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Immunotherapy Pancreatic

Angus G Dalgleish, Satvinder Mudan, Alberto Fusi
BACKGROUND: The use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) has revolutionised the treatment of metastatic melanoma. However still more than the half the patients do not respond to single-agent immunotherapy. This has led to the development of combining these agents in an attempt to enhance the anti-cancer activity. More than 300 different studies with 15 different drug doses are currently ongoing. Combining different checkpoint inhibitors (CPIs) does indeed lead to an increase in response rate, but this is associated with significant toxicity...
August 14, 2018: Journal of Translational Medicine
Chiara Oltolini, Marco Ripa, Andrea Andolina, Elena Brioschi, Marta Cilla, Giovanna Petrella, Vanesa Gregorc, Barbara Castiglioni, Chiara Tassan Din, Paolo Scarpellini
The widespread use of T lymphocyte-associated antigen-4 (CTLA-4) and programmed death (PD)-1 and PD ligand-1 (PDL1)-targeted agents in cancer patients as immunotherapy has raised some issues on their safety profile. Regarding infectious complications, it has emerged that these compounds do not intrinsically increase susceptibility to opportunistic infections, which mainly correlate with the co-administration of systemic immunosuppressive therapy (high-dose corticosteroids and anti-tumor necrosis factors inhibitors) to cure immune-related adverse events (colitis, hepatitis, pneumonitis and pancreatitis), well-known complications of these targeted drugs...
August 13, 2018: Mycopathologia
Anahid Jewett, Janko Kos, Yuman Fong, Meng-Wei Ko, Tahmineh Safaei, Milica Perišić Nanut, Kawaljit Kaur
We have recently shown that natural killer (NK) cells select and differentiate cancer stem cells (CSCs)/undifferentiated tumors via secreted and membrane bound IFN-gamma (IFN-γ) and TNF-alpha (TNF-α), preventing tumor growth and inducing remodeling of the tumor microenvironment. Since many conventional therapeutic strategies, including chemotherapy and radiotherapy remain fairly unsuccessful in treating CSCs/poorly differentiated tumors, there has been an increasing interest in NK cell-targeted immunotherapy for the treatment of aggressive tumors...
August 3, 2018: Seminars in Cancer Biology
Bo Ren, Ming Cui, Gang Yang, Huanyu Wang, Mengyu Feng, Lei You, Yupei Zhao
Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis...
July 30, 2018: Molecular Cancer
Naihan Chen, Charles J Kroger, Roland M Tisch, Eric M Bachelder, Kristy M Ainslie
Type 1 diabetes (T1D) is a common autoimmune disease with no cure. T1D subjects are dependent on daily exogenous insulin administration, due to the loss of functional insulin-producing β cells. Needed are immunotherapies that prevent and/or treat T1D. One approach of immunotherapy is to administer an autoantigen to selectively tolerize diabetogenic effector T cells without global immunosuppression. To date, however, strategies of antigen-specific immunotherapy are largely ineffective in the clinic. Using an antigen-specific approach, a biodegradable polymeric delivery vehicle, acetalated dextran microparticles (Ace-DEX MPs), is applied and T1D development is prevented through coadministration of the immunosuppressant rapamycin and the diabetogenic peptide P31 (Rapa/P31/MPs), via alterations of both innate and adaptive immunity...
July 26, 2018: Advanced Healthcare Materials
Vinod Nadella, Sandhya Singh, Aklank Jain, Manju Jain, Karen M Vasquez, Ashok Sharma, Pranay Tanwar, Goura Kishore Rath, Hridayesh Prakash
Solid tumors are covered by stroma, which is hypoxic in nature and composed of various non-malignant components such as endothelial cells, fibroblasts, and pericytes that support tumor growth. Tumor stroma represents a mechanical barrier for tumor infiltration of CD8+ effector T cells in particular. In this context, our previous studies have demonstrated the therapeutic impact of Low-Dose Radiation (LDR)-primed and M1-retuned (iNOS+) peritumoral macrophages that produce inducible nitric oxide, have immunological roles on tumor infiltration of effector T cells, cancer-related inflammation, and subsequent tumor immune rejection in a mouse model of pancreatic cancer...
July 23, 2018: Molecular Carcinogenesis
Erin M Wesley, Gang Xin, Donna McAllister, Subramaniam Malarkannan, Debra K Newman, Michael B Dwinell, Weiguo Cui, Bryon D Johnson, Matthew J Riese
Targeting negative regulators downstream of the T cell receptor (TCR) represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase ζ (DGKζ), a regulator of Ras and PKