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Pancreatic cancer immunotherapy

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https://www.readbyqxmd.com/read/29416816/comprehensive-immunotherapy-combined-with-intratumoral-injection-of-zoledronate-pulsed-dendritic-cells-intravenous-adoptive-activated-t-lymphocyte-and-gemcitabine-in-unresectable-locally-advanced-pancreatic-carcinoma-a-phase-i-ii-trial
#1
Yoshiki Hirooka, Hiroki Kawashima, Eizaburo Ohno, Takuya Ishikawa, Takashi Kamigaki, Shigenori Goto, Masashi Takahara, Hidemi Goto
Dendritic cell (DC)-based vaccines prepared using various antigen loading methods have been studied for cancer immunotherapy. The in vivo provocation of immunity by the direct injection of DCs without using tumor-specific antigens into tumors after apoptosis-inducing chemotherapy is more applicable. We previously reported that zoledronate-pulsed DCs (Zol-DCs) may induce tumor-antigen-specific CD8+ T cells by activating Vγ9γδT cells. In this report, we studied the feasibility, safety, and efficacy of a comprehensive immunotherapy involving the combined intratumoral injection of Zol-DC, gemcitabine (GEM) and αβT cells in locally advanced pancreatic carcinoma...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29409480/contrasting-roles-of-h3k4me3-and-h3k9me3-in-regulation-of-apoptosis-and-gemcitabine-resistance-in-human-pancreatic-cancer-cells
#2
Chunwan Lu, Dafeng Yang, Maria E Sabbatini, Aaron H Colby, Mark W Grinstaff, Nicholas H Oberlies, Cedric Pearce, Kebin Liu
BACKGROUND: Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor cell factors, likely the deregulated apoptosis pathway, are key mechanisms underlying PDAC non-response to these therapies, rather than the therapeutic agents themselves...
February 6, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29404962/recovery-of-immunoglobulin-vj-recombinations-from-pancreatic-cancer-exome-files-strongly-correlates-with-reduced-survival
#3
Jacob C Kinskey, Yaping N Tu, Wei Lue Tong, John M Yavorski, George Blanck
We assessed pancreatic cancer, lymphocyte infiltrates with a computational genomics approach. We took advantage of tumor-specimen exome files available from the cancer genome atlas to mine T- and B-cell immune receptor recombinations, using highly efficient, scripted algorithms established in several previous reports. Surprisingly, the results indicated that pancreatic cancer exomes represent one of the highest level yields for immune receptor recombinations, significantly higher than two comparison cancers used in this study, head and neck and bladder cancer...
February 5, 2018: Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society
https://www.readbyqxmd.com/read/29385739/precision-immuno-oncology-prospects-of-individualized-immunotherapy-for-pancreatic-cancer
#4
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/29361690/contemporary-management-of-localized-resectable-pancreatic-cancer
#5
REVIEW
Anuhya Kommalapati, Sri Harsha Tella, Gaurav Goyal, Wen Wee Ma, Amit Mahipal
Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15-20% of patients at the time of initial diagnosis. Accumulating evidence suggests that the neoadjuvant approach may improve R0 resection rate in localized resectable and borderline resectable diseases, and potentially downstage locally advanced disease to achieve surgical resection, though the impact on survival is to be determined...
January 20, 2018: Cancers
https://www.readbyqxmd.com/read/29346215/challenges-and-perspectives-for-immunotherapy-in-adenocarcinoma-of-the-pancreas-the-cancer-immunity-cycle
#6
Markus Kieler, Matthias Unseld, Daniela Bianconi, Gerald Prager
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a devastating 5-year overall survival of only approximately 7%. Although just 4% of all malignant diseases are accounted to PDAC, it will become the second leading cause of cancer-related deaths before 2030. Immunotherapy has proven to be a promising therapeutic option in various malignancies such as melanoma, non-small cell lung cancer (NSCLC), microsatellite instability-high gastrointestinal cancer, urinary tract cancer, kidney cancer, and others...
