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Immunotherapy Pancreatic

Manisit Das, Limei Shen, Qi Liu, Tyler J Goodwin, Leaf Huang
Local immunomodulation can be a promising strategy to augment the efficacy and decrease off-target toxicities associated with cancer treatment. Pancreatic cancer is resistant to immunotherapies due to the immunosuppressive tumor microenvironment. Herein, we investigated a therapeutic approach involving delivery of a short interfering double-stranded RNA (dsRNA), specific to Bcl2, with 5' triphosphate ends, by lipid calcium phosphate nanoparticles, in an orthotopic allograft KPC model of pancreatic cancer. Retinoic acid-inducible gene I (RIG-I)-like receptors can bind to 5' triphosphate dsRNA (ppp dsRNA), a pathogen-associated molecular pattern, producing type I interferon, while Bcl2 silencing can drive apoptosis of cancer cells...
November 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Xiangfei Yuan, Wencong Tian, Yang Hua, Lijuan Hu, Jing Yang, Junmuzi Xie, Jiacai Hu, Feng Wang
The immunosuppressive tumor microenvironment limits the application of adoptive immunotherapy for solid tumors. Hypoxia is closely associated with the formation of the immunosuppressive tumor microenvironment. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-sensitive transcriptional activator that drives the transcription of several immunosuppressive molecules. In addition, previous studies confirmed that rhein downregulated the expression of HIF-1α, a subunit of HIF-1, in pancreatic cancer cells. The present study established correlations between mRNA expression levels of HIF-1α and six immunosuppressive molecules in colorectal cancer (CRC) tissue samples...
December 2018: Experimental and Therapeutic Medicine
Tomas Zemanek, Bohuslav Melichar, Martin Lovecek, Pavel Soucek, Beatrice Mohelnikova-Duchonova
Pancreatic carcinoma is usually diagnosed late when treatment options are limited and is considered a chemo-resistant malignancy. However, early stage, good performance status and specific patient subgroup are thought to have a more favorable prognosis. Search for novel molecular biomarkers, which could predict treatment resistance, represents a major opportunity, but also a challenge in further research. This review summarizes most aspects of individualized therapy of pancreatic cancer including promising biomarkers, BRCA-deficient pancreatic cancer and its etiology...
December 12, 2018: Pharmacogenomics
S R Chandana, H M Babiker, D Mahadevan
Prognosis remains dismal for pancreatic ductal adenocarcinoma (PDAC). Genomics and proteomics has depicted heterogeneity in PDAC. Collectively, this information could be useful in improving diagnosis, prognosis, modalities of therapy, treatment responses, deciphering drug resistance and new drug development. Areas Covered: We describe major advances in the cellular and molecular subtypes based on next generation sequencing and their predictive and prognostic value in PDAC patients. We review aberrant genes involving in defined cellular processes in PDAC...
December 12, 2018: Expert Opinion on Investigational Drugs
Afreen Idris Shariff, Sohail Syed, Rebecca A Shelby, Jeremy Force, Jeffrey Melson Clarke, David D'Alessio, Leonor Corsino
Over the last decade, there has been a shift in the focus of cancer therapy from conventional cytotoxic drugs to therapies more specifically directed to cancer cells. These novel therapies include immunotherapy, targeted therapy and precision medicine, each developed in great part with a goal of limiting collateral destruction of normal tissues, while enhancing tumor destruction. Although this approach is sound in theory, even new, specific therapies have some undesirable, 'off target effects', in great part due to molecular pathways shared by neoplastic and normal cells...
February 1, 2019: Journal of Molecular Endocrinology
Y Kanjanapan, D Day, M O Butler, L Wang, A M Joshua, D Hogg, N B Leighl, A R Abdul Razak, A R Hansen, S Boujos, M Chappell, K Chow, B Sherwin, L-A Stayner, L Soultani, A Zambrana, L L Siu, P L Bedard, A Spreafico
BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs...
