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Immunotherapy Pancreatic

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https://www.readbyqxmd.com/read/30302387/eus-fine-needle-pancreatic-core-biopsy-can-determine-eligibility-for-tumor-agnostic-immunotherapy
#1
Ferga C Gleeson, Michael J Levy, Anja C Roden, Lisa A Boardman, Frank A Sinicrope, Robert R McWilliams, Lizhi Zhang
Background and study aims  The US FDA recently approved a cancer treatment with pembrolizumab based upon the tumor biomarker status of deficient mismatch repair (dMMR) rather than a specific disease-based approach. We sought to determine if endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) could determine dMMR and quantification of PD-L1 expression to potentially guide the delivery of tumor agnostic immunotherapy. Patients and methods  Immunohistochemistry was performed on archived pancreas core biopsy specimens...
October 2018: Endoscopy International Open
https://www.readbyqxmd.com/read/30301530/far-upstream-element-binding-protein-1-is-up-regulated-in-pancreatic-cancer-and-modulates-immune-response-by-increasing-programmed-death-ligand-1
#2
Ping Fan, Jinlong Ma, Xin Jin
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. So far, almost all treatments are almost ineffective for pancreatic cancer. Thus, there is an urgent need to develop novel therapeutics for pancreatic cancer treatment. Immune checkpoints blockade therapies, including anti-PD-L1 and anti-PD-1, show promising anti-tumor efficacy for a various type of solid tumors. However, pancreatic cancer is disappointed for anti-PD-L1 therapy alone. The expression level of PD-L1 is considered as one of determinant of checkpoint immunotherapy efficacy...
October 6, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/30284649/the-use-of-radiofrequency-ablation-in-pancreatic-cancer-in-the-midst-of-the-dawn-of-immuno-oncology
#3
EDITORIAL
Isabella Reccia, Jayant Kumar, Nagy Habib, Mikael Sodergren
Despite significant improvement in treatment, the prognosis of pancreatic ductal adenocarcinoma remains poor as the biology of the tumour affects survival even when a radical resection has been performed. Pancreatic cancer remains resistant to currently available chemotherapeutic options. Recently, immunotherapy has achieved significant results in certain types of cancer. However, for pancreatic cancer, results were not initially encouraging as pancreatic cancer microenvironment is highly immunosuppressive...
October 4, 2018: Medical Oncology
https://www.readbyqxmd.com/read/30284618/diabetes-mellitus-induced-by-pd-1-and-pd-l1-inhibitors-description-of-pancreatic-endocrine-and-exocrine-phenotype
#4
Lucien Marchand, Arnaud Thivolet, Stéphane Dalle, Karim Chikh, Sophie Reffet, Julien Vouillarmet, Nicole Fabien, Christine Cugnet-Anceau, Charles Thivolet
AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors...
October 4, 2018: Acta Diabetologica
https://www.readbyqxmd.com/read/30269996/pdl1-is-expressed-in-the-islets-of-people-with-type-1-diabetes-and-is-up-regulated-by-interferons-%C3%AE-and-%C3%AE-via-irf1-induction
#5
Maikel L Colli, Jessica L E Hill, Laura Marroquí, Jessica Chaffey, Reinaldo S Dos Santos, Pia Leete, Alexandra Coomans de Brachène, Flavia M M Paula, Anne Op de Beeck, Angela Castela, Lorella Marselli, Lars Krogvold, Knut Dahl-Jorgensen, Piero Marchetti, Noel G Morgan, Sarah J Richardson, Décio L Eizirik
BACKGROUND: Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated. METHODS: The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot...
September 27, 2018: EBioMedicine
https://www.readbyqxmd.com/read/30261853/engaging-the-older-cancer-patient-patient-activation-through-counseling-exercise-and-mobilization-pancreatic-biliary-tract-and-lung-cancer-pace-mobil-pbl-study-protocol-of-a-randomized-controlled-trial
#6
Marta Kramer Mikkelsen, Cecilia Margareta Lund, Anders Vinther, Anders Tolver, Anne-Mette Ragle, Julia Sidenius Johansen, Inna Chen, Lotte Engell-Noerregaard, Finn Ole Larsen, Bo Zerahn, Dorte Lisbet Nielsen, Mary Jarden
BACKGROUND: Several intervention studies have demonstrated that exercise training has beneficial effects among cancer patients. However, older cancer patients are underrepresented in clinical trials, and only few exercise-based studies have focused specifically on older patients with cancer. In particular, research investigating the effects of exercise training among older patients with advanced cancer is lacking. The purpose of the current study is to investigate the effect of a 12-week multimodal and exercise-based intervention among older patients (≥65 years) with advanced pancreatic, biliary tract or lung cancer, who are treated with first-line palliative chemotherapy, immunotherapy or targeted therapy...
September 27, 2018: BMC Cancer
https://www.readbyqxmd.com/read/30261620/the-current-status-and-future-prospects-of-oncolytic-viruses-in-clinical-trials-against-melanoma-glioma-pancreatic-and-breast-cancers
#7
REVIEW
Ibrahim Ragab Eissa, Itzel Bustos-Villalobos, Toru Ichinose, Shigeru Matsumura, Yoshinori Naoe, Noriyuki Miyajima, Daishi Morimoto, Nobuaki Mukoyama, Wu Zhiwen, Maki Tanaka, Hitoki Hasegawa, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya
Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic® ) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials...
September 26, 2018: Cancers
https://www.readbyqxmd.com/read/30253648/local-blockade-of-interleukin-10-and-c-x-c-motif-chemokine-ligand-12-with-nano-delivery-promotes-antitumor-response-in-murine-cancers
#8
Limei Shen, Jingjing Li, Qi Liu, Wantong Song, Xueqiong Zhang, Karthik Tiruthani, Haiyang Hu, Manisit Das, Tyler Jay Goodwin, Rihe Liu, Leaf Huang
In many cancers, the tumor microenvironment (TME) is largely immune suppressive, blocking the antitumor immunity and resulting in immunotherapy resistance. Interleukin 10 (IL-10) is a major player controlling the immunosuppressive TME in different murine tumor models. Increased IL-10 production suppresses intratumoral dendritic cell production of interleukin 12, thereby limiting antitumor cytotoxic T-cell responses and activation of NK cells during therapy. We engineered, formulated, and delivered genes encoding an IL-10 protein trap to change immunosuppressive TME, which could enhance antitumor immunity...
September 28, 2018: ACS Nano
https://www.readbyqxmd.com/read/30237494/proinsulin-mediated-induction-of-type-1-diabetes-in-hla-dr4-transgenic-mice
#9
Johan Verhagen, Emma L Smith, Emily M Whettlock, Benedict Macintyre, Mark Peakman
Antigen-specific immunotherapy of autoimmune disease currently remains the only potentially curative approach. However, translation of promising pre-clinical results into successful clinical application has proven challenging. In part, this is because pre-clinical findings in mouse models have to be redesigned for human application due to differences in MHC II. To reduce the gap between pre-clinical and clinical studies, we have created a novel mouse model that expresses human HLA-DR4, but no endogenous MHC on antigen-presenting cells...
September 20, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30236153/single-cell-transcriptomics-reveal-that-pd-1-mediates-immune-tolerance-by-regulating-proliferation-of-regulatory-t-cells
#10
Cherry S Leung, Kevin Y Yang, Xisheng Li, Vicken W Chan, Manching Ku, Herman Waldmann, Shohei Hori, Jason C H Tsang, Yuk Ming Dennis Lo, Kathy O Lui
BACKGROUND: We have previously reported an antigen-specific protocol to induce transplant tolerance and linked suppression to human embryonic stem cell (hESC)-derived tissues in immunocompetent mice through coreceptor and costimulation blockade. However, the exact mechanisms of acquired immune tolerance in this model have remained unclear. METHODS: We utilize the NOD.Foxp3hCD2 reporter mouse line and an ablative anti-hCD2 antibody to ask if CD4+ FOXP3+ regulatory T cells (Treg) are required for coreceptor and costimulation blockade-induced immune tolerance...
September 20, 2018: Genome Medicine
https://www.readbyqxmd.com/read/30231203/stromal-modulation-reverses-primary-resistance-to-immune-checkpoint-blockade-in-pancreatic-cancer
#11
Jun Zhao, Zhilan Xiao, Tingting Li, Huiqin Chen, Ying Yuan, Y Alan Wang, Cheng-Hui Hsiao, Diana S-L Chow, Willem W Overwijk, Chun Li
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to treat. It is refractory to most existing therapies, including immunotherapies, due to the presence of an excessive desmoplastic stroma, which restricts penetration of drugs and cytotoxic CD8+ T cells. Stromal modulation has shown promising results in the enhancement of immune checkpoint blockade treatment in PDAC. We demonstrate here effective stromal modulation by a polymeric micelle-based nanoformulation to codeliver a sonic hedgehog inhibitor (cyclopamine, abbreviated as CPA) and a cytotoxic chemotherapy drug (paclitaxel, abbreviated as PTX)...
September 21, 2018: ACS Nano
https://www.readbyqxmd.com/read/30214445/pd1-cd28-fusion-protein-enables-cd4-t-cell-help-for-adoptive-t-cell-therapy-in-models-of-pancreatic-cancer-and-non-hodgkin-lymphoma
#12
Felicitas Rataj, Fabian B T Kraus, Michael Chaloupka, Simon Grassmann, Constanze Heise, Bruno L Cadilha, Peter Duewell, Stefan Endres, Sebastian Kobold
Background: Interaction of the programmed death receptor 1 (PD-1) and its ligand, PD-L1, suppresses T cell activity and permits tumors to evade T cell-mediated immune surveillance. We have recently demonstrated that antigen-specific CD8+ T cells transduced with a PD1-CD28 fusion protein are protected from PD-1-mediated inhibition. We have now investigated the potential of PD1-CD28 fusion protein-transduced CD4+ T cells alone or in combination with CD8+ T cells for immunotherapy of pancreatic cancer and non-Hodgkin lymphoma...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30197477/p21-activated-kinase-signalling-in-pancreatic-cancer-new-insights-into-tumour-biology-and-immune-modulation
#13
REVIEW
Kai Wang, Graham S Baldwin, Mehrdad Nikfarjam, Hong He
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance...
September 7, 2018: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/30196915/clinical-update-on-k-ras-targeted-therapy-in-gastrointestinal-cancers
#14
REVIEW
Shubham Pant, Joleen Hubbard, Erika Martinelli, Tanios Bekaii-Saab
KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras...
October 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/30178242/genomic-profiling-and-potentially-targetable-alterations-in-pancreatic-ductal-adenocarcinoma
#15
REVIEW
Ferga C Gleeson, Michael J Levy
PURPOSE OF REVIEW: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-associated mortality with continued poor outcome and a short-lived treatment response to conventional therapy. However, with the rapidly evolving field of precision oncology, new and novel genomic information is emerging, identifying tumor subtypes by revealing somatic and germline mutations. RECENT FINDINGS: There is growing interest in determining the tumor BRCA status to guide potential PARP inhibitor targeted therapy and for evaluating tumor microsatellite instability status for immune checkpoint inhibitor therapy which has been reported in up to 3% of PDAC patients...
