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immune-checkpoint blockade

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https://www.readbyqxmd.com/read/29055015/small-molecule%C3%A2-inhibition-of-pd-1-transcription-is-an-effective-alternative-to-antibody-blockade-in-cancer-therapy
#1
Alison Taylor, David Rothstein, Christopher Rudd
The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29051990/clinicopathologic-implications-of-cd8-foxp3-ratio-and-mir-574-3p-pd-l1-axis-in-spinal-chordoma-patients
#2
Ming-Xiang Zou, Ke-Miao Guo, Guo-Hua Lv, Wei Huang, Jing Li, Xiao-Bin Wang, Yi Jiang, Xiao-Ling She
Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3(+), CD8(+), PD-1(+) and PD-L1(+)) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients...
October 20, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29051790/current-immunotherapeutic-strategies-in-hepatocellular-carcinoma-recent-advances-and-future-directions
#3
REVIEW
Hwi Young Kim, Joong-Won Park
Hepatocellular carcinoma (HCC) is a common and serious health problem with high mortality. Treatment for HCC remains largely unsatisfactory owing to its high recurrence rates and frequent accompanying cirrhosis. In addition, the unique immune environment of the liver promotes tolerance, which, in conjunction with immune evasion by the disease, makes HCC a less promising target for conventional immunotherapy. However, recent advances in the immunotherapy have led to novel approaches to overcome these obstacles by manipulating and enhancing tumor-specific immune responses against HCC by using various modalities, such as cancer vaccines and immune checkpoint blockade...
October 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/29050367/expression-and-clinical-association-of-programmed-cell-death-1-programmed-death-ligand-1-and-cd8-lymphocytes-in-primary-sarcomas-is-subtype-dependent
#4
Anke E M van Erp, Yvonne M H Versleijen-Jonkers, Melissa H S Hillebrandt-Roeffen, Laurens van Houdt, Mark A J Gorris, Laura S van Dam, Thomas Mentzel, Marije E Weidema, C Dilara Savci-Heijink, Ingrid M E Desar, Hans H M Merks, Max M van Noesel, Janet Shipley, Winette T A van der Graaf, Uta E Flucke, Friederike A G Meyer-Wentrup
In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively)...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29045526/lag-3-tumor-infiltrating-lymphocytes-in-breast-cancer-clinical-correlates-and-association-with-pd-1-pd-l1-tumors
#5
S Burugu, D Gao, S Leung, S K Chia, T O Nielsen
BACKGROUND: Novel immune checkpoint blockade strategies are being evaluated in clinical trials and include targeting the lymphocyte activation gene 3 (LAG-3) checkpoint, alone or in combination with PD-1/PD-L1 blockade. We investigated LAG-3 expression and its prognostic value in a large series of breast cancer patients, and correlated LAG-3 expression with key biomarkers including PD-1 and PD-L1. EXPERIMENTAL DESIGN: LAG-3 expression was evaluated by immunohistochemistry (IHC) on two tissue microarray series incorporating 4322 breast cancer primary excision specimens (N=330 in the training and N= 3,992 in the validation set) linked to detailed clinico-pathological, biomarker and long term clinical outcome data...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29045524/combined-irradiation-and-targeted-therapy-or-immune-checkpoint-blockade-in-brain-metastases-toxicities-and-efficacy
#6
A V Tallet, F Dhermain, E Le Rhun, G Noël, Y M Kirova
Background: Targeted therapies (TT) and immune checkpoint inhibitors (ICI) are currently modifying the landscape of metastatic cancer management and are increasingly used over the course of many cancers treatment. They allow long-term survival with controlled extra-cerebral disease, contributing to the increasing incidence of brain metastases (BMs). Radiation therapy remains the cornerstone of BMs treatment (either whole brain irradiation or stereotactic radiosurgery), and investigating the safety profile of radiation therapy combined with TT or ICI is of high interest...
