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RANDOMIZED CONTROLLED TRIAL
Luis Paz-Ares, Alexander Luft, David Vicente, Ali Tafreshi, Mahmut Gümüş, Julien Mazières, Barbara Hermes, Filiz Çay Şenler, Tibor Csőszi, Andrea Fülöp, Jerónimo Rodríguez-Cid, Jonathan Wilson, Shunichi Sugawara, Terufumi Kato, Ki Hyeong Lee, Ying Cheng, Silvia Novello, Balazs Halmos, Xiaodong Li, Gregory M Lubiniecki, Bilal Piperdi, Dariusz M Kowalski
BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles...
November 22, 2018: New England Journal of Medicine
#2
MULTICENTER STUDY
Patrick A Ott, Yung-Jue Bang, Sarina A Piha-Paul, Albiruni R Abdul Razak, Jaafar Bennouna, Jean-Charles Soria, Hope S Rugo, Roger B Cohen, Bert H O'Neil, Janice M Mehnert, Juanita Lopez, Toshihiko Doi, Emilie M J van Brummelen, Razvan Cristescu, Ping Yang, Kenneth Emancipator, Karen Stein, Mark Ayers, Andrew K Joe, Jared K Lunceford
PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors. METHODS: KEYNOTE-028 ( ClinicalTrials...
February 1, 2019: Journal of Clinical Oncology
#3
REVIEW
Jake S O'Donnell, Michele W L Teng, Mark J Smyth
Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape...
March 2019: Nature Reviews. Clinical Oncology
#4
JOURNAL ARTICLE
Kuo-Hao Ho, Chih-Ju Chang, Tzu-Wen Huang, Chwen-Ming Shih, Ann-Jeng Liu, Peng-Hsu Chen, Kur-Ta Cheng, Ku-Chung Chen
Tumor-infiltrating lymphocytes are related to positive clinical prognoses in numerous cancer types. Programmed death ligand 1 (PD-L1), a mediator of the PD-1 receptor, plays an inhibitory role in cancer immune responses. PD-L1 upregulation can impede infiltrating T-cell functions in lung adenocarcinoma (LUAD), a lung cancer subtype. However, associations between the expression of PD-L1 and infiltration of B cells (a major immunoregulatory cell) remain unknown. Therefore, we investigated the role of infiltrating B cells in LUAD progression and its correlation with PD-L1 expression...
2018: PloS One
#5
JOURNAL ARTICLE
Laurence C Menard, Paul Fischer, Bijal Kakrecha, Peter S Linsley, Erik Wambre, Maochang C Liu, Blake J Rust, Deborah Lee, Becky Penhallow, Nataly Manjarrez Orduno, Steven G Nadler
Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung, and colon cancer. In healthy donors, peripheral T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (<5%)...
2018: Frontiers in Immunology
#6
REVIEW
Sing Yu Moorcraft, David Gonzalez, Brian A Walker
DNA sequencing is now faster and cheaper than ever before, due to the development of next generation sequencing (NGS) technologies. NGS is now widely used in the research setting and is becoming increasingly utilised in clinical practice. However, due to evolving clinical commitments, increased workload and lack of training opportunities, many oncologists may be unfamiliar with the terminology and technology involved. This can lead to oncologists feeling daunted by issues such as how to interpret the vast amounts of data generated by NGS and the differences between sequencing platforms...
December 2015: Critical Reviews in Oncology/hematology
#7
REVIEW
Pascale André, Caroline Denis, Caroline Soulas, Clarisse Bourbon-Caillet, Julie Lopez, Thomas Arnoux, Mathieu Bléry, Cécile Bonnafous, Laurent Gauthier, Ariane Morel, Benjamin Rossi, Romain Remark, Violette Breso, Elodie Bonnet, Guillaume Habif, Sophie Guia, Ana Ines Lalanne, Caroline Hoffmann, Olivier Lantz, Jérôme Fayette, Agnès Boyer-Chammard, Robert Zerbib, Pierre Dodion, Hormas Ghadially, Maria Jure-Kunkel, Yannis Morel, Ronald Herbst, Emilie Narni-Mancinelli, Roger B Cohen, Eric Vivier
Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells...
