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Pancreatic cancer and immune checkpoint

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https://www.readbyqxmd.com/read/29301364/immune-evasion-in-pancreatic-cancer-from-mechanisms-to-therapy
#1
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
#2
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
#3
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
#4
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
#5
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...
December 4, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29180478/perioperative-spatiotemporally-coordinated-activation-of-t-and-nk-cells-prevents-recurrence-of-pancreatic-cancer
#6
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 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...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29113292/nod-mice-susceptible-to-pancreatic-autoimmunity-demonstrate-delayed-growth-of-pancreatic-cancer
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/29066497/t-cell-localization-activation-and-clonal-expansion-in-human-pancreatic-ductal-adenocarcinoma
#11
Ingunn M Stromnes, Ayaka Hulbert, Robert H Pierce, Philip D Greenberg, Sunil R Hingorani
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells, and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared with stroma and tumor cell nests...
November 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#12
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29043413/cholecystokinin-receptor-antagonist-alters-pancreatic-cancer-microenvironment-and-increases-efficacy-of-immune-checkpoint-antibody-therapy-in-mice
#13
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/28961038/focused-ultrasound-for-immuno-adjuvant-treatment-of-pancreatic-cancer-an-emerging-clinical-paradigm-in-the-era-of-personalized-oncotherapy
#14
Ezekiel Maloney, Tanya Khokhlova, Venu G Pillarisetty, George R Schade, Elizabeth A Repasky, Yak-Nam Wang, Lorenzo Giuliani, Matteo Primavera, Joo Ha Hwang
Current clinical treatment regimens, including many emergent immune strategies (e.g., checkpoint inhibitors) have done little to affect the devastating course of pancreatic ductal adenocarcinoma (PDA). Clinical trials for PDA often employ multi-modal treatment, and have started to incorporate stromal-targeted therapies, which have shown promising results in early reports. Focused ultrasound (FUS) is one such therapy that is uniquely equipped to address local and systemic limitations of conventional cancer therapies as well as emergent immune therapies for PDA...
November 2, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/28915646/interleukin-15-stimulates-natural-killer-cell-mediated-killing-of-both-human-pancreatic-cancer-and-stellate-cells
#15
Jonas R M Van Audenaerde, Jorrit De Waele, Elly Marcq, Jinthe Van Loenhout, Eva Lion, Johan M J Van den Bergh, Ralf Jesenofsky, Atsushi Masamune, Geert Roeyen, Patrick Pauwels, Filip Lardon, Marc Peeters, Evelien L J Smits
Pancreatic ductal adenocarcinoma (PDAC) is the 4(th) leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC)...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28893836/immunotherapy-against-endocrine-malignancies-immune-checkpoint-inhibitors-lead-the-way
#16
REVIEW
Lucas Leite Cunha, Marjory Alana Marcello, Vinicius Rocha-Santos, Laura Sterian Ward
Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors...
December 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28874593/egfr-exon-19-deletion-in-pancreatic-adenocarcinoma-responds-to-erlotinib-followed-by-t790m-mediated-resistance
#17
Michael Cecchini, Jeffrey Sklar, Jill Lacy
The prognosis of metastatic pancreatic cancer remains poor despite recent advances in treatment with multidrug chemotherapy regimens. Use of immune checkpoint inhibitors and molecular targeted therapies has so far been disappointing. This report describes a patient with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) whose tumor was characterized by an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR). He experienced response to erlotinib for 10 months, and then developed disease progression in association with emergence of the T790M mutation...
September 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28856392/ctla-4-cd80-pathway-regulates-t-cell-infiltration-into-pancreatic-cancer
#18
Fee Bengsch, Dawson M Knoblock, Anni Liu, Florencia McAllister, Gregory L Beatty
The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications...
December 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28826722/pd-1-pd-l1-and-immunotherapy-for-pancreatic-cancer
#19
REVIEW
Mengyu Feng, Guangbing Xiong, Zhe Cao, Gang Yang, Suli Zheng, Xujun Song, Lei You, Lianfang Zheng, Taiping Zhang, Yupei Zhao
Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer...
October 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28809532/transient-and-local-expression-of-chemokine-and-immune-checkpoint-traps-to-treat-pancreatic-cancer
#20
Lei Miao, Jingjing Li, Qi Liu, Richard Feng, Manisit Das, C Michael Lin, Tyler J Goodwin, Oleksandra Dorosheva, Rihe Liu, Leaf Huang
Pancreatic tumors are known to be resistant to immunotherapy due to the extensive immune suppressive tumor microenvironment (TME). We hypothesized that CXCL12 and PD-L1 are two key molecules controlling the immunosuppressive TME. Fusion proteins, called traps, designed to bind with these two molecules with high affinity (Kd = 4.1 and 0.22 nM, respectively) were manufactured and tested for specific binding with the targets. Plasmid DNA encoding for each trap was formulated in nanoparticles and intravenously injected to mice bearing orthotopic pancreatic cancer...
September 26, 2017: ACS Nano
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