Epigenetics and immunotherapy: The current state of play

doi:10.1016/J.MOLIMM.2017.04.012

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Epigenetics and immunotherapy: The current state of play

Journal Article•DOI•

Epigenetics and immunotherapy: The current state of play

J. Dunn¹, Sudha Rao¹•Institutions (1)

University of Canberra¹

01 Jul 2017-Molecular Immunology (Mol Immunol)-Vol. 87, pp 227-239

TL;DR: The exciting role of epigenetic immunomodulation in tumour immune escape is discussed, emphasising its significance in priming and sensitising the host immune system to immunotherapies through mechanisms such as the activation of the viral defence pathway.

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About: This article is published in Molecular Immunology.The article was published on 2017-07-01 and is currently open access. It has received 156 citations till now. The article focuses on the topics: Immune checkpoint & Epigenetic therapy.

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Journal Article•DOI•

Cold Tumors: A Therapeutic Challenge for Immunotherapy.

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Paola Bonaventura¹, Tala Shekarian¹, Vincent Alcazer¹, Jenny Valladeau-Guilemond¹, Sandrine Valsesia-Wittmann¹, Sebastian Amigorena², Christophe Caux¹, Stéphane Depil¹, Stéphane Depil³ - Show less +5 more•Institutions (3)

French Institute of Health and Medical Research¹, PSL Research University², Claude Bernard University Lyon 1³

08 Feb 2019-Frontiers in Immunology

TL;DR: The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors.

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Abstract: Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called "cold tumors." In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ''supra-physiological'' therapies, such as T cell recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism involved, especially in MHC class I negative tumors. The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors.

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640 citations

Journal Article•DOI•

Neoantigen-directed immune escape in lung cancer evolution

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Rachel Rosenthal¹, Rachel Rosenthal², Elizabeth Larose Cadieux², Roberto Salgado³, Maise Al Bakir², David A. Moore¹, Crispin T. Hiley¹, Crispin T. Hiley², Tom Lund¹, Miljana Tanic¹, James L. Reading¹, Kroopa Joshi¹, Jake Y. Henry¹, Ehsan Ghorani¹, Gareth A. Wilson¹, Gareth A. Wilson², Nicolai Juul Birkbak¹, Nicolai Juul Birkbak², Mariam Jamal-Hanjani¹, Selvaraju Veeriah¹, Zoltan Szallasi⁴, Sherene Loi³, Matthew D. Hellmann⁵, Matthew D. Hellmann⁶, Andrew Feber¹, Benny Chain¹, Javier Herrero¹, Sergio A. Quezada¹, Jonas Demeulemeester⁷, Jonas Demeulemeester², Peter Van Loo², Peter Van Loo⁷, Stephan Beck¹, Nicholas McGranahan¹, Charles Swanton², Charles Swanton¹ - Show less +32 more•Institutions (7)

University College London¹, Francis Crick Institute², Peter MacCallum Cancer Centre³, Boston Children's Hospital⁴, Cornell University⁵, Memorial Sloan Kettering Cancer Center⁶, Katholieke Universiteit Leuven⁷

28 Mar 2019-Nature

TL;DR: It is suggested that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.

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Abstract: The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.

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563 citations

Journal Article•DOI•

Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study

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Ursula A. Matulonis¹, Ronnie Shapira-Frommer², Alessandro D. Santin³, Alla Lisyanskaya, Sandro Pignata, Ignace Vergote⁴, Francesco Raspagliesi, Gabe S. Sonke⁵, Michael J. Birrer⁶, Diane Provencher⁷, Jalid Sehouli⁸, Nicoletta Colombo⁹, Antonio González-Martín¹⁰, Ana Oaknin¹¹, Petronella B. Ottevanger¹², Vilius Rudaitis¹³, Kia Katchar¹⁴, H. Wu, Stephen Michael Keefe¹⁴, Jane Ruman¹⁴, Jonathan A. Ledermann¹⁵ - Show less +17 more•Institutions (15)

Harvard University¹, Sheba Medical Center², Yale University³, Katholieke Universiteit Leuven⁴, Netherlands Cancer Institute⁵, University of Alabama at Birmingham⁶, Université de Montréal⁷, Free University of Berlin⁸, European Institute of Oncology⁹, University of Navarra¹⁰, Hebron University¹¹, Radboud University Nijmegen¹², Vilnius University¹³, Merck & Co.¹⁴, University College London¹⁵

01 Jul 2019-Annals of Oncology

TL;DR: Pembrolizumab 200mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years in patients with advanced recurrent ovarian cancer (ROC) as discussed by the authors.

