Scholar Logo Some data provided by SemanticScholar