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immune-checkpoint blockade

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https://www.readbyqxmd.com/read/28819565/genomic-and-immune-heterogeneity-are-associated-with-differential-responses-to-therapy-in-melanoma
#1
Alexandre Reuben, Christine N Spencer, Peter A Prieto, Vancheswaran Gopalakrishnan, Sangeetha M Reddy, John P Miller, Xizeng Mao, Mariana Petaccia De Macedo, Jiong Chen, Xingzhi Song, Hong Jiang, Pei-Ling Chen, Hannah C Beird, Haven R Garber, Whijae Roh, Khalida Wani, Eveline Chen, Cara Haymaker, Marie-Andrée Forget, Latasha D Little, Curtis Gumbs, Rebecca L Thornton, Courtney W Hudgens, Wei-Shen Chen, Jacob Austin-Breneman, Robert Szczepaniak Sloane, Luigi Nezi, Alexandria P Cogdill, Chantale Bernatchez, Jason Roszik, Patrick Hwu, Scott E Woodman, Lynda Chin, Hussein Tawbi, Michael A Davies, Jeffrey E Gershenwald, Rodabe N Amaria, Isabella C Glitza, Adi Diab, Sapna P Patel, Jianhua Hu, Jeffrey E Lee, Elizabeth A Grimm, Michael T Tetzlaff, Alexander J Lazar, Ignacio I Wistuba, Karen Clise-Dwyer, Brett W Carter, Jianhua Zhang, P Andrew Futreal, Padmanee Sharma, James P Allison, Zachary A Cooper, Jennifer A Wargo
Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort...
2017: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/28819064/the-tumor-microenvironment-regulates-sensitivity-of-murine-lung-tumors-to-pd-1-pdl1-antibody-blockade
#2
Howard Y Li, Maria V McSharry, Bonnie Bullock, Teresa T Nguyen, Jeff Kwak, Joanna M Poczobutt, Trisha R Sippel, Lynn E Heasley, Mary C Weiser-Evans, Eric T Clambey, Raphael A Nemenoff
Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non-small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate pre-clinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in--- syngeneic mice, and response to anti-PD-1/PD-L1 therapy was determined...
August 17, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28819022/%C3%AE-adrenergic-signaling-in-mice-housed-at-standard-temperatures-suppresses-an-effector-phenotype-in-cd8-t-cells-and-undermines-checkpoint-inhibitor-therapy
#3
Mark J Bucsek, Guanxi Qiao, Cameron R MacDonald, Thejaswini Giridharan, Lauren Evans, Brian Niedzwecki, Haichao Liu, Kathleen M Kokolus, Jason W-L Eng, Michelle N Messmer, Kristopher Attwood, Scott I Abrams, Bonnie L Hylander, Elizabeth A Repasky
The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8(+) T cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies - physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-adrenergic receptor knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28817405/cutaneous-eruptions-in-patients-receiving-immune-checkpoint-blockade-clinicopathologic-analysis-of-the-nonlichenoid-histologic-pattern
#4
Genevieve J Kaunitz, Manisha Loss, Hira Rizvi, Sowmya Ravi, Jonathan D Cuda, Karen B Bleich, Jessica Esandrio, Inbal Sander, Dung T Le, Luis A Diaz, Julie R Brahmer, Charles G Drake, Travis J Hollmann, Mario E Lacouture, Matthew D Hellmann, Evan J Lipson, Janis M Taube
Cutaneous eruptions are among the most common immune-related adverse events (irAEs) associated with anti-programmed cell death protein 1/programmed cell death ligand 1 therapy, and are often clinically and histologically characterized as lichenoid. Nonlichenoid patterns may also occur and are likely to be encountered by surgical pathologists, given the increasing clinical use of these agents. The purpose of this study is to describe the histopathologic features of nonlichenoid cutaneous irAEs from patients receiving anti-programmed cell death protein 1/programmed cell death ligand 1 therapies for a variety of underlying advanced malignancies...
August 15, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28816141/combined-radiation-therapy-and-immune-checkpoint-blockade-therapy-for-breast-cancer
#5
REVIEW
Zishuo I Hu, Alice Y Ho, Heather L McArthur
PURPOSE: Treatment with checkpoint inhibitors has shown durable responses in a number of solid tumors, including melanoma, lung, and renal cell carcinoma. However, most breast cancers are resistant to monotherapy with checkpoint inhibitors. Radiation therapy (RT) has been shown to have a number of immunostimulatory effects, including priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. RT therefore represents a promising adjuvant therapy to checkpoint blockade in breast cancer...