September 3, 2018: Current Treatment Options in Gastroenterology
https://www.readbyqxmd.com/read/30142009/prior-exposure-of-pancreatic-tumors-to-sorafenib-vorinostat-enhances-the-efficacy-of-an-anti-pd-1-antibody
#16
Laurence Booth, Jane Lisa Roberts, Andrew Poklepovic, Paul Dent
Checkpoint immunotherapy antibodies have not shown efficacy in pancreatic adenocarcinoma. Pre-clinical studies and subsequently an on-going phase I trial have demonstrated the safety and efficacy of combinatorial radio-chemotherapy plus surgery in this malignancy, including the combination of sorafenib and vorinostat. The lethality of [sorafenib + vorinostat] was enhanced by gemcitabine. Exposure to [sorafenib + vorinostat] reduced the expression of β-catenin, ERBB1, BCL-XL and MCL-1, and the phosphorylation of AKT T308, AKT S473, GSK3 S9/21, mTORC1 and mTORC2...
August 24, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/30140382/identification-of-a-novel-hla-a24-restricted-cytotoxic-t-lymphocyte-epitope-peptide-derived-from-mesothelin-in-pancreatic-cancer
#17
Mariko Tsukagoshi, Satoshi Wada, Seiko Hirono, Shintaro Yoshida, Erica Yada, Tetsuro Sasada, Ken Shirabe, Hiroyuki Kuwano, Hiroki Yamaue
Pancreatic cancer involves highly malignant tumors, and the development of new therapeutic strategies is critical. Mesothelin is overexpressed in infiltrating pancreatic cancer cells and plays an important role in the invasion and migration processes. In this study, we focused on mesothelin as a tumor-specific antigen target for a pancreatic cancer vaccine. We first investigated the mesothelin-derived epitope peptide restricted to HLA-A* 2402. A total of 19 candidate peptides were synthesized, and we then determined their potential to induce peptide-specific cytotoxic T lymphocytes (CTLs)...
July 31, 2018: Oncotarget
https://www.readbyqxmd.com/read/30135623/neutralizing-tgf-%C3%AE-promotes-anti-tumor-immunity-of-dendritic-cells-against-pancreatic-cancer-by-regulating-t-lymphocytes
#18
Ning Pu, Guochao Zhao, Shanshan Gao, Yutong Cui, Yadong Xu, Yang Lv, Abulimiti Nuerxiati, Wenchuan Wu
Previous fundamental or clinical trials of dendritic cell (DC) vaccine against pancreatic ductal adenocarcinoma (PDAC) revealed the burgeoning neoadjuvant immunotherapy. Microarray studies indicated that multiple ingredients of the transfer growth factor beta (TGF-β) pathway were overexpressed in PDAC, which inhibited the intratumoral immune response. To explore whether the DC volume in tumor microenvironment contributes to the differentiation of T cell cohort and test the hypothesis that combining DC vaccine with TGF-β inhibitors will elevate the anti-tumor immune response, we managed to co-culture T cells in vitro with pancreatic cancer cells and DCs in different concentrations, and combine TGF-β blockage with DC vaccine therapy in a murine model of pancreatic cancer...
2018: Central-European Journal of Immunology
https://www.readbyqxmd.com/read/30128712/harnessing-the-immune-system-in-pancreatic-cancer
#19
REVIEW
Satya Das, Jordan Berlin, Dana Cardin
Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients...
August 20, 2018: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/30121627/switchable-car-t-cells-mediate-remission-in-metastatic-pancreatic-ductal-adenocarcinoma
#20
Deepak Raj, Ming-Hsin Yang, David Rodgers, Eric N Hampton, Julfa Begum, Arif Mustafa, Daniela Lorizio, Irene Garces, David Propper, James G Kench, Travis S Young, Alexandra Aicher, Christopher Heeschen
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a disease of unmet medical need. While immunotherapy with chimeric antigen receptor T (CAR-T) cells has shown much promise in haematological malignancies, their efficacy for solid tumours is challenged by the lack of tumour-specific antigens required to avoid on-target, off-tumour effects. Switchable CAR-T cells whereby activity of the CAR-T cell is controlled by dosage of a tumour antigen-specific recombinant Fab-based 'switch' to afford a fully tunable response may overcome this translational barrier...
August 18, 2018: Gut
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