December 6, 2018: European Journal of Cancer
Luca G Campana, Ibrahim Edhemovic, Declan Soden, Anna M Perrone, Marco Scarpa, Laura Campanacci, Maja Cemazar, Sara Valpione, Damijan Miklavčič, Simone Mocellin, Elisabetta Sieni, Gregor Sersa
The treatment of tumors with electrochemotherapy (ECT) has surged over the past decade. Thanks to the transient cell membrane permeabilization induced by the short electric pulses used by ECT, cancer cells are exposed to otherwise poorly permeant chemotherapy agents, with consequent increased cytotoxicity. The codification of the procedure in 2006 led to a broad diffusion of the procedure, mainly in Europe, and since then, the progressive clinical experience, together with the emerging technologies, have extended the range of its application...
December 1, 2018: European Journal of Surgical Oncology
Qianqian Ni, Ngoc B Pham, Wilson S Meng, Guizhi Zhu, Xiaoyuan Chen
Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of pancreatic β cells, the source of glucose regulator insulin. While T1DM can be successfully managed with insulin replacement therapy, approaches that can modify the underlying immuno-pathology of β cell destruction has been long sought after. Immunotherapy can attenuate T cell responses against β cell antigens. Given the detailed cellular and molecular definitions of T1DM immune responses, rational immunomodulation can be and have been developed in mouse models, and in some instances, tested in humans...
December 6, 2018: Advanced Drug Delivery Reviews
Jaemin Lee, Tae Heung Kang, Wonbeak Yoo, Hyunji Choi, Seongyea Jo, Kyungsu Kong, Sang-Rae Lee, Sun-Uk Kim, Ji-Su Kim, Duck Cho, Janghwan Kim, Jeong-Yoon Kim, Eun-Soo Kwon, Seokho Kim
Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer (PC). Despite their usefulness, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK cell-homing protein, named NK cell-recruiting protein-conjugated antibody (NRP-body)...
December 4, 2018: Cancer Immunology Research
Junaid Raja, Johannes M Ludwig, Scott N Gettinger, Kurt A Schalper, Hyun S Kim
BACKGROUND: Immunotherapy is at the forefront of modern oncologic care. Various novel therapies have targeted all three layers of tumor biology: tumor, niche, and immune system with a range of promising results. One emerging class in both primary and salvage therapy is oncolytic viruses. This therapy offers a multimodal approach to specifically and effectively target and destroy malignant cells, though a barrier oncoviral therapies have faced is a limited therapeutic response to currently delivery techniques...
December 4, 2018: Journal for Immunotherapy of Cancer
Michael H Gerber, Patrick W Underwood, Sarah M Judge, Daniel Delitto, Andrea E Delitto, Rachel L Nosacka, Bayli B DiVita, Ryan M Thomas, Jennifer B Permuth, Steven J Hughes, Shannon M Wallet, Andrew R Judge, Jose G Trevino
Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed...
December 1, 2018: International Journal of Molecular Sciences
Javed Mahmood, Hem D Shukla, Sandrine Soman, Santanu Samanta, Prerna Singh, Shriya Kamlapurkar, Ali Saeed, Neha P Amin, Zeljko Vujaskovic
Pancreatic cancer (PC) has the highest mortality rate amongst all other cancers in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of 8% for all stages of PC combined. The Whipple procedure, or pancreaticoduodenectomy, can increase survival for patients with resectable PC, however, less than 20% of patients are candidates for surgery at time of presentation. Most of the patients are diagnosed with advanced PC, often with regional and distant metastasis...
November 28, 2018: Cancers
Aaron M Miller, Milad Bahmanof, Dietmar Zehn, Ezra E W Cohen, Stephen P Schoenberger
Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors, but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas...
November 27, 2018: Cancer Immunology Research
Helena Verdaguer, Alvaro Arroyo, Teresa Macarulla
Only a limited number of therapeutic strategies are available for patients diagnosed with pancreatic adenocarcinoma, and disease recurrence and mortality are consequently high. For metastatic disease, two combinations are approved in the first line setting: a triplet with 5-fluoruracil, irinotecan, and oxaliplatin, and the combination of gemcitabine and nab-paclitaxel. In patients who have progressed on gemcitabine, a new nanoliposomal formulation of irinotecan has recently been approved. While these treatments have demonstrated some efficacy, there has been little increase in survival rates for metastatic pancreatic cancer patients...
November 23, 2018: Targeted Oncology
Xiuyun Jiang, Y David Seo, Kevin M Sullivan, Venu G Pillarisetty
Although immunotherapy is currently being widely applied to treat a variety of cancers, there is great heterogeneity in the response to these treatments. Many in the field hypothesize that this may be attributable to the characteristics of each individual tumor immune microenvironment, in addition to systemic immune factors. Therefore, understanding the immune cell microenvironment in a variety of tumors is critically important. Specifically, the interactions among immune, stromal, and cancer cells, along with other factors in tumors, may hold the key to developing rational personalized combinations of immunotherapeutic drugs...
2019: Methods in Molecular Biology
Mirna Perusina Lanfranca, Jenny Lazarus, Xia Shao, Hari Nathan, Marina Pasca Di Magliano, Weiping Zou, Morand Piert, Timothy L Frankel
BACKGROUND: The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contains abundant immunosuppressive tumor-associated macrophages. High level of infiltration is associated with poor outcome and is thought to represent a major roadblock to lymphocyte-based immunotherapy. Efforts to block macrophage infiltration have been met with some success, but noninvasive means to track tumor-associated macrophagess in PDAC are lacking. Translocator protein (TSPO) is a mitochondrial membrane receptor which is upregulated in activated macrophages...
December 2018: Journal of Surgical Research
Huiyun Zhu, Tuo Li, Yiqi Du, Min Li
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, with increasing incidence. The mortality rate of pancreatic cancer is rising rapidly, and is projected to be the second most common of all malignant tumors by 2030. However, the diagnosis and therapy of pancreatic cancer remain a formidable challenge. Recently, enormous efforts have been made to develop several new methods for the early diagnosis and treatment of pancreatic cancer. We briefly introduce the most groundbreaking advances in pancreatic cancer diagnosis and clinical treatment strategies over the past 15 years, including surgery, chemotherapy, endoscopic therapy, immunotherapy and personalized medicine...
November 22, 2018: BMC Medicine
Zishuo Ian Hu, Matthew D Hellmann, Jedd D Wolchok, Monika Vyas, Jinru Shia, Zsofia K Stadler, Luis A Diaz, Eileen M O'Reilly
BACKGROUND: MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer. CASE PRESENTATION: A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9...
November 20, 2018: Journal for Immunotherapy of Cancer
Eseosaserea Igbinigie, Fengbiao Guo, Shi-Wen Jiang, Cullen Kelley, Jinping Li
Dickkopf-1 (Dkk1)'s dysregulation has been implicated in the pathogenesis of a variety of cancers. It is part of the Dkk family of proteins that includes Dkk2, Dkk3 and Dkk4. This family of secreted proteins shares similar conserved cysteine domains and inhibits the Wnt/b-catenin pathway by causing proteasomal B-catenin degradation, inducing apoptosis, and preventing cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer mortality in the United States due to the late stage of diagnosis and the limited effectiveness of current therapy...
November 16, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Elaine Tan, Bassel El-Rayes
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most aggressive and lethal diseases in the world. The success of immunotherapy in other types of malignancy has led to further trials to understand better the role of immunotherapy in PDAC. However, initial studies with immunotherapy, namely, the checkpoint inhibitors, in PDAC have not been met with the same outcomes. The purpose of this review is to identify and discuss the various resistance mechanisms of PDAC to immunotherapy (pancreatic stroma, genetic predisposition/epigenetics, and the immune inhibitory cells, cytokines, soluble factors, and enzymes that comprise the tumor microenvironment) and the solutions currently being studied to overcome them...
November 17, 2018: Journal of Gastrointestinal Cancer
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