September 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28815885/novel-landscape-of-hla-g-isoforms-expressed-in-clear-cell-renal-cell-carcinoma-patients
#6
Diana Tronik-Le Roux, Julie Renard, Jérôme Vérine, Victor Renault, Emmanuel Tubacher, Joel LeMaoult, Nathalie Rouas-Freiss, Jean-François Deleuze, François Desgrandschamps, Edgardo D Carosella
Immune-checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. HLA-G, a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anti-cancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth, the HLA-G isoforms expressed in these tumors...
August 16, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28815048/society-for-immunotherapy-of-cancer-consensus-statement-on-immunotherapy-for-the-treatment-of-bladder-carcinoma
#7
Ashish M Kamat, Joaquim Bellmunt, Matthew D Galsky, Badrinath R Konety, Donald L Lamm, David Langham, Cheryl T Lee, Matthew I Milowsky, Michael A O'Donnell, Peter H O'Donnell, Daniel P Petrylak, Padmanee Sharma, Eila C Skinner, Guru Sonpavde, John A Taylor, Prasanth Abraham, Jonathan E Rosenberg
The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guérin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28815043/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#8
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28813415/cdk4-6-inhibition-triggers-anti-tumour-immunity
#9
Shom Goel, Molly J DeCristo, April C Watt, Haley BrinJones, Jaclyn Sceneay, Ben B Li, Naveed Khan, Jessalyn M Ubellacker, Shaozhen Xie, Otto Metzger-Filho, Jeremy Hoog, Matthew J Ellis, Cynthia X Ma, Susanne Ramm, Ian E Krop, Eric P Winer, Thomas M Roberts, Hye-Jung Kim, Sandra S McAllister, Jean J Zhao
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28811964/pd-l2-expression-in-colorectal-cancer-independent-prognostic-effect-and-targetability-by-deglycosylation
#10
Huanbin Wang, Han Yao, Chushu Li, Lunxi Liang, Yao Zhang, Hubing Shi, Chongzhi Zhou, Yingxuan Chen, Jing-Yuan Fang, Jie Xu
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and immune checkpoint blockade therapy provides an opportunity for improving the outcome of CRC patients. Recent studies suggest that programmed death ligand-1 (PD-L1) is only expressed in 12% of CRCs. Here, we demonstrate that PD-L2 is expressed in approximately 40% CRCs, and its expression independently associates with poor survival of CRC patients. By detection of PD-L2 expression by immunofluorescence in 124 CRC cases with 10-y survival data, we found significant association between PD-L2 overexpression in cancer cells and worse overall survival (46...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811961/pd-l1-immune-suppression-in-cancer-tumor-cells-or-host-cells
#11
Jan Willem Kleinovink, Thorbald van Hall, Ferry Ossendorp, Marieke F Fransen
Four recent publications reported the role of PD-L1 expression on host versus malignant cells within the tumor for PD-1/PD-L1 checkpoint blockade therapy. All four research groups harmoniously report: PD-L1 expressed by both host as well as tumor cells are capable of suppressing T cell functions. Thus, checkpoint therapy can be effective, if malignant cells do not express PD-L1.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811958/soluble-nkg2d-ligands-are-biomarkers-associated-with-the-clinical-outcome-to-immune-checkpoint-blockade-therapy-of-metastatic-melanoma-patients
#12
Cristina Maccalli, Diana Giannarelli, Carla Chiarucci, Ornella Cutaia, Gianluca Giacobini, Wouter Hendrickx, Giovanni Amato, Diego Annesi, Davide Bedognetti, Maresa Altomonte, Riccardo Danielli, Luana Calabrò, Anna Maria Di Giacomo, Francesco M Marincola, Giorgio Parmiani, Michele Maio
The introduction of immune checkpoint blockade into the clinical practice resulted in improvement of survival of a significant portion of melanoma patients. Consequently, predictive biomarkers of response are needed to optimize patient's stratification and the development of combination therapies. The aim of this study was to determine whether levels of soluble NKG2D ligands (MICA, MICB, ULBP1, 2 and 3; sNKG2DLs) in the serum of melanoma patients can serve as useful predictors of response to the treatment with immune checkpoint blockade...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28810147/macrophage-polarization-contributes-to-glioblastoma-eradication-by-combination-immunovirotherapy-and-immune-checkpoint-blockade
#13
Dipongkor Saha, Robert L Martuza, Samuel D Rabkin
Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Δ expressing murine IL-12 (G47Δ-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Δ-mIL12 cured most mice in two glioma models...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28808502/clinical-significance-of-tumor-infiltrating-lymphocytes-for-gastric-cancer-in-the-era-of-immunology
#14
REVIEW
Byung Woog Kang, Jong Gwang Kim, In Hee Lee, Han Ik Bae, An Na Seo
Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth...
July 15, 2017: World Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28807024/society-for-immunotherapy-of-cancer-consensus-statement-on-immunotherapy-for-the-treatment-of-bladder-carcinoma
#15
Ashish M Kamat, Joaquim Bellmunt, Matthew D Galsky, Badrinath R Konety, Donald L Lamm, David Langham, Cheryl T Lee, Matthew I Milowsky, Michael A O'Donnell, Peter H O'Donnell, Daniel P Petrylak, Padmanee Sharma, Eila C Skinner, Guru Sonpavde, John A Taylor, Prasanth Abraham, Jonathan E Rosenberg
The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guérin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28807001/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#16
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28806575/lessons-from-ctla-4-deficiency-and-checkpoint-inhibition
#17
REVIEW
Bernice Lo, Ussama M Abdel-Motal
CTLA-4 is a crucial negative regulator of immune responses. Absence of CTLA-4 in mice causes autoimmunity and lethal multiorgan lymphocytic infiltration and tissue destruction. Recently, heterozygous CTLA4 or biallelic LRBA mutations leading to functional CTLA-4 deficiency and autoimmunity have been discovered. LRBA was identified as a novel regulator of steady-state CTLA-4 protein levels in Tregs and activated T cells. CTLA-4 deficiency due to checkpoint blockade cancer immunotherapy has also been found to lead to autoimmune reactions...
August 11, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28803728/distinct-cellular-mechanisms-underlie-anti-ctla-4-and-anti-pd-1-checkpoint-blockade
#18
Spencer C Wei, Jacob H Levine, Alexandria P Cogdill, Yang Zhao, Nana-Ama A S Anang, Miles C Andrews, Padmanee Sharma, Jing Wang, Jennifer A Wargo, Dana Pe'er, James P Allison
Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations...
August 9, 2017: Cell
https://www.readbyqxmd.com/read/28799242/negative-regulation-of-nlrp3-inflammasome-activation-by-tim-3-protects-against-peritonitis
#19
Wei Wang, Qingzhu Shi, Shuaijie Dou, Ge Li, Xinhui Shi, Xingwei Jiang, Zhiding Wang, Dandan Yu, Guojiang Chen, Wang Ren Xi, He Xiao, Chunmei Hou, Jiannan Feng, Beifen Shen, Yuanfang Ma, Gencheng Han
The NLRP3 inflammasome plays roles in host defense against invading pathogens and in the development of autoimmune damage. Strict regulation of these responses is important to avoid detrimental effects. Here, we demonstrate that Tim-3, an immune checkpoint inhibitor, inhibits NLRP3 inflammasome activation by damping basal and LPS-induced NF-κB-mediated upregulation of NLRP3 and IL-1β during the priming step and basal and ATP/LPS-induced ATP production, K(+) efflux, and ROS production during the activation step...
August 11, 2017: Immunology
https://www.readbyqxmd.com/read/28798308/prognostic-value-of-programmed-cell-death-protein-1-expression-on-cd8-t-lymphocytes-in-pancreatic-cancer
#20
Tao Shen, Liangjing Zhou, Hua Shen, Chengfei Shi, Shengnan Jia, Guo Ping Ding, Liping Cao
Pancreatic cancer is one of the most aggressive malignancies and has a highly immunosuppressive tumour microenvironment. Immune checkpoint blockade has led to remarkable and durable objective responses in a number of malignancies and antibody-based strategies targeting programmed cell death protein 1 (PD-1) are showing promise where traditional modalities of surgery, radiotherapy, and chemotherapy have failed. In this study, we examined the clinical value of PD-1 protein expression by CD8+ peripheral T lymphocytes or tumour-infiltrating T lymphocytes (TILs) in pancreatic ductal adenocarcinoma (PDAC)...
August 10, 2017: Scientific Reports
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