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Pancreatic cancer immunotherapy

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https://www.readbyqxmd.com/read/28527946/the-microbiome-and-hepatobiliary-pancreatic-cancers
#1
Kosuke Mima, Shigeki Nakagawa, Hiroshi Sawayama, Takatsugu Ishimoto, Katsunori Imai, Masaaki Iwatsuki, Daisuke Hashimoto, Yoshifumi Baba, Yo-Ichi Yamashita, Naoya Yoshida, Akira Chikamoto, Hideo Baba
The human intestinal microbiome encompasses at least 100 trillion microorganisms that can influence host immunity and disease conditions, including cancer. Hepatobiliary and pancreatic cancers have been associated with poor prognosis owing to their high level of tumor invasiveness, distant metastasis, and resistance to conventional treatment options, such as chemotherapy. Accumulating evidence from animal models suggests that specific microbes and microbial dysbiosis can potentiate hepatobiliary-pancreatic tumor development by damaging DNA, activating oncogenic signaling pathways, and producing tumor-promoting metabolites...
May 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28511795/mir-142-5p-regulates-tumor-cell-pd-l1-expression-and-enhances-anti-tumor-immunity
#2
Long Jia, Qing Xi, Huafeng Wang, Zimu Zhang, Hongkun Liu, Yingnan Cheng, Xiangdong Guo, Jieyou Zhang, Qi Zhang, Lijuan Zhang, Zhenyi Xue, Yan Li, Yurong Da, Peng Zhao, Rongxin Zhang
Cancer immunotherapy has many great achievements in recent years. One of the most promising cancer immunotherapies is PD-1/PD-L1 pathway blockade. miRNAs (MicroRNAs) belongs to small noncoding RNA and can regulate gene expression by binding to the 3'UTR. Many miRNAs can inhibit cancer growth by regulating the PD-L1 expression in cancer cells. Herein, we firstly found that PD-L1 could be the target of miR-142-5p by using bioinformatics methods, then we conduct luciferase activity assay, RT-PCR and western blot experiments to demonstrate that miR-142-5p can regulate PD-L1 expression by binding to its 3'UTR...
May 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28470686/tumor-cell-expression-of-immune-inhibitory-molecules-and-tumor-infiltrating-lymphocyte-count-predict-cancer-specific-survival-in-pancreatic-and-ampullary-cancer
#3
Kostandinos Sideras, Katharina Biermann, Kevin Yap, Shanta Mancham, Patrick P C Boor, Bettina E Hansen, Hans J A Stoop, Maikel P Peppelenbosch, Casper H van Eijck, Stefan Sleijfer, Jaap Kwekkeboom, Marco J Bruno
Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic (n=148) and ampullary (n=76) cancer was used to construct tissue-microarrays...
May 3, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28464583/-advances-in-immunotherapy-of-pancreatic-ductal-adenocarcinoma
#4
J Q Yang, T Wei, Y W Chen, X L Bai, T B Liang
The morbidity of pancreatic ductal adenocarcinoma (PDAC) has been increasing over years, while the treatment efficacy and prognosis of PDAC remain far from satisfying. The newly-ermerged tumor immunotherapy has not only made lots of breakthroughs in various malignancies, but also brought an opportunity to the treatment of pancreatic cancer.PDAC immunotherapies, mainly including vaccine therapy, adoptive T cell thanfer therapy, checkpoint blockade therapy, have achieved a certain effect, however, the clinical outcomes have not been satisfactory...
May 1, 2017: Zhonghua Wai Ke za Zhi [Chinese Journal of Surgery]
https://www.readbyqxmd.com/read/28460571/muc4-mucin-a-therapeutic-target-for-pancreatic-ductal-adenocarcinoma
#5
Shailendra K Gautam, Sushil Kumar, Andrew Cannon, Bradley Hall, Rakesh Bhatia, Mohd Wasim Nasser, Sidharth Mahapatra, Surinder Batra, Maneesh Jain
Pancreatic cancer (PC) is characterized by mucin overexpression and MUC4 is the most differentially overexpressed membrane bound mucins that plays functional role in disease progression and therapy resistance. Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC...
May 2, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28454381/optimized-construction-of-muc1-vntrn-dna-vaccine-and-its-anti-pancreatic-cancer-efficacy
#6
Yuan-Feng Gong, Quan-Bo Zhou, Ya-Di Liao, Cong Mai, Tie-Jun Chen, Yun-Qiang Tang, Ru-Fu Chen
Considering mucin 1-variable number tandem repeat (MUC1-VNTRn) as a novel target for pancreatic cancer immunotherapy, the present study aimed to screen and identify the pVAX1-MUC1-VNTRn DNA vaccine with the strongest immunogenicity. Following construction of a pVAX1-MUC1-VNTRn plasmid, immature dendritic cells (DCs) were subjected to transfection, and mature DCs were then co-cultured with autologous T-cells. The numbers of cytotoxic T lymphocytes (CTLs) secreting interferon (IFN)-γ were determined using an enzyme-linked immunospot assay, and CytoTox(®) was also used to examine the MUC1-VNTRn-specific Lethal effect of CTLs on Capan2 cells...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28430580/expression-status-of-folate-receptor-alpha-is-a-predictor-of-survival-in-pancreatic-ductal-adenocarcinoma
#7
Lei Cai, Theodoros Michelakos, Cristina R Ferrone, Liyuan Zhang, Vikram Deshpande, Qi Shen, Albert De Leo, Teppei Yamada, Gong Zhang, Soldano Ferrone, Xinhui Wang
Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognosis among malignancies. Thus, the identification of markers useful in developing innovative diagnostic and therapeutic methods is an imperative need. Folate receptor alpha (FRα) has been associated with prognosis in several cancers and has served as a target of novel anti-tumor therapies. However, FRα expression in PDAC and its correlation with the clinical course of the disease has not been thoroughly investigated. In this study, we analyzed FRα expression in 140 PDAC specimens and 7 PDAC cell lines in order to define the significance of FRα expression in PDAC and its potential role as a target for immunotherapy...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407327/oncolytic-viral-therapy-for-pancreatic-cancer
#8
REVIEW
Ahmad Rahal, Benjamin Musher
Outcomes of pancreatic adenocarcinoma (PDA) remain dismal despite extensive clinical investigation. Combination chemotherapy provides modest improvements in survival above best supportive care, and immunotherapy has thus far not proven effective. Nevertheless, growing insight into antitumor immunity and the tumor microenvironment has inspired the discovery of novel agents targeting PDA. Oncolytic viruses represent an emerging class of immunotherapeutic agents that have undergone extensive preclinical investigation and warrant further investigation in well-designed clinical trials...
April 13, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28405527/jak-stat-mediated-chronic-inflammation-impairs-cytotoxic-t-lymphocyte-activation-to-decrease-anti-pd-1-immunotherapy-efficacy-in-pancreatic-cancer
#9
Chunwan Lu, Asif Talukder, Natasha M Savage, Nagendra Singh, Kebin Liu
Human pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28396056/connecting-the-metabolic-and-immune-responses-to-cancer
#10
REVIEW
Thomas R Flint, Douglas T Fearon, Tobias Janowitz
Separate research fields have advanced our understanding of, on the one hand, cancer immunology and, on the other hand, cachexia, the fatal tumor-induced wasting syndrome. A link between the host's immune and metabolic responses to cancer remained unexplored. Emerging work in preclinical models of colorectal and pancreatic cancer has unveiled tumor-induced reprogramming of liver metabolism in cachexia that leads to suppression of antitumor immunity and failure of immunotherapy. As research efforts in metabolism and immunology in cancer are rapidly expanding, it is timely to discuss the metabolic and immunological determinants of the cancer-host interaction...
April 7, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28393575/using-circulating-cell-free-dna-to-monitor-personalized-cancer-therapy
#11
Michael Oellerich, Ekkehard Schütz, Julia Beck, Philipp Kanzow, Piers N Plowman, Glen J Weiss, Philip D Walson
High-quality genomic analysis is critical for personalized pharmacotherapy in patients with cancer. Tumor-specific genomic alterations can be identified in cell-free DNA (cfDNA) from patient blood samples and can complement biopsies for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. cfDNA can be especially useful when tumor tissue is unavailable or insufficient for testing. For blood-based genomic profiling, next-generation sequencing (NGS) and droplet digital PCR (ddPCR) have been successfully applied...
May 2017: Critical Reviews in Clinical Laboratory Sciences
https://www.readbyqxmd.com/read/28388966/vaccination-with-poly-ic-lc-and-peptide-pulsed-autologous-dendritic-cells-in-patients-with-pancreatic-cancer
#12
Shikhar Mehrotra, Carolyn D Britten, Steve Chin, Elizabeth Garrett-Mayer, Colleen A Cloud, Mingli Li, Gina Scurti, Mohamed L Salem, Michelle H Nelson, Melanie B Thomas, Chrystal M Paulos, Andres M Salazar, Michael I Nishimura, Mark P Rubinstein, Zihai Li, David J Cole
BACKGROUND: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). METHODS: We generated autologous DCs from the peripheral blood of HLA-A2(+) patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV...