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395 citations

Journal Article•DOI•

Tumor neoantigens: from basic research to clinical applications.

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Tao Jiang¹, Tao Jiang², Tao Shi³, Henghui Zhang, Jie Hu¹, Yuanlin Song¹, Jia Wei³, Shengxiang Ren², Caicun Zhou² - Show less +5 more•Institutions (3)

Fudan University¹, Tongji University², Nanjing University³

06 Sep 2019-Journal of Hematology & Oncology

TL;DR: This review systematically summarize the recent advances of understanding and identification of tumor-specific neoantigens and its role on current cancer immunotherapies and the ongoing development of strategies based on neoantigen and its future clinical applications.

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Abstract: Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor-specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor-specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications.

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232 citations

Journal Article•DOI•

Immune checkpoint therapy in liver cancer.

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Feng Xu¹, Feng Xu², Tianqiang Jin², Yuwen Zhu¹, Chaoliu Dai² - Show less +1 more•Institutions (2)

Anschutz Medical Campus¹, China Medical University (PRC)²

29 May 2018-Journal of Experimental & Clinical Cancer Research

TL;DR: Current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma are summarized and the mechanisms underlying its effects are clarified.

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Abstract: Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

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226 citations

Cites background from "Epigenetics and immunotherapy: The ..."

...7.26 (1.0–2.5) PD-L1/PD-1 neoplastic and inflammatory cells 2016 [24] Human HCC 176 97/52 112/64 5.3 (PD-L1 low)/ 4.9 (PD-L1 high) PD-L1 CD68+ macrophages 2016 [27] Human HCC 90 Operable, resected 73/17 4.2 (1.3–15) PD-L1 peritumoral hepatocytes 2017 [25] Human HCC 294 59/87 140/6 110( 5) /36(≥5) PD-L1/PD-1 and CTLA-4 tumor infiltrating 2017 [26] Human HCC 69 35/34 50/19 7/21(Tim-3 low)/ 17/24 (Tim-3 high) Tim-3 CD14+ monocytes 2015 [28] Human HCC 171 100/71 NR 98/73 PD-1 and Tim-3 neoplastic and inflammatory cells 2016 [29] Human ICC 31 9/22 13/18 20 (<5) / 11 (>5) PD-L1 and PD-1 neoplastic and inflammatory cells 2009 [38] Human ICC 27 16/11 19/8 NR PD-L1 ICC cells 2016 [36] HCC hepatocellular carcinoma, ICC Intrahepatic cholangiocarcinoma, NR not reported demonstrated as an independent poor prognostic factor for disease-free survival in the high CD8+ TILs group....
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...APC: Antigen presenting cell; ASCO: American Society of Clinical Oncology; BTLA: B- and T-lymphocyte attenuator; CTLA-4: Cytotoxic T lymphocyte– associated antigen 4; DNMT1: DNA methyltransferase 1; DNMTi: DNA methyltransferase inhibitors; GITR: Glucocorticoid-induced tumor necrosis factor receptor-related gene; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HDACi: Histone deacetylase inhibitors; HLA: Human leukocyte antigens; HVEM: Herpesvirus entry mediator; ICC: Intrahepatic cholangiocarcinoma; IDO: Indoleamine 2,3-dioxygenase; KIRs: Killer cell Metastatic melanoma 71 Pembrolizumab 5-AZA Phase 2 Recruiting Non-Randomized NCT02816021 NSCLC 120 Nivolumab 5-AZA and/or entinostat Phase 2 Recruiting Randomized NCT01928576 NSCLC 60 Nivolumab 5-AZA- CdR/ tetrahydrouridine Phase 2 Recruiting Randomized NCT02795923 Advanced solid tumors 60 Durvalumab 5-AZA Phase 2 Recruiting Single Group Assignment NCT02811497 Advanced/metastatic NSCLC 100 Pembrolizumab Oral azacytidine Phase 2 Active, not recruiting Randomized NCT02546986 PR recurrent OC 38 Pembrolizumab Guadecitabine Phase 2 Recruiting Single Group Assignment NCT02901899 PR recurrent OC 20 Pembrolizumab Oral azacytidine Phase 2 Recruiting Randomized NCT02900560 MDS 120 Durvalumab Oral azacytidine Phase 2 Recruiting Randomized NCT02281084 MDS, AML 213 Durvalumab Azacytidine Phase 2 Active, not recruiting Randomized NCT02775903 Refractory/recurrent epithelial OC 138 Avelumab Entinostat Phase 2 Recruiting Randomized NCT02915523 DLBCL 304 Rituximab 5-AZA Phase 3 Recruiting Randomized NCT02951156 HCC hepatocellular carcinoma, NSCLC Non-small cell lung cancer, HER2 human epidermal growth factor receptor 2, CRC colorectal cancer, 5-AZA Azacitydine, MSS Microsatellite stable, MDS Myelodysplastic syndromes, DNMTi DNA methyltransferase inhibitor, MM Multiple myeloma, DLBCL Diffuse large B cell lymphoma, HNSCC head and neck squamous cell carcinoma, SGC salivary gland cancer, AML Acute myeloid leukaemia, OC ovarian cancer immunoglobulin-like receptors; LAG-3: Anti-lymphocyte activation gene-3; lncRNAs: long noncoding RNAs; miRNAs: microRNAs; PD-1: Programmed cell death protein-1; PD-L1: Programmed cell death ligand 1; TAA: Tumor-associated antigens; TAM: Tumor-associated macrophages; TILs: Tumor-infiltrating lymphocytes; Tim-3: T-cell immunoglobulin- and mucin-domain-containing molecule-3; Tregs: Regulatory T cells; VISTA: V-domain Ig suppressor of T-cell activation...
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...HDAC is have been shown to sensitize cancer cells to immune checkpoint therapy by upregulating the immune checkpoints CTLA-4, PD-1, PD-L1, and PD-L2 on tumor cells and TILs [55]....
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...High levels of PD-L1 expression were also found in Western patients with ICC, which resulted in tumor poor differentiation, higher malignant tumor stage and higher levels of apoptotic CD8+ TILs, and therefore led to lower chance of survival [42]....
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...Immunohistochemistry data in 294 HCC tissue samples showed PD-1 and PD-L1 expression was significantly related to high CD8+ tumor-infiltrating lymphocytes (TILs)....
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Journal Article•DOI•

