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https://www.readbyqxmd.com/read/29143108/immune-checkpoint-inhibitor-colitis-the-flip-side-of-the-wonder-drugs
#1
Naziheh Assarzadegan, Elizabeth Montgomery, Robert A Anders
Immune checkpoint inhibitors block the co-inhibitory receptors on T cells to activate their cytotoxic immune function and are rapidly being explored for the treatment of various advanced-stage malignancies. These novel drugs have already significantly increased survival rates. The first available immune checkpoint inhibitors were cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors (such as ipilimumab), followed by programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors (such as pembrolizumab and nivolumab)...
November 15, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29138371/-adaptation-of-anti-pd-1-anti-pd-l1-antibody-from-the-viewpoint-of-analysis-of-tumor-microenvironment
#2
Kousaku Mimura, Yuko Nakayama, Tadao Nakazawa, Koji Kono
The response rate of anti-PD-1/anti-PD-L1antibody alone is about 20 to 30%and the development of biomarker for them is important to know their indication. Based on previous reports and our research results, we suggested that basic candidates of biomarker for anti-PD-1/anti-PD-L1antibody are the expression of PD-L1and HLA class I on cancer cells and the invasion of CD8 positive T cells in tumor microenvironment. Furthermore, in addition to these conditions, regulatory T cells and immune cells expressing PD-L1in tumor microenvironment, and microsatellite instability of cancer cells will be considered in the future...
November 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/29138368/-regulatory-mechanisms-of-pd-l1-expression-and-its-role-in-immune-evasion
#3
Keisuke Kataoka
Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers...
November 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/29138342/immunotherapy-of-hepatocellular-carcinoma-facts-and-hopes
#4
Mercedes Iñarrairaegui, Ignacio Melero, Bruno Sangro
Treatment of patients with hepatocellular carcinoma in the advanced stage remains a great challenge, with very few drugs approved. After decades of failures of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with hepatocellular carcinoma in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells, and mostly provide immunosuppressive signals...
November 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29137714/checkpoint-blockade-plus-oncolytic-virus-a-hot-therapeutic-cancer-strategy
#5
Caroline Robert
How can we transform an immune desert into a 'hot tumor' that is prone to respond to anti-programmed death (PD)-1 immunotherapy? This might be possible by injecting an oncolytic virus, engineered to induce local immune stimulation, prior to anti-PD-1 therapy. A recent study demonstrated that this combination - evaluated in a Phase Ib metastatic melanoma clinical study - yields promising results.
November 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29137331/hdac-inhibitors-enhance-the-immunotherapy-response-of-melanoma-cells
#6
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Paul Dent
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136692/-expression-and-prognostic-values-of-pd-1-pd-l1-and-ido-1-in-sinonasal-malignant-mucosal-melanoma
#7
H Q Liu, B Q Zou, S Y Wang
Objective: To investigate the correlation between the expression of programmed death-1(PD-1), PD ligand-1(PD-L1), indoleamine 2, 3-dioxygenase 1(IDO-1) and clinical parameters in sinonasal malignant mucosal melanoma (SNM). Methods: Samples from 86 SNM patients who did not receive immune-targeted therapy and radio-chemotherapy were analyzed for PD-1, PD-L1, and IDO-1 expression by immunohistochemistry. Results: High clinical/pathologic staging, brain metastases and advanced age were independent risk factors of poor prognosis...
November 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/29135534/the-multiple-faces-of-programmed-cell-death-ligand-1-expression-in-malignant-and-nonmalignant-cells
#8
Edwin R Parra, Pamela Villalobos, Jaime Rodriguez-Canales
Preliminary data suggest that tumor expression of programmed cell death ligand 1 (PD-L1) protein in human cancers, as determined by immunohistochemistry in formalin-fixed, paraffin-embedded tissue samples, may predict clinical response to anti-PD-1/PD-L1 therapy. PD-L1 is not a specific tumor marker and its expression is also observed in various nonmalignant cells, such as macrophages and lymphocytes, causing confusion in immunohistochemistry analysis when these inflammatory cells are overlapping with tumors cells...
November 13, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29134128/a-preliminary-study-for-the-assessment-of-pd-l1-and-pd-l2-on-circulating-tumor-cells-by-microfluidic-based-chipcytometry
#9
Jinkai Teo, Anja Mirenska, Meihui Tan, Yifang Lee, Janice Oh, Lewis Z Hong, Richard Wnek, Yoon-Sim Yap, Shian-Jiun Shih, Ali Asgar S Bhagat, Chih-Liang Chin, David Ag Skibinski
Aim: Expression of PD-L1 in the tumor is associated with more favorable responses to anti-PD-1 therapy in multiple cancers. However, obtaining tumor biopsies for PD-L1 interrogation is an invasive procedure and challenging to assess repeatedly as the disease progresses. Materials & methods: Here we assess an alternative, minimally invasive approach to analyze blood samples for circulating tumor cells (CTCs) that have broken away from the tumor and entered the periphery...
November 2017: Future Science OA
https://www.readbyqxmd.com/read/29132144/a-neoantigen-fitness-model-predicts-tumour-response-to-checkpoint-blockade-immunotherapy
#10
Marta Łuksza, Nadeem Riaz, Vladimir Makarov, Vinod P Balachandran, Matthew D Hellmann, Alexander Solovyov, Naiyer A Rizvi, Taha Merghoub, Arnold J Levine, Timothy A Chan, Jedd D Wolchok, Benjamin D Greenbaum
Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells...
November 8, 2017: Nature
https://www.readbyqxmd.com/read/29129918/intratumoral-cd40-activation-and-checkpoint-blockade-induces-t-cell-mediated-eradication-of-melanoma-in-the-brain
#11
Manisha Singh, Christina Vianden, Mark J Cantwell, Zhimin Dai, Zhilan Xiao, Meenu Sharma, Hiep Khong, Ashvin R Jaiswal, Faisal Faak, Yared Hailemichael, L M E Janssen, Uddalak Bharadwaj, Michael A Curran, Adi Diab, Roland L Bassett, David J Tweardy, Patrick Hwu, Willem W Overwijk
CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8(+) T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8(+) T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29126881/triple-negative-breast-cancer-key-role-of-tumor-associated-macrophages-in-regulating-the-activity-of-anti-pd-1-pd-l1-agents
#12
REVIEW
Matteo Santoni, Emanuela Romagnoli, Tiziana Saladino, Laura Foghini, Stefania Guarino, Marco Capponi, Massimo Giannini, Paolo Decembrini Cognigni, Gerardo Ferrara, Nicola Battelli
Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches...
November 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29126088/in-the-immuno-oncology-era-is-anti-pd-1-or-anti-pd-l1-immunotherapy-modifying-the-sensitivity-to-conventional-cancer-therapies
#13
Sandrine Aspeslagh, Margarida Matias, Virginia Palomar, Laurent Dercle, Emilie Lanoy, Jean-Charles Soria, Sophie Postel-Vinay
INTRODUCTION: The advent of anti-programmed death receptor-1/ligand-1 antibodies (anti-PD(L)1) is profoundly changing the therapeutic strategy of oncology. As anti-PD(L)1 modulate tumour microenvironment, it might impact sensitivity to conventional cancer therapy (CCT). Therefore, we explored whether sensitivity to CCT was different before and after anti-PD(L)1 therapy. METHODS: Patients who started anti-PD(L)1 treatment at Gustave Roussy Cancer Centre between February 2012 and December 2015, and who received at least one line of CCT immediately before and immediately after anti-PD(L)1, were eligible...
November 7, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29125731/imaging-pd-l1-expression-with-immunopet
#14
Charles Truillet, Hsueh Ling J Oh, Siok Ping Yeo, Chia-Yin Lee, Loc T Huynh, Junnian Wei, Matthew F L Parker, Collin Blakely, Natalia Sevillano, Yung-Hua Wang, Yuqin S Shen, Victor Olivas, Khaled M Jami, Anna Moroz, Benoit Jego, Emilie Jaumain, Lawrence Fong, Charles S Craik, Albert J Chang, Trever G Bivona, Cheng-I Wang, Michael J Evans
High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that (89)Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy...
November 15, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29123966/pd-1-blockade-at-the-time-of-tumor-escape-potentiates-the-immune-mediated-antitumor-effects-of-a-melanoma-targeting-monoclonal-antibody
#15
Laetitia They, Henri-Alexandre Michaud, Ondine Becquart, Virginie Lafont, Bernard Guillot, Florence Boissière-Michot, Marta Jarlier, Caroline Mollevi, Jean-François Eliaou, Nathalie Bonnefoy, Laurent Gros
Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29123963/blocking-c5ar-signaling-promotes-the-anti-tumor-efficacy-of-pd-1-pd-l1-blockade
#16
Haoran Zha, Xiao Han, Ying Zhu, Fei Yang, Yongsheng Li, Qijing Li, Bo Guo, Bo Zhu
Anti-PD-1/PD-L1 therapy has achieved great success in the clinic; however, only a small fraction of cancer patient benefit from PD-1/PD-L1 blockade therapy, and overcoming resistance to PD-1/PD-L1 blockade has thus become a primary priority. In this study, we demonstrated that administration of PD-1/PD-L1 antibodies resulted in the activation of the complement system and massive generation of C5a. Generation of C5a did not change the accumulation of MDSCs in either the tumor or spleen but enhanced their inhibitory potential...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29123953/pd-1-blockade-augments-anti-neuroblastoma-immune-response-induced-by-anti-gd2-antibody-ch14-18-cho
#17
Nikolai Siebert, Maxi Zumpe, Madlen Jüttner, Sascha Troschke-Meurer, Holger N Lode
Immunotherapy with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients and is mainly based on GD2-specific Ab-dependent cellular cytotoxicity (ADCC). Strategies to further enhance the efficacy are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± IL-2. Recently, expression of programmed death 1 (PD-1) inhibitory receptor by effector cells and its ligand (PD-L1) by tumor cells has been shown. Here, we report for the first time effects of PD-1 blockade on ch14...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29123950/immune-evasion-mechanisms-and-immune-checkpoint-inhibition-in-advanced-merkel-cell-carcinoma
#18
REVIEW
Dirk Schadendorf, Paul Nghiem, Shailender Bhatia, Axel Hauschild, Philippe Saiag, Lisa Mahnke, Subramanian Hariharan, Howard L Kaufman
Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29120224/is-there-a-role-for-programmed-death-ligand-1-testing-and-immunotherapy-in-colorectal-cancer-with-microsatellite-instability-part-ii-the-challenge-of-programmed-death-ligand-1-testing-and-its-role-in-microsatellite-instability-high-colorectal-cancer
#19
Esmeralda Celia Marginean, Barbara Melosky
CONTEXT: - The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti-programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability-high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability-high CRC...
November 9, 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/29119407/pd-l1-testing-in-guiding-patient-selection-for-pd-1-pd-l1-inhibitor-therapy-in-lung-cancer
#20
Katerina Ancevski Hunter, Mark A Socinski, Liza C Villaruz
Immunotherapy with programmed death 1 (PD-1)- and programmed death-ligand 1 (PD-L1)-targeted monoclonal antibodies has dramatically changed the therapeutic and prognostic landscape for several types of malignancy. PD-1 and PD-L1 are immune checkpoint proteins whose binding ultimately result in T cell exhaustion and self-tolerance. Blocking this pathway 'releases the brakes' on the immune system and allows for attack of tumor cells that express PD-L1. The clinical trials that led to the US Food and Drug Administration (FDA) approval of these agents used different immunohistochemical (IHC) platforms with various PD-L1 antibodies to assess for PD-L1 expression on either tumor cells or tumor-infiltrating immune cells...
November 8, 2017: Molecular Diagnosis & Therapy
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