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Pancreatic cancer and immune checkpoint

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https://www.readbyqxmd.com/read/29705789/immunotherapy-and-combination-strategies-in-pancreatic-cancer-current-status-and-emerging-trends
#1
Phyllis F Cheung, Manfred Lutz, Jens T Siveke
Pancreatic cancer is among the most aggressive malignancies with no effective therapeutic options thus far. Immunotherapy has recently emerged as a promising alternative for the treatment of various solid tumors. In particular, promising results in clinical trials were observed for therapies targeting immune checkpoint molecules. Efforts have been put into investigating the potential of immunotherapy in treating pancreatic cancer. While most of the clinical trial results are still being awaited, several intrinsic features of pancreatic cancer such as low mutational load and the presence of highly immunosuppressive desmoplasia significantly hamper the efficacy of immunotherapy in this disease...
2018: Oncology Research and Treatment
https://www.readbyqxmd.com/read/29605510/immunotherapy-for-pancreatic-cancer-a-long-and-hopeful-journey
#2
Jian-Wei Xu, Lei Wang, Yu-Gang Cheng, Guang-Yong Zhang, San-Yuan Hu, Bin Zhou, Han-Xiang Zhan
Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials...
July 1, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29587663/development-of-primary-human-pancreatic-cancer-organoids-matched-stromal-and-immune-cells-and-3d-tumor-microenvironment-models
#3
Susan Tsai, Laura McOlash, Katie Palen, Bryon Johnson, Christine Duris, Qiuhui Yang, Michael B Dwinell, Bryan Hunt, Douglas B Evans, Jill Gershan, Michael A James
BACKGROUND: Patient-derived tumor models are the new standard for pre-clinical drug testing and biomarker discovery. However, the emerging technology of primary pancreatic cancer organoids has not yet been broadly implemented in research, and complex organotypic models using organoids in co-culture with stromal and immune cellular components of the tumor have yet to be established. In this study, our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer...
March 27, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29567829/the-pancreatic-cancer-microbiome-promotes-oncogenesis-by-induction-of-innate-and-adaptive-immune-suppression
#4
Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, Constantinos P Zambirinis, Emma Kurz, Ankita Mishra, Navyatha Mohan, Berk Aykut, Mykhaylo Usyk, Luisana E Torres, Gregor Werba, Kevin Zhang, Yuqi Guo, Qianhao Li, Neha Akkad, Sarah Lall, Benjamin Wadowski, Johana Gutierrez, Juan Andres Kochen Rossi, Jeremy W Herzog, Brian Diskin, Alejandro Torres-Hernandez, Josh Leinwand, Wei Wang, Pardeep S Taunk, Shivraj Savadkar, Malvin Janal, Anjana Saxena, Xin Li, Deirdre Cohen, R Balfour Sartor, Deepak Saxena, George Miller
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation...
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29561217/immunological-mutational-signature-in-adenosquamous-cancer-of-pancreas-an-exploratory-study-of-potentially-therapeutic-targets
#5
Nicola Silvestris, Oronzo Brunetti, Rosamaria Pinto, Daniela Petriella, Antonella Argentiero, Livia Fucci, Stefania Tommasi, Katia Danza, Simona De Summa
OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP...
March 27, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29523759/landscape-of-tumor-mutation-load-mismatch-repair-deficiency-and-pd-l1-expression-in-a-large-patient-cohort-of-gastrointestinal-cancers
#6
Mohamed E Salem, Alberto Puccini, Axel Grothey, Derek Raghavan, Richard M Goldberg, Joanne Xiu, W Michael Korn, Benjamin A Weinberg, Jimmy J Hwang, Anthony F Shields, John L Marshall, Philip A Philip, Heinz-Josef Lenz
The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform...