February 2018: Pancreas
https://www.readbyqxmd.com/read/29336814/inhibition-of-interleukin-10-in-the-tumor-microenvironment-can-restore-mesothelin-chimeric-antigen-receptor-t-cell-activity-in-pancreatic-cancer-in-vitro
#7
Ramesh B Batchu, Oksana V Gruzdyn, Ebrahem M Mahmud, Fatme Chukr, Rajesh Dachepalli, Santosh K Manmari, Gamal Mostafa, Donald W Weaver, Scott A Gruber
BACKGROUND: Pancreatic cancer cells are known to shield themselves from immunosurveillance by secreting immune inhibitory cytokines such as Interleukin-10. Using mesothelin, a differentiating antigen that is overexpressed in pancreatic cancer, we assessed the negative effect of the tumor microenvironment on chimeric antigen receptor T cell-based immunotherapy and its reversal via depletion of Interleukin-10. METHODS: T cells cultured in pancreatic cancer-cell-conditioned medium were transduced with lentiviruses encoding mesothelin-chimeric antigen receptor in the presence or absence of anti-Interleukin-10-blocking antibody...
January 11, 2018: Surgery
https://www.readbyqxmd.com/read/29329208/advances-in-molecular-profiling-and-categorisation-of-pancreatic-adenocarcinoma-and-the-implications-for-therapy
#8
REVIEW
Rille Pihlak, Jamie M J Weaver, Juan W Valle, Mairéad G McNamara
Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents...
January 12, 2018: Cancers
https://www.readbyqxmd.com/read/29301364/immune-evasion-in-pancreatic-cancer-from-mechanisms-to-therapy
#9
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/29288236/cd47-blockade-as-an-adjuvant-immunotherapy-for-resectable-pancreatic-cancer
#10
Alex D Michaels, Timothy E Newhook, Sara J Adair, Sho Morioka, Bernadette J Goudreau, Sarbajeet Nagdas, Matthew G Mullen, Jesse B Persily, Timothy Bullock, Craig L Slingluff, Kodi S Ravichandran, J Thomas Parsons, Todd W Bauer
PURPOSE: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. EXPERIMENTAL DESIGN: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors...
December 29, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29273547/-molecular-characterisation-defines-several-subtypes-of-pancreatic-ductal-adenocarcinoma
#11
REVIEW
Jérôme Raffenne, Jérôme Cros
Multi-omics high throughput analyses lead to the description of multiple molecular subtypes of pancreatic adenocarcinoma with major prognostic impact for most of them. There is no consensual multilevel integrative classification yet like in colon or breast cancers. Genomic classifications have identified a tumor subtype (15% of the patients) with deficient homologous DNA repair-system leading to increase sensitivity to platinum-based therapies and possibly to PARP inhibitors and immunotherapies. Transcriptomic classifications are still debated but all have identified an aggressive subtype with a very poor prognosis, presumably unfit for a surgical approach...
December 19, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29242097/emerging-trends-in-the-immunotherapy-of-pancreatic-cancer
#12
Kasturi Banerjee, Sushil Kumar, Kathleen A Ross, Shailendra Gautam, Brittany Poelaert, Mohd Wasim Nasser, Abhijit Aithal, Rakesh Bhatia, Michael J Wannemuehler, Balaji Narasimhan, Joyce C Solheim, Surinder K Batra, Maneesh Jain
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 45,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating patient's immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC...
December 11, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29221990/molecular-and-cellular-mechanisms-of-chemoresistance-in-pancreatic-cancer
#13
REVIEW
Aleksandra Adamska, Omar Elaskalani, Aikaterini Emmanouilidi, Minkyoung Kim, Norbaini Binti Abdol Razak, Pat Metharom, Marco Falasca
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most chemoresistant cancers, and current therapies targeting cancer-associated molecular pathways have not given satisfactory results, owing in part to rapid upregulation of alternative compensatory pathways. Most of the available treatments are palliative, focussing on improving the quality of life. At present, available options are surgery, embolization, radiation, chemotherapy, immunotherapy and use of other more targeted drugs. In this review, we describe the cellular and molecular effects of current chemotherapy drugs such as gemcitabine, FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and ABRAXANE (nab-Paclitaxel), which have shown a survival benefit, although modest, for pancreatic cancer patients...
