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Checkpoint blockade

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https://www.readbyqxmd.com/read/28929192/role-of-pd-1-in-immunity-and-diseases
#1
Kenji Chamoto, Muna Al-Habsi, Tasuku Honjo
Immunity developed to defend our bodies from foreign particles, including bacteria and viruses. Although effector cells responsible for acquired immunity, mainly T cells, and B cells, are able to distinguish self from non-self, they sometimes attack the body's tissues because of imperfect central tolerance. Several immune check points developed to limit overactivation of these cells. One of the most important immune checkpoints is programmed cell death-1 (PD-1), which is expressed mainly on activated lymphocytes...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28928380/predictors-of-responses-to-immune-checkpoint-blockade-in-advanced-melanoma
#2
N Jacquelot, M P Roberti, D P Enot, S Rusakiewicz, N Ternès, S Jegou, D M Woods, A L Sodré, M Hansen, Y Meirow, M Sade-Feldman, A Burra, S S Kwek, C Flament, M Messaoudene, C P M Duong, L Chen, B S Kwon, A C Anderson, V K Kuchroo, B Weide, F Aubin, C Borg, S Dalle, O Beatrix, M Ayyoub, B Balme, G Tomasic, A M Di Giacomo, M Maio, D Schadendorf, I Melero, B Dréno, A Khammari, R Dummer, M Levesque, Y Koguchi, L Fong, M Lotem, M Baniyash, H Schmidt, I M Svane, G Kroemer, A Marabelle, S Michiels, A Cavalcanti, M J Smyth, J S Weber, A M Eggermont, L Zitvogel
Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28928158/characterization-of-the-immune-microenvironment-in-hepatocellular-carcinoma-hcc
#3
Mark Yarchoan, Dongmei Xing, Lan Luan, Haiying Xu, Rajni Sharma, Aleksandra Popovic, Timothy M Pawlik, Amy K Kim, Qingfeng Zhu, Elizabeth M Jaffee, Janis Taube, Robert A Anders
PURPOSE: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. EXPERIMENTAL DESIGN: To characterize the immune microenvironment in HCC, immunohistochemical (IHC) staining was performed for CD8 positive T lymphocytes, PD-1 positive and LAG-3 positive lymphocytes, CD163 positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. RESULTS: Expression of CD8 was reduced in tumor and expression of CD163 was reduced at the tumor interface...
September 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28923358/targets-for-immunotherapy-of-liver-cancer
#4
REVIEW
Tim F Greten, Bruno Sangro
Drug development in HCC has been characterized in the past by many failures. Despite good rationales and promising phase II data, many phase III trials failed. Immunotherapy represents an alternate treatment approach and has been successful in many different types of cancer. Being an inflammation induced cancer HCC represents a very interesting target for immune based approaches and indeed early results from clinical trials testing immune checkpoint inhibitors are not only promising but have already led to evaluation of such in a phase III setting...
September 15, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28920005/the-frequency-of-neoantigens-per-somatic-mutation-rather-than-overall-mutational-load-or-number-of-predicted-neoantigens-per-se-is-a-prognostic-factor-in-ovarian-clear-cell-carcinoma
#5
Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919992/molecular-and-clinical-characterization-of-tim-3-in-glioma-through-1-024-samples
#6
Guanzhang Li, Zheng Wang, Chuanbao Zhang, Xing Liu, Jinquan Cai, Zhiliang Wang, Huimin Hu, Fan Wu, Zhaoshi Bao, Yanwei Liu, Liang Zhao, Tingyu Liang, Fan Yang, Ruoyu Huang, Wei Zhang, Tao Jiang
Background: Researches on immunotherapy of glioma has been increasing exponentially in recent years. However, autoimmune-like side effects of current immune checkpoint blockade hindered the clinical application of immunotherapy in glioma. The discovery of the TIM-3, a tumor-specific immune checkpoint, has shed a new light on solution of this dilemma. We aimed at investigating the role of TIM-3 at transcriptome level and its relationship with clinical practice in glioma. Methods: A cohort of 325 glioma patients with RNA-seq data from Chinese Glioma Genome Atlas (CGGA project) was analyzed, and the results were well validated in TCGA RNA-seq data of 699 gliomas...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919986/immune-biomarkers-for-prognosis-and-prediction-of-responses-to-immune-checkpoint-blockade-in-cutaneous-melanoma
#7
REVIEW
Nicolas Jacquelot, Jonathan M Pitt, David P Enot, Maria Paula Roberti, Connie P M Duong, Sylvie Rusakiewicz, Alexander M Eggermont, Laurence Zitvogel