May 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29515971/the-expression-and-prognostic-impact-of-immune-cytolytic-activity-related-markers-in-human-malignancies-a-comprehensive-meta-analysis
#7
Constantinos Roufas, Dimitrios Chasiotis, Anestis Makris, Christodoulos Efstathiades, Christos Dimopoulos, Apostolos Zaravinos
Background: Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29426021/a-sub-type-of-familial-pancreatic-cancer-evidence-and-implications-of-loss-of-function-polymorphisms-in-indoleamine-2-3-dioxygenase-2
#8
Avinoam Nevler, Alexander J Muller, Joseph A Cozzitorto, Austin Goetz, Jordan M Winter, Theresa P Yeo, Harish Lavu, Charles J Yeo, George C Prendergast, Jonathan R Brody
BACKGROUND: Variation in an individual's genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop...
April 2018: Journal of the American College of Surgeons
https://www.readbyqxmd.com/read/29385739/precision-immuno-oncology-prospects-of-individualized-immunotherapy-for-pancreatic-cancer
#9
REVIEW
Jiajia Zhang, Christopher L Wolfgang, Lei Zheng
Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival...
January 30, 2018: Cancers
https://www.readbyqxmd.com/read/29367431/evaluating-mismatch-repair-deficiency-in-pancreatic-adenocarcinoma-challenges-and-recommendations
#10
Zishuo I Hu, Jinru Shia, Zsofia K Stadler, Anna M Varghese, Marinela Capanu, Erin Salo-Mullen, Maeve A Lowery, Luis A Diaz, Diana Mandelker, Kenneth H Yu, Alice Zervoudakis, David P Kelsen, Christine A Iacobuzio-Donahue, David S Klimstra, Leonard B Saltz, Ibrahim H Sahin, Eileen M O'Reilly
Purpose: Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC...
March 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29301364/immune-evasion-in-pancreatic-cancer-from-mechanisms-to-therapy
#11
REVIEW
Neus Martinez-Bosch, Judith Vinaixa, Pilar Navarro
Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery...
January 3, 2018: Cancers
https://www.readbyqxmd.com/read/29276214/new-perspective-on-the-treatment-of-intractable-gastrointestinal-cancers-role-of-combination-therapies
#12
Dan G Duda
Unresectable gastrointestinal cancers, such as gastric, hepatocellular, biliary tract or pancreatic carcinomas, are often resistant to anti-cancer systemic therapies, and often recur locally or even after aggressive local therapies leading to dismal survival rates. Recent developments in oncology, have offered renewed hoped for the development of more efficacious therapies. For example, our understanding of the oncogenic drivers in carcinogenesis has increased exponentially, and may potentially allow personalization of therapy...
2017: Keio Journal of Medicine
https://www.readbyqxmd.com/read/29258858/emerging-biomarkers-for-immunomodulatory-cancer-treatment-of-upper-gastrointestinal-pancreatic-and-hepatic-cancers
#13
REVIEW
Belinda Lee, Ryan Hutchinson, Hui-Li Wong, Jeanne Tie, Tracy Putoczki, Ben Tran, Peter Gibbs, Michael Christie
Carcinomas of the oesophagus, stomach, pancreas and liver are common and account for a disproportionately high number of cancer deaths. There is a need for new treatment options for patients with advanced disease. Immunomodulatory treatments including immune checkpoint blockade offer a promising new approach, with efficacy shown in other solid tumour types. However, only a small proportion of patients with carcinomas of the oesophagus, stomach, pancreas and liver have responded to single agent checkpoint inhibitors, and there is a need for markers that are predictive of response to guide treatment of individual patients...
December 16, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29207939/tocilizumab-for-the-management-of-immune-mediated-adverse-events-secondary-to-pd-1-blockade
#14
Chipman Rg Stroud, Aparna Hegde, Cynthia Cherry, Abdul R Naqash, Nitika Sharma, Srikala Addepalli, Sulochana Cherukuri, Teresa Parent, Jessica Hardin, Paul Walker
Background Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs. Methods The character and clinical course of irAEs were abstracted from the medical record and analyzed...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29204701/combination-of-mab-ar20-5-anti-pd-l1-and-polyiclc-inhibits-tumor-progression-and-prolongs-survival-of-muc1-tg-mice-challenged-with-pancreatic-tumors
#15
Kamiya Mehla, Jarrod Tremayne, James A Grunkemeyer, Kelly A O'Connell, Maria M Steele, Thomas C Caffrey, Xinyi Zhu, Fang Yu, Pankaj K Singh, Birgit C Schultes, Ragupathy Madiyalakan, Christopher F Nicodemus, Michael A Hollingsworth
A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1...
March 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29180478/perioperative-spatiotemporally-coordinated-activation-of-t-and-nk-cells-prevents-recurrence-of-pancreatic-cancer
#16
Jennifer Brooks, Bettina Fleischmann-Mundt, Norman Woller, Julia Niemann, Silvia Ribback, Kristin Peters, Ihsan Ekin Demir, Nina Armbrecht, Guralp O Ceyhan, Michael P Manns, Thomas C Wirth, Stefan Kubicka, Gunter Bernhardt, Mark J Smyth, Diego F Calvisi, Engin Gürlevik, Florian Kühnel
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells...
January 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29113292/nod-mice-susceptible-to-pancreatic-autoimmunity-demonstrate-delayed-growth-of-pancreatic-cancer
#17
James Dooley, Emanuela Pasciuto, Vasiliki Lagou, Yulia Lampi, Tom Dresselaers, Uwe Himmelreich, Adrian Liston
Pancreatic cancer is a high mortality form of cancer, with a median survival only six months. There are multiple associated risk factors associated, most importantly type 2 diabetes, obesity, pancreatitis and smoking. The relative rarity of the disease, however, has made it difficult to dissect causative risk factors, especially with related risk factors. A major unanswered question with important therapeutic implications is the effect of immunological responses on pancreatic cancer formation, with data from other cancers suggesting the potential for local immunological responses to either increase cancer development or increase cancer elimination...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29100397/correlating-programmed-death-ligand-1-pd-l1-expression-mismatch-repair-deficiency-and-outcomes-across-tumor-types-implications-for-immunotherapy
#18
Seung Tae Kim, Samuel J Klempner, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Kyoung-Mee Kim, Jeeyun Lee
The identification of biomarkers associated with response to therapeutic agents is central to optimizing patient outcomes. Expression of the immune checkpoint proteins PD-1/L1, and DNA mismatch repair deficiency (dMMR) status may be predictive response biomarkers for immunotherapies, but their overlap requires further study. We prospectively conducted PD-L1 and MMR immunohistochemistry (IHC) on 430 consecutive patients with advanced gastrointestinal (GI) cancers, genitourinary (GU) cancers or rare cancers between June 2012 and March 2016...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29100036/nafamostat-mesilate-a-serine-protease-inhibitor-suppresses-interferon-gamma-induced-up-regulation-of-programmed-cell-death-ligand-1-in-human-cancer-cells
#19
Sadamu Homma, Kazumi Hayashi, Kosaku Yoshida, Yukiko Sagawa, Yuko Kamata, Masaki Ito
Programmed cell death ligand-1 (PD-L1) plays a pivotal role in the suppression of antitumour immunity by binding to programmed cell death-1 (PD-1) on tumouricidal cytotoxic T lymphocytes (CTLs), rendering them inactive. As blockade of PD-1/PD-L1 interaction by the monoclonal antibodies induced effective T cell-mediated antitumour response, suppression of PD-L1 expression in tumour cells by the chemical agent might contribute to treatment against malignant tumours. Nafamostat mesilate (NM), a serine protease inhibitor that is frequently used in the clinic, potently suppressed interferon-gamma (IFN-gamma)-induced up-regulation of PD-L1 in cultured human lung cancer cells (HLC-1) at both the messenger RNA (mRNA) and protein levels...
January 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29081663/prognostic-value-of-pd-l1-overexpression-for-pancreatic-cancer-evidence-from-a-meta-analysis
#20
Yongxun Zhuan-Sun, Fengting Huang, Min Feng, Xinbao Zhao, Wenying Chen, Zhe Zhu, Shineng Zhang
Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is often activated in cancer and plays a pivotal role in the initiation and progression of cancer. However, the clinicopathologic significance and prognostic value of PD-L1 in pancreatic cancer (PC) remains controversial. In this study, we conducted a meta-analysis to retrospectively evaluate the relationship between PD-L1 and PC. PubMed and other databases were searched for the clinical studies published up to March 21, 2017, to be included in the meta-analysis...
2017: OncoTargets and Therapy
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