August 2, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29043574/characterization-and-implications-of-thyroid-dysfunction-induced-by-immune-checkpoint-inhibitors-in-real-life-clinical-practice-a-long-term-prospective-study-from-a-referral-institution
#7
F Guaraldi, R La Selva, M T Samà, V D'Angelo, D Gori, P Fava, M T Fierro, P Savoia, E Arvat
PURPOSE: Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. METHODS: 52 patients (30 F; age 61 ± 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i...
October 17, 2017: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29043413/cholecystokinin-receptor-antagonist-alters-pancreatic-cancer-microenvironment-and-increases-efficacy-of-immune-checkpoint-antibody-therapy-in-mice
#8
Jill P Smith, Shangzi Wang, Sandeep Nadella, Sandra A Jablonski, Louis M Weiner
Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing fibrosis...
October 17, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29042417/restoration-of-natural-killer-cell-anti-metastatic-activity-by-il-12-and-checkpoint-blockade
#9
Isabel Ohs, Laura Ducimetiere, Joana Marinho, Paulina Kulig, Burkhard Becher, Sonia Tugues
Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of co-inhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL-12. Exposure to IL-12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population which expressed high levels of the co-inhibitory molecules PD-1, Lag-3 and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases...
October 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/29040995/role-of-immune-checkpoint-blockade-in-the-treatment-for-human-hepatocellular-carcinoma
#10
Naoshi Nishida, Masatoshi Kudo
With the development of molecular targeting therapy, several treatment options for advanced hepatocellular carcinoma (HCC) have become available in cases where curative and other palliative treatments, such as radiofrequency ablation, surgical resection, and transarterial chemoembolization, are not applicable. However, with the detection of a variety of mutations in cancer-related genes in a single tumor, molecular heterogeneity is commonly observed in HCC. Therefore, mutations in the major cellular signaling pathways underlie the development of resistance to molecular targeting agents...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/29038296/a-blueprint-to-advance-colorectal-cancer-immunotherapies
#11
Dung T Le, Vanessa M Hubbard-Lucey, Michael A Morse, Christopher R Heery, Andrea Dwyer, Thomas H Marsilje, Arthur N Brodsky, Emily Chan, Dustin A Deming, Luis A Diaz, Wolf H Fridman, Richard M Goldberg, Stanley R Hamilton, Franck Housseau, Elizabeth M Jaffee, S Peter Kang, Smitha S Krishnamurthi, Christopher H Lieu, Wells Messersmith, Cynthia L Sears, Neil H Segal, Arvin Yang, Rebecca A Moss, Edward Cha, Jill O'Donnell-Tormey, Nancy Roach, Anjelica Q Davis Davis, Keavy E McAbee, Sharyn Worrall, Al B Benson
Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer (CRC) had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in CRCs with defective mismatch repair (microsatellite instability high [MSI-H] tumors) has re-ignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in CRC and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy...
October 16, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29037958/expression-of-pd-1-and-pd-l1-in-poorly-differentiated-neuroendocrine-carcinomas-of-the-digestive-system-a-potential-target-for-anti-pd-1-pd-l1-therapy
#12
Jordan A Roberts, Raul S Gonzalez, Satya Das, Jordan Berlin, Chanjuan Shi
Poorly-differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly-differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports and pathology slides were reviewed for demographics, clinical history and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1 and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas...
October 13, 2017: Human Pathology
https://www.readbyqxmd.com/read/29037259/immuno-thermal-ablations-boosting-the-anticancer-immune-response
#13
REVIEW
Ryan Slovak, Johannes M Ludwig, Scott N Gettinger, Roy S Herbst, Hyun S Kim
The use of immunomodulation to treat malignancies has seen a recent explosion in interest. The therapeutic appeal of these treatments is far reaching, and many new applications continue to evolve. In particular, immune modulating drugs have the potential to enhance the systemic anticancer immune effects induced by locoregional thermal ablation. The immune responses induced by ablation monotherapy are well documented, but independently they tend to be incapable of evoking a robust antitumor response. By adding immunomodulators to traditional ablative techniques, several researchers have sought to amplify the induced immune response and trigger systemic antitumor activity...
