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Immunotherapy Pancreatic

Vrishketan Sethi, Gerardo A Vitiello, Deepak Saxena, George Miller, Vikas Dudeja
Our understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The "germ theory of cancer" was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori and later, Fusobacterium nucleatum were implicated in the development of gastric and colorectal cancers respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome-cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described...
February 12, 2019: Gastroenterology
Hongwei Du, Koichi Hirabayashi, Sarah Ahn, Nancy Porterfield Kren, Stephanie Ann Montgomery, Xinhui Wang, Karthik Tiruthani, Bhalchandra Mirlekar, Daniel Michaud, Kevin Greene, Silvia Gabriela Herrera, Yang Xu, Chuang Sun, Yuhui Chen, Xingcong Ma, Cristina Rosa Ferrone, Yuliya Pylayeva-Gupta, Jen Jen Yeh, Rihe Liu, Barbara Savoldo, Soldano Ferrone, Gianpietro Dotti
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3...
February 11, 2019: Cancer Cell
Thuy B Tran, Vijay K Maker, Ajay V Maker
BACKGROUND: Adjuvant immunotherapy has improved outcomes in patients with advanced melanoma; however, the potential benefit for patients with pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study is to determine the impact of adjuvant chemotherapy and immunotherapy (CTx-IT) compared to CTx alone on patient survival following resection of PDAC. STUDY DESIGN: Patients who underwent resection of PDAC from 2004 to 2015 were identified from the National Cancer Database (NCDB)...
February 8, 2019: Journal of the American College of Surgeons
Jing Liu, Wenna Jiang, Kaili Zhao, Hongwei Wang, Tianxing Zhou, Weiwei Bai, Xiuchao Wang, Tiansuo Zhao, Chongbiao Huang, Song Gao, Tai Qin, Wenwen Yu, Bo Yang, Xin Li, Danqi Fu, Wei Tan, Shengyu Yang, He Ren, Jihui Hao
Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells...
February 7, 2019: Journal of Experimental Medicine
Ines A Batista, Sonia A Melo
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, associated with a late diagnosis and a five-year survival rate of 8%. Currently available treatments fall short in improving the survival and quality of life of PDAC patients. The only possible curative option is still the surgical resection of the tumor. Exosomes are extracellular vesicles secreted by cells that transport proteins, lipids, and nucleic acids to other cells, triggering phenotypic changes in the recipient cells. Tumor cells often secrete increased amounts of exosomes...
January 29, 2019: International Journal of Molecular Sciences
Ligia I Bastea, Geou-Yarh Liou, Veethika Pandey, Alicia K Fleming, Christina A Von Roemeling, Heike Doeppler, Zhimin Li, Yushi Qiu, Brandy Edenfield, John A Copland, Han W Tun, Peter Storz
During development of pancreatic cancer, alternatively-activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively-activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4 (IRF4), a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively-activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL-1α and presence of activated (IFNγ positive) CD4+ and CD8+ T cell populations...
January 29, 2019: Cancer Research
Mengjie Zhang, Jiali Yang, Jian Zhou, Weiwu Gao, Yi Zhang, Yuxin Lin, Huaizhi Wang, Zhihua Ruan, Bing Ni
Programmed death-1 (PD-1), a key immune checkpoint molecule, has been developed as an oncotherapy target for various carcinomas. However, treatment with anti-PD-1 elicited only a minimal effect in pancreatic ductal adenocarcinoma (PDAC). Subsequent studies revealed the existence of a subset of PD-1+ T cells coexpressing CD38 and CD101, representing a fixed dysfunctional subpopulation that are not able to be rescued by anti-PD-1 immunotherapy. However, whether this subpopulation of PD-1 expressing CD8+ T cells could be useful in predicting PDAC stage or prognosing survival is unknown...
January 28, 2019: Immunological Investigations
Nikhil Yegya-Raman, Mihir M Shah, Miral S Grandhi, Elizabeth Poplin, David A August, Timothy J Kennedy, Usha Malhotra, Kristen R Spencer, Darren R Carpizo, Salma K Jabbour
Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials...