April 7, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28373404/precancer-atlas-to-drive-precision-prevention-trials
#13
Avrum Spira, Matthew B Yurgelun, Ludmil Alexandrov, Anjana Rao, Rafael Bejar, Kornelia Polyak, Marios Giannakis, Ali Shilatifard, Olivera J Finn, Madhav Dhodapkar, Neil E Kay, Esteban Braggio, Eduardo Vilar, Sarah A Mazzilli, Timothy R Rebbeck, Judy E Garber, Victor E Velculescu, Mary L Disis, Douglas C Wallace, Scott M Lippman
Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity - basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape...
April 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28373365/current-and-emerging-therapies-in-metastatic-pancreatic-cancer
#14
EDITORIAL
Gulam Abbas Manji, Kenneth P Olive, Yvonne M Saenger, Paul Oberstein
Targeted therapies and immunotherapy have changed the face of multiple solid malignancies, including metastatic melanoma and lung cancer, but no such therapies exist for pancreatic ductal adenocarcinoma (PDAC) despite the knowledge of key mutations and an increasing understanding of the tumor microenvironment. Until now, most clinical studies have not been biomarker driven in this highly immunosuppressive and heterogeneous cancer. Ongoing basic and translational studies are better classifying the disease in hopes of identifying critical pathways that distinguish the unique PDAC subtypes, which will lead to personalized therapies...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28373364/strategies-for-increasing-pancreatic-tumor-immunogenicity
#15
EDITORIAL
Burles A Johnson, Mark Yarchoan, Valerie Lee, Daniel A Laheru, Elizabeth M Jaffee
Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28367234/differentiation-by-nk-cells-is-a-prerequisite-for-effective-targeting-of-cancer-stem-cells-poorly-differentiated-tumors-by-chemopreventive-and-chemotherapeutic-drugs
#16
Anna Karolina Kozlowska, Paytsar Topchyan, Kawaljit Kaur, Han-Ching Tseng, Antonia Teruel, Toru Hiraga, Anahid Jewett
Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28348045/stratification-of-pancreatic-ductal-adenocarcinoma-combinatorial-genetic-stromal-and-immunological-markers
#17
Erik Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W Botros, Vladimir Makarov, Nadeem Riaz, Vinod P Balachandran, Steven D Leach, Debrah M Thompson, Timothy A Chan, Agnieszka K Witkiewicz
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunological features of PDAC to delineate impact on prognosis and to more effectively employ immunotherapy. EXPERIMENTAL DESIGN: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunological subtypes of PDAC that were confirmed in the Cancer Genome Atlas data set...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28345379/the-role-of-%C3%AE-%C3%AE-t-cells-in-pancreatic-cancer-what-could-this-mean-for-the-clinic
#18
Donnele Daley, George Miller
Pancreatic cancer is a devastating disease where the 5-year survival is less that 10%. Recent studies have shown that ?? T cells are a dominant lymphocyte subset in pancreatic cancer and they promote the progression of the disease. With the emerging use of T cell- based therapy for cancer, ?? T cells are an attractive target for novel immunotherapy in pancreatic cancer.
March 26, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28344866/cd13-hi-neutrophil-like-myeloid-derived-suppressor-cells-exert-immune-suppression-through-arginase-1-expression-in-pancreatic-ductal-adenocarcinoma
#19
Jing Zhang, Xiongfei Xu, Min Shi, Ying Chen, Danghui Yu, Chenyan Zhao, Yan Gu, Biao Yang, Shiwei Guo, Guiling Ding, Gang Jin, Chin-Lee Wu, Minghua Zhu
Perineural invasion and immunosuppressive tumor microenvironment are the distinct features of pancreatic ductal adenocarcinoma (PDAC). Heterogeneous myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity, posing obstacles for cancer immunotherapy. Increasing evidences have demonstrated the accumulation of MDSCs in PDAC patients. However, the role of MDSCs in perineural invasion of PDAC and the existence of novel MDSC subsets during PDAC remain unclear. This study found that lymphocytic perineural cuffs were frequently present in chronic pancreatitis (CP) tissues and adjacent non-neoplastic pancreatic tissues (ANPTs), but not in PDAC with perineural invasion...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28286568/immunotherapy-in-pancreatic-cancer-treatment-a-new-frontier
#20
REVIEW
Komal Thind, Leslie J Padrnos, Ramesh K Ramanathan, Mitesh J Borad
Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy...
January 2017: Therapeutic Advances in Gastroenterology
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