Existing clinical, anatomopathological and molecular biomarkers fail to reliably predict the prognosis of cutaneous melanoma. Biomarkers for determining which patients receive adjuvant therapies are needed. The emergence of new technologies and the discovery of new immune populations with different prognostic values allow the immune network in the tumor to be better understood. Importantly, new molecules identified and expressed by immune cells have been shown to reduce the antitumor immune efficacy of therapies, prompting researchers to develop antibodies targeting these so-called "immune checkpoints", which have now entered the oncotherapeutic armamentarium...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28916749/checkpoint-blockade-immunotherapy-reshapes-the-high-dimensional-phenotypic-heterogeneity-of-murine-intratumoural-neoantigen-specific-cd8-t-cells
#8
M Fehlings, Y Simoni, H L Penny, E Becht, C Y Loh, M M Gubin, J P Ward, S C Wong, R D Schreiber, E W Newell
The analysis of neoantigen-specific CD8(+) T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8(+) T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28916658/t-cells-deficient-in-diacylglycerol-kinase-%C3%AE-are-resistant-to-pd-1-inhibition-and-help-create-persistent-host-immunity-to-leukemia
#9
Weiqing Jing, Jill Alane Gershan, Sandra Holzhauer, James Weber, Katie Palen, Laura McOlash, Kirthi Pulakanti, Erin Wesley, Sridhar Rao, Bryon D Johnson, Matthew J Riese
Efforts to improve the efficacy of adoptive T cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the anti-leukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase-zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28916225/stereotactic-radiosurgery-of-early-melanoma-brain-metastases-after-initiation-of-anti-ctl-4-treatment-is-associated-with-improved-intracranial-control
#10
Yi An, Wen Jiang, Betty Y S Kim, Jack M Qian, Chad Tang, Penny Fang, Jennifer Logan, Neil M D'Souza, Lauren E Haydu, Xin A Wang, Kenneth R Hess, Harriet Kluger, Isabella C Glitza, Anita Mahajan, James W Welsh, Steven H Lin, James B Yu, Michael A Davies, Patrick Hwu, Erik P Sulman, Paul D Brown, Veronica L S Chiang, Jing Li
BACKGROUND: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy...
September 12, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28915720/pseudoprogression-in-microsatellite-instability-high-colorectal-cancer-during-treatment-with-combination-t-cell-mediated-immunotherapy-a-case-report-and-literature-review
#11
Young Kwang Chae, Si Wang, Halla Nimeiri, Aparna Kalyan, Francis J Giles
Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915554/resistance-to-ctla-4-checkpoint-inhibition-reversed-through-selective-elimination-of-granulocytic-myeloid-cells
#12
Paul E Clavijo, Ellen C Moore, Jianhong Chen, Ruth J Davis, Jay Friedman, Young Kim, Carter Van Waes, Zhong Chen, Clint T Allen
PURPOSE: Local immunosuppression remains a critical problem that limits clinically meaningful response to checkpoint inhibition in patients with head and neck cancer. Here, we assessed the impact of MDSC elimination on responses to CTLA-4 checkpoint inhibition. EXPERIMENTAL DESIGN: Murine syngeneic carcinoma immune infiltrates were characterized by flow cytometry. Granulocytic MDSCs (gMDSCs) were depleted and T-lymphocyte antigen-specific responses were measured...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914674/frequent-pd-l1-expression-in-malignant-melanomas-of-the-vulva
#13
Banafsheh Saleh, Jörg Kriegsmann, Stephan Falk, Sebastian Aulmann
Blockade of immune checkpoint pathways such as the programmed cell death protein 1 pathway (PD-1/PD-L1) is an emerging approach in the treatment of solid tumors. In malignant melanoma, the efficiacy of antibodies against PD-L1 has been shown to be associated with PD-L1 protein expression. To evaluate whether this approach may be of use in the rare cases of primary melanoma of the vulva, we have evaluated a series of 13 cases for PD-L1 expression as well as additional molecular alterations of KIT, NRAS, KRAS, and BRAF...
September 13, 2017: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/28912399/-adoptive-cell-therapy-with-immune-checkpoint-blockade
#14
Atsushi Aruga
Cancer immunotherapy are taking a leading role of cancer therapy due to the development of the immune checkpoint blockade. To date, however, only about 20% of patients have clinical responses and the cancer-specific T cells in cancer site are required to obtain beneficial effects. There has been an innovative development in the field of adoptive cell therapy, especially receptor gene-modified T cells in recent years. The effector cells mostly express PD-1, therefore the cytotoxic reactivity of the effector cells are inhibited by PD-L1...