August 2018: Annals of pancreatic cancer
Scott A Soefje
Pancreatic cancer is typically diagnosed in the late stage of the disease, making it the fourth leading cause of cancer-related death in the United States. It is also one of the few cancers with an increasing incidence, particularly in the younger population. By 2030, it is expected to become the second leading cause of cancer-related death. Patients with pancreatic cancer encounter monthly medical costs 15 times higher than those without, with costs highest in the later stages of the disease. Treatments for pancreatic cancer include surgery (available to fewer than 20% of newly diagnosed patients) and, for advanced disease, chemotherapy with gemcitabine with nab-paclitaxel or FOLFIRINOX, which can increase overall survival (OS) by a few months...
January 2019: American Journal of Managed Care
Guofu Hu, Nan He, Chuanqi Cai, Fei Cai, Ping Fan, Zhikun Zheng, Xin Jin
Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths worldwide. Despite immune checkpoints based immunotherapy highlights a new therapeutic strategy and achieves a remarkable therapeutic effect in various types of malignant tumors. Pancreatic cancer is one of the non-immunogenic cancers and is resistant to immunotherapy. Programmed death ligand 1 (PD-L1) is expressed on the surface of tumor cells and its level is a key determinant of the checkpoint immunotherapy efficacy...
January 16, 2019: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Jingyuan Zhao, Zibo Meng, Chao Xie, Chong Yang, Zhiqiang Liu, Shihong Wu, Bo Wang, Ping Fan, Xin Jin, Heshui Wu
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. PDAC is resistant to chemotherapy and radiotherapy which leads to the poor prognosis of PDAC patients and a 5-year survival rate of less than 5%. Exploring the mechanism of the pancreatic cancer tumorigenesis is the key to finding a novel therapeutic strategy for cancer treatment. B7-H3 belongs to the B7 family of immunoregulatory proteins, and the overexpression of B7-H3 is found in various types of cancer. The regulation of B7-H3 expression in pancreatic cancer is still unclear...
January 18, 2019: International Journal of Biochemistry & Cell Biology
Vinod P Balachandran, Gregory L Beatty, Stephanie K Dougan
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer in the US by 2025 1 , with 5-year survival at less than 10% 2 . In other recalcitrant cancers, immunotherapy has shown unprecedented response rates, including durable remissions after drug discontinuation. However, responses to immunotherapy in PDAC are rare. Accumulating evidence in mice and humans suggests that this remarkable resistance is linked to the complex, dueling role of the immune system in simultaneously promoting and restraining PDAC...
January 17, 2019: Gastroenterology
Ying Hu, Wanzhen Chen, Zhanpeng Yan, Jingxia Ma, Fangshi Zhu, Jiege Huo
BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression was reported to be associated with poor prognosis in various solid tumors. However, the prognosis value of PD-L1 in pancreatic cancer remained inconclusive. We performed a meta-analysis to assess the clinical value of PD-L1 as a novel prognostic biomarker of pancreatic cancer. METHODS: PubMed, Embase, and Web of Science were searched up to October 2018. The HRs and 95% CIs for overall survival (OS) and cancer-specific survival (CSS) according to the expressional status of PD-L1 were pooled...
January 2019: Medicine (Baltimore)
Marsha Pellegrino, Antonino Crinò, Manuela M Rosado, Alessandra Fierabracci
Type 1 diabetes is an autoimmune disease where autoreactive T lymphocytes destroy pancreatic beta cells. We previously reported a defect in CD4+ Tregs cell proliferation and reduced CD4+ Tregs PD-1 expression in patients. Another 'memory-like' regulatory subset, CD8+ Tregs, evaluated as CD8+CD25+FOXP3+, has recently raised interest for their effective suppressive activity. Different CD8+ T cell populations, their proliferation capacity and expression of PD-1 molecule were evaluated by flow-cytometer analysis in newly diagnosed, long-term Type 1 diabetes patients compared to healthy normal donors...
2019: PloS One
Hayley S Ma, Bibhav Poudel, Evanthia T Roussos Torres, John-William Sidhom, Tara M Robinson, Brian J Christmas, Blake A Scott, Kayla A Cruz, Skylar Woolman, Valerie Z Wall, Todd D Armstrong, Elizabeth M Jaffee
In cancers with tumor infiltrating lymphocytes (TIL), monoclonal antibodies (mAbs) that block immune checkpoints such as CTLA-4 and PD-1/PD-L1 promote antitumor T cell immunity. Unfortunately most cancers fail to respond to single agent immunotherapies. T regulatory cells, myeloid derived suppressor cells (MDSCs), and extensive stromal networks within the tumor microenvironment (TME) dampen antitumor immune responses by preventing T-cell infiltration and/or activation. Few studies have explored combinations of immune checkpoint antibodies that target multiple suppressive cell populations within the TME, and fewer have studied the combinations of both agonist and antagonist mAbs on changes within the TME...
January 14, 2019: Cancer Immunology Research
Jiahong Jiang, Huaixiang Zhou, Chao Ni, Xiaoge Hu, Yiping Mou, Dongsheng Huang, Liu Yang
Pancreatic cancer (PC), one of the most lethal diseases, remains a challenging problem. Novel cancer therapy targeting the immune system has been explored. Although immunotherapy has yielded a favorable response in pre-clinical models, no significant improvement has been confirmed in clinical trials for PC. This may be partly attributable to the unique immunosuppressive tumor microenvironment of PC. Studies focusing on combination therapy showed the ability to break the immunosuppressive tumor microenvironment and enhance the immune response, which can translate to clinical benefits...
January 11, 2019: Cancer Letters
Michel Ducreux, Thomas Seufferlein, Jean-Luc Van Laethem, Pierre Laurent-Puig, Cristina Smolenschi, David Malka, Valérie Boige, Antoine Hollebecque, Thierry Conroy
Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%...
December 27, 2018: Seminars in Oncology
Jia-Wei Lv, Zi-Qi Zheng, Zi-Xian Wang, Guan-Qun Zhou, Lei Chen, Yan-Ping Mao, Ai-Hua Lin, Russel J Reiter, Jun Ma, Yu-Pei Chen, Ying Sun
We performed comprehensive genomic analyses of the melatonergic system within the tumor microenvironment and their clinical relevance across a broad spectrum of solid tumors. RNA-seq data from The Cancer Genome Atlas (TCGA) of 14 solid tumors representing 6,658 human samples were analyzed. The tumor melatonergic system was characterised by the rates of melatonin synthesis and metabolism using a two-gene expression model (melatonin synthesis/metabolism index). We calculated three indexes according to different melatonin metabolism isoenzymes (Index-I [ASMT:CYP1A1], Index-II [ASMT:CYP1A2], and Index-III [ASMT:CYP1B1])...
January 14, 2019: Journal of Pineal Research
Jorge Blando, Anu Sharma, Maria Gisela Higa, Hao Zhao, Luis Vence, Shalini S Yadav, Jiseong Kim, Alejandro M Sepulveda, Michael Sharp, Anirban Maitra, Jennifer Wargo, Michael Tetzlaff, Russell Broaddus, Matthew H G Katz, Gauri R Varadhachary, Michael Overman, Huamin Wang, Cassian Yee, Chantale Bernatchez, Christine Iacobuzio-Donahue, Sreyashi Basu, James P Allison, Padmanee Sharma
Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67)...
January 11, 2019: Proceedings of the National Academy of Sciences of the United States of America
Zhongshi Zhou, Hongdan Chen, Rui Xie, Hongjie Wang, Senlin Li, Qianqian Xu, Na Xu, Qi Cheng, Ying Qian, Rongrong Huang, Zekun Shao, Ming Xiang
Forkhead box transcription factor M1 (FOXM1) is a proliferation-associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor-specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow-derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer...
January 9, 2019: Molecular Oncology
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