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.

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F. Stephen Hodi¹, Steven J. O'Day, David F. McDermott¹, R. W. Weber, Jeffrey A. Sosman², John B. A. G. Haanen³, Rene Gonzalez⁴, Caroline Robert⁵, Dirk Schadendorf⁶, Jessica C. Hassel⁷, Wallace Akerley⁸, Alfons J.M. van den Eertwegh⁹, Jose Lutzky¹⁰, Paul Lorigan, Julia Vaubel⁶, Gerald P. Linette¹¹, David W. Hogg, Christian H. Ottensmeier¹², Céleste Lebbé¹³, Christian Peschel¹⁴, Ian Quirt, Joseph I. Clark¹⁵, Jedd D. Wolchok¹⁶, Jeffrey S. Weber¹⁷, Jason Tian¹⁸, Michael Yellin¹⁸, Geoffrey M. Nichol¹⁸, Axel Hoos¹⁹, Walter J. Urba - Show less +25 more•Institutions (19)

Harvard University¹, Vanderbilt University², Netherlands Cancer Institute³, University of Colorado Denver⁴, Institut Gustave Roussy⁵, University of Duisburg-Essen⁶, University of Mannheim⁷, University of Utah⁸, VU University Amsterdam⁹, Mount Sinai Hospital¹⁰, Washington University in St. Louis¹¹, University Hospital Southampton NHS Foundation Trust¹², University of Paris¹³, Technische Universität München¹⁴, Loyola University Chicago¹⁵, Memorial Sloan Kettering Cancer Center¹⁶, University of South Florida¹⁷, Medarex¹⁸, Bristol-Myers Squibb¹⁹

18 Aug 2010-The New England Journal of Medicine

TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.

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Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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13,081 citations

Journal Article•DOI•

The blockade of immune checkpoints in cancer immunotherapy

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Drew M. Pardoll¹•Institutions (1)

Johns Hopkins University School of Medicine¹

22 Mar 2012-Nature Reviews Cancer

TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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10,602 citations

"Epigenetics and immunotherapy: The ..." refers background in this paper

...PD- L1 is expressed on a variety of cell types including epithelium, muscle, mesenchymal stem cells, T and B cells, DCs, macrophages, and cancer cells, while PD-L2 expression is restricted to immune-related cells such as DCs, macrophages, and mast cells (Pardoll, 2012)....
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...The PD-1 receptor is expressed on T cells, B cells, NK cells, monocytes, macrophages, and DCs (Pardoll, 2012)....
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...An improved understanding of these molecular mechanisms underlying immune regulation has resurrected the concept of targeting cancer immunologically (Pardoll, 2012; Dolan and Gupta, 2014)....
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...While CTLA-4 is essential during early activation of T cells in secondary lymphoid organs, PD-1 is primarily involved in modulating T cell activation in peripheral tissues including the TME (Pardoll, 2012)....
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...In addition, suppression of co-stimulatory molecules can result in CTLs only receiving a partial activating signal which can lead to a state of cell exhaustion, a key feature of which is the increased expression of inhibitory receptors on the T cell surface (e.g., PD-1) (Pardoll, 2012)....
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Journal Article•DOI•

Chromatin Modifications and Their Function

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Tony Kouzarides¹•Institutions (1)

University of Cambridge¹

23 Feb 2007-Cell

TL;DR: The surface of nucleosomes is studded with a multiplicity of modifications that can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA.