December 13, 2018: Cell
#8
REVIEW
Spandana R Kopalli, Tae-Bong Kang, Kwang-Ho Lee, Sushruta Koppula
BACKGROUND: In the last few decades, cancer immunotherapy has been extensively researched, and novel checkpoint signaling mechanisms involving Programmed Death (PD)-1 and PDLigand 1 (PD-L1) receptors have been targeted. The PD-1/PD-L1 binding and interaction play a critical role in the development of malignancies. OBJECTIVE: The present review focuses on recent patents on the pharmacological and biological cancerregulating properties of PD-1/PD-L1 inhibitors involved in immunotherapeutic cancer drug development...
2019: Recent Patents on Anti-cancer Drug Discovery
#9
JOURNAL ARTICLE
Meili Zhang, Bernard Wen, Olga M Anton, Zhengsheng Yao, Sigrid Dubois, Wei Ju, Noriko Sato, David J DiLillo, Richard N Bamford, Jeffrey V Ravetch, Thomas A Waldmann
The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors...
November 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
#10
JOURNAL ARTICLE
Russell J Diefenbach, Jenny H Lee, Helen Rizos
Genetic material derived from tumours is constantly shed into the circulation of cancer patients both in the form of circulating free nucleic acids and within circulating cells or extracellular vesicles. Monitoring cancer-specific genomic alterations, particularly mutant allele frequencies, in circulating nucleic acids allows for a non-invasive liquid biopsy for detecting residual disease and response to therapy. The advent of molecular targeted treatments and immunotherapies with increasing effectiveness requires corresponding effective molecular biology methods for the detection of biomarkers such as circulating nucleic acid to monitor and ultimately personalise therapy...
October 29, 2018: American Journal of Clinical Dermatology
#11
JOURNAL ARTICLE
Alicia Latham, Preethi Srinivasan, Yelena Kemel, Jinru Shia, Chaitanya Bandlamudi, Diana Mandelker, Sumit Middha, Jaclyn Hechtman, Ahmet Zehir, Marianne Dubard-Gault, Christina Tran, Carolyn Stewart, Margaret Sheehan, Alexander Penson, Deborah DeLair, Rona Yaeger, Joseph Vijai, Semanti Mukherjee, Jesse Galle, Mark A Dickson, Yelena Janjigian, Eileen M O'Reilly, Neil Segal, Leonard B Saltz, Diane Reidy-Lagunes, Anna M Varghese, Dean Bajorin, Maria I Carlo, Karen Cadoo, Michael F Walsh, Martin Weiser, Julio Garcia Aguilar, David S Klimstra, Luis A Diaz, Jose Baselga, Liying Zhang, Marc Ladanyi, David M Hyman, David B Solit, Mark E Robson, Barry S Taylor, Kenneth Offit, Michael F Berger, Zsofia K Stadler
PURPOSE: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status...
February 1, 2019: Journal of Clinical Oncology
#12
JOURNAL ARTICLE
Laura A Vitale, Lawrence J Thomas, Li-Zhen He, Thomas O'Neill, Jenifer Widger, Andrea Crocker, Karuna Sundarapandiyan, James R Storey, Eric M Forsberg, Jeffrey Weidlick, April R Baronas, Lauren E Gergel, James M Boyer, Crystal Sisson, Joel Goldstein, Henry C Marsh, Tibor Keler
Limitations of immunotherapy include poorly functioning events early in the immune response cycle, such as efficient antigen presentation and T cell priming. CD40 signaling in dendritic cells leads to upregulation of cell surface costimulatory and MHC molecules and the generation of cytokines, which promotes effective priming of CD8+ effector T cells while minimizing T cell anergy and the generation of regulatory T cells. This naturally occurs through interaction with CD40 ligand (CD40L) expressed on CD4+ T-helper cells...
February 2019: Cancer Immunology, Immunotherapy: CII
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