November 22, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29189327/the-pancreatic-cancer-microenvironment
#14
Stephanie K Dougan
Pancreatic ductal adenocarcinoma (PDAC) is composed of a minority of malignant cells within a microenvironment of extracellular matrix, fibroblasts, endothelial cells, and immune cells. Therapeutic failures of chemotherapy, targeted therapy, and immunotherapy have all been attributed to the PDAC microenvironment. In this review, we dissect the components of the microenvironment and explain how each cell type contributes to form a highly immunosuppressive, hypoxic, and desmoplastic cancer. New efforts in single-cell profiling will enable a better understanding of the composition of the microenvironment in primary and metastatic PDAC, as well as an understanding of how the microenvironment may respond to novel therapeutic approaches...
November 2017: Cancer Journal
https://www.readbyqxmd.com/read/29180759/nano-enabled-pancreas-cancer-immunotherapy-using-immunogenic-cell-death-and-reversing-immunosuppression
#15
Jianqin Lu, Xiangsheng Liu, Yu-Pei Liao, Felix Salazar, Bingbing Sun, Wen Jiang, Chong Hyun Chang, Jinhong Jiang, Xiang Wang, Anna M Wu, Huan Meng, Andre E Nel
While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP)...
November 27, 2017: Nature Communications
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 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/29132146/identification-of-unique-neoantigen-qualities-in-long-term-survivors-of-pancreatic-cancer
#17
Vinod P Balachandran, Marta Łuksza, Julia N Zhao, Vladimir Makarov, John Alec Moral, Romain Remark, Brian Herbst, Gokce Askan, Umesh Bhanot, Yasin Senbabaoglu, Daniel K Wells, Charles Ian Ormsby Cary, Olivera Grbovic-Huezo, Marc Attiyeh, Benjamin Medina, Jennifer Zhang, Jennifer Loo, Joseph Saglimbeni, Mohsen Abu-Akeel, Roberta Zappasodi, Nadeem Riaz, Martin Smoragiewicz, Z Larkin Kelley, Olca Basturk, Mithat Gönen, Arnold J Levine, Peter J Allen, Douglas T Fearon, Miriam Merad, Sacha Gnjatic, Christine A Iacobuzio-Donahue, Jedd D Wolchok, Ronald P DeMatteo, Timothy A Chan, Benjamin D Greenbaum, Taha Merghoub, Steven D Leach
Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival...
November 23, 2017: Nature
https://www.readbyqxmd.com/read/29123084/re-designing-interleukin-12-to-enhance-its-safety-and-potential-as-an-anti-tumor-immunotherapeutic-agent
#18
Pengju Wang, Xiaozhu Li, Jiwei Wang, Dongling Gao, Yuenan Li, Haoze Li, Yongchao Chu, Zhongxian Zhang, Hongtao Liu, Guozhong Jiang, Zhenguo Cheng, Shengdian Wang, Jianzeng Dong, Baisui Feng, Louisa S Chard, Nicholas R Lemoine, Yaohe Wang
Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti-tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa)...
November 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/29119057/dendritic-cells-based-immunotherapy
#19
REVIEW
Na Shang, Matteo Figini, Junjie Shangguan, Bin Wang, Chong Sun, Liang Pan, Quanhong Ma, Zhuoli Zhang
Dendritic cells (DCs) are the most potent antigen-presenting cells, and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes (CTLs) in lymphatic tissues. DC vaccination is a newly emerging and potent form of cancer immunotherapy and has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The efficacy of DC-vaccines is strongly influenced by various techniques for the priming antigen loading onto DCs and their ability to migrate to the draining lymph nodes (LNs)...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/29115428/inhibition-of-p21-activated-kinase-enhances-tumour-immune-response-and-sensitizes-pancreatic-cancer-to-gemcitabine
#20
Kai Wang, Nhi Huynh, Xiao Wang, Graham Baldwin, Mehrdad Nikfarjam, Hong He
Pancreatic ductal adenocarcinoma (PDA) is one of the major types of cancer that exhibit high mortality worldwide because of the late diagnosis and the lack of effective treatment. Immunotherapy appears to be ineffective in PDA treatment due to the existence of a unique immune-suppressive microenvironment in PDA. Gemcitabine-based therapy is still the most commonly used chemotherapy to treat PDA patients with only marginal increased survival rates. This prompted us to continue the search for more effective therapy for PDA treatment...
November 7, 2017: International Journal of Oncology
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