October 17, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29035907/relationship-between-pd-l1-expression-and-cd8-t-cell-immune-responses-in-hepatocellular-carcinoma
#14
Chun-Yu Huang, Ying Wang, Guang-Yu Luo, Feng Han, Yong-Qiang Li, Zhong-Guo Zhou, Guo-Liang Xu
As PD-1/PD-L1 immune checkpoint inhibitors exhibited promising clinical outcomes in various types of solid tumors, PD-1/PD-L1 blockades have been explored for the treatment of hepatocellular carcinoma (HCC). However, the association of PD-L1 with antitumor immunoregulation is not clearly defined in HCC. Here, we evaluated the characteristics of PD-L1 expression, CD8 T-cell infiltration and their relationship in HCC. A total of 411 resected tumor specimens from HCC patients were immunostained for PD-L1 and CD8...
October 13, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29034589/involvement-of-local-renin-angiotensin-system-in-immunosuppression-of-tumor-microenvironment
#15
Kenta Nakamura, Tomonori Yaguchi, Gaku Ohmura, Asuka Kobayashi, Naoshi Kawamura, Takashi Iwata, Yukiko Kiniwa, Ryuhei Okuyama, Yutaka Kawakami
To improve the current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSCs) which were shown to be negative factors in the immune-checkpoint blockade therapy, need to be developed. In this study, we have evaluated the role of local renin-angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Administration of angiotensin II receptor blockers (ARBs) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells...
October 16, 2017: Cancer Science
https://www.readbyqxmd.com/read/29033936/coinhibitory-receptor-expression-and-immune-checkpoint-blockade-maintaining-a-balance-in-cd8-t-cell-responses-to-chronic-viral-infections-and-cancer
#16
REVIEW
Isobel S Okoye, Michael Houghton, Lorne Tyrrell, Khaled Barakat, Shokrollah Elahi
In cancer and chronic viral infections, T cells are exposed to persistent antigen stimulation. This results in expression of multiple inhibitory receptors also called "immune checkpoints" by T cells. Although these inhibitory receptors under normal conditions maintain self-tolerance and prevent immunopathology, their sustained expression deteriorates T cell function: a phenomenon called exhaustion. Recent advances in cancer immunotherapy involve blockade of cytotoxic T lymphocyte antigen-4 and programmed cell death 1 in order to reverse T cell exhaustion and reinvigorate immunity, which has translated to dramatic clinical remission in many cases of metastatic melanoma and lung cancer...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29033130/tumor-and-microenvironment-evolution-during-immunotherapy-with-nivolumab
#17
Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, Walter J Urba, Jennifer S Sims, F Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F Gajewski, Craig L Slingluff, Diego Chowell, Sviatoslav M Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G T Morris, John-William Sidhom, Jonathan P Schneck, Christine E Horak, Nils Weinhold, Timothy A Chan
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy...
October 11, 2017: Cell
https://www.readbyqxmd.com/read/29032735/sarcoidosis-malignancy-and-immune-checkpoint-blockade
#18
Elizabeth M Gaughan
No abstract text is available yet for this article.
October 2017: Immunotherapy
https://www.readbyqxmd.com/read/29032503/cd4-and-cd8-t-lymphocyte-interplay-in-controlling-tumor-growth
#19
REVIEW
Dmitrij Ostroumov, Nora Fekete-Drimusz, Michael Saborowski, Florian Kühnel, Norman Woller
The outstanding clinical success of immune checkpoint blockade has revived the interest in underlying mechanisms of the immune system that are capable of eliminating tumors even in advanced stages. In this scenario, CD4 and CD8 T cell responses are part of the cancer immune cycle and both populations significantly influence the clinical outcome. In general, the immune system has evolved several mechanisms to protect the host against cancer. Each of them has to be undermined or evaded during cancer development to enable tumor outgrowth...
October 14, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29029399/a-cellular-platform-for-the-evaluation-of-immune-checkpoint-molecules
#20
Sabrina Jutz, Annika Hennig, Wolfgang Paster, Ömer Asrak, Dejana Dijanovic, Florian Kellner, Winfried F Pickl, Johannes B Huppa, Judith Leitner, Peter Steinberger
Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways...
September 12, 2017: Oncotarget
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