September 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28912267/antitumor-immunity-is-defective-in-t-cell-specific-microrna-155-deficient-mice-and-is-rescued-by-immune-checkpoint-blockade
#15
Thomas B Huffaker, Soh-Hyun Lee, William W Tang, Jared A Wallace, Margaret Alexander, Marah C Runtsch, Dane K Larsen, Jacob Thompson, Andrew G Ramstead, Warren P Voth, Ruozhen Hu, June L Round, Matthew A Williams, Ryan M O'Connell
MicroRNA-155 (miR-155) regulates antitumor immune responses. However, its specific functions within distinct immune cell types have not been delineated in conditional knockout (KO) mouse models. In this study, we investigated the role of miR-155 specifically within T cells during the immune response to syngeneic tumors. We found that miR-155 expression within T cells is required to limit syngeneic tumor growth and promote interferon gamma (IFNγ) production by T cells within the tumor microenvironment. Consequently, we found that miR-155 expression by T cells is necessary for proper tumor-associated macrophage (TAM) expression of IFNγ-inducible genes...
September 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28912137/enhanced-cancer-immunotherapy-by-chimeric-antigen-receptor-modified-t-cells-engineered-to-secrete-checkpoint-inhibitors
#16
Pin Wang, Si Li, Natnaree Siriwon, Xiaoyang Zhang, Shuai Yang, Tao Jin, Feng He, Yu Jeong Kim, John Mac, Zhengfei Lu, Sijie Wang, Xiaolu Han
PURPOSE: Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. EXPERIMENTAL DESIGN: To evaluate the effector function and expansion capacity of CAR...
September 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28904226/tumor-lymphangiogenesis-promotes-t-cell-infiltration-and-potentiates-immunotherapy-in-melanoma
#17
Manuel Fankhauser, Maria A S Broggi, Lambert Potin, Natacha Bordry, Laura Jeanbart, Amanda W Lund, Elodie Da Costa, Sylvie Hauert, Marcela Rincon-Restrepo, Christopher Tremblay, Elena Cabello, Krisztian Homicsko, Olivier Michielin, Douglas Hanahan, Daniel E Speiser, Melody A Swartz
In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C...
September 13, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28904067/whole-genome-sequencing-reveals-breast-cancers-with-mismatch-repair-deficiency
#18
Helen Davies, Sandro Morganella, Colin A Purdie, Se Jin Jang, Elin Borgen, Hege Russnes, Dominik Glodzik, Xueqing Zou, Alain Viari, Andrea L Richardson, Anne-Lise Børresen-Dale, Alastair Thompson, Jorunn E Eyfjord, Gu Kong, Michael R Stratton, Serena Nik-Zainal
Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients...
September 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28903381/tumor-location-impacts-immune-response-in-mouse-models-of-colon-cancer
#19
Xianda Zhao, Lihua Li, Timothy K Starr, Subbaya Subramanian
Existing preclinical models of human colorectal cancer (CRC) that rely on syngeneic subcutaneous grafts are problematic, because of increasing evidence that the immune microenvironment in subcutaneous tissue is significantly different from the gastrointestinal tract. Similarly, existing orthotopic models that use a laparotomy for establishing grafts are also problematic, because the surgical procedure results in extensive inflammation, thereby creating a nonphysiologic tumor microenvironment. To facilitate the bench-to-bedside translation of CRC immunotherapy strategies, we developed a novel orthotopic model in mice that uses endoscopy-guided microinjection of syngeneic cancer cells...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901560/erythema-nodosum-like-panniculitis-mimicking-disease-recurrence-a-novel-toxicity-from-immune-checkpoint-blockade-therapy-report-of-two-patients
#20
Michael T Tetzlaff, Amir A Jazaeri, Carlos A Torres-Cabala, Brinda Rao Korivi, Genie A Landon, Priyadharsini Nagarajan, Adrienne Choksi, Leon Chen, Marc Uemura, Phyu P Aung, Adi Diab, Padmanee Sharma, Michael A Davies, Rodabe Amaria, Victor G Prieto, Jonathan L Curry
Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have demonstrated substantial clinical benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases...
September 13, 2017: Journal of Cutaneous Pathology
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