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10,046 citations

"Epigenetics and immunotherapy: The ..." refers background in this paper

...These epigenetic changes (or marks) include DNA methylation and post-translational histone modifications (PTMs) (Jones and Takai, 2001; Kouzarides, 2007)....
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...The most abundant histone modifications are acetylation, methylation, phosphorylation, and ubiquitylation; however, many other modifications have been reported (Kouzarides, 2007)....
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Journal Article•DOI•

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer

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Julie R. Brahmer¹, Karen L. Reckamp², Paul Baas³, Lucio Crinò, Wilfried Eberhardt⁴, Elena Poddubskaya⁵, Scott J. Antonia⁶, Adam Pluzanski, Everett E. Vokes⁷, Esther Holgado, David M. Waterhouse, Neal Ready⁸, Justin F. Gainor⁹, Osvaldo Arén Frontera, Libor Havel¹⁰, Martin Steins¹¹, Marina Chiara Garassino¹², Joachim G.J.V. Aerts¹³, Manuel Domine¹⁴, Luis Paz-Ares, Martin Reck, Christine Baudelet¹¹, Christopher T. Harbison¹¹, Brian Lestini¹¹, David R. Spigel¹² - Show less +21 more•Institutions (14)

Johns Hopkins University¹, City of Hope National Medical Center², Netherlands Cancer Institute³, University of Duisburg-Essen⁴, Russian Academy⁵, University of South Florida⁶, University of Chicago⁷, Duke University⁸, Harvard University⁹, Charles University in Prague¹⁰, Bristol-Myers Squibb¹¹, Sarah Cannon Research Institute¹², Erasmus University Rotterdam¹³, Autonomous University of Madrid¹⁴

08 Jul 2015-The New England Journal of Medicine

TL;DR: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level.

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Abstract: BackgroundPatients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population. MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 3...

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6,869 citations

Journal Article•DOI•

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.

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James Larkin¹, Vanna Chiarion-Sileni², Rene Gonzalez³, Jean-Jacques Grob⁴, C. Lance Cowey⁵, Christopher D. Lao⁶, Dirk Schadendorf, Reinhard Dummer⁷, Michael Smylie⁸, Piotr Rutkowski, Pier Francesco Ferrucci⁹, A. Hill¹⁰, John Wagstaff¹¹, Matteo S. Carlino¹², John B A G Haanen¹³, Michele Maio¹⁴, Ivan Marquez-Rodas¹¹, Grant A. McArthur¹⁵, Paolo A. Ascierto, Georgina V. Long¹⁶, Margaret K. Callahan¹⁷, Michael A. Postow¹⁸, Michael A. Postow¹⁷, Kenneth F. Grossmann¹⁹, Mario Sznol²⁰, Brigitte Dréno, Lars Bastholt²¹, Arvin Yang²², Linda Rollin²², Christine Horak, F. Stephen Hodi²³, Jedd D. Wolchok¹⁷, Jedd D. Wolchok¹⁸ - Show less +29 more•Institutions (23)

The Royal Marsden NHS Foundation Trust¹, European Institute of Oncology², University of Colorado Denver³, Aix-Marseille University⁴, Baylor University⁵, University of Michigan⁶, University of Zurich⁷, Cross Cancer Institute⁸, Peter MacCallum Cancer Centre⁹, Netherlands Cancer Institute¹⁰, Hospital General Universitario Gregorio Marañón¹¹, Memorial Sloan Kettering Cancer Center¹², Huntsman Cancer Institute¹³, Yale University¹⁴, University of Melbourne¹⁵, University of Sydney¹⁶, Cornell University¹⁷, Ludwig Institute for Cancer Research¹⁸, University of Utah¹⁹, Yale Cancer Center²⁰, Odense University Hospital²¹, Bristol-Myers Squibb²², Harvard University²³

01 Jul 2015-The New England Journal of Medicine

TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.

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Abstract: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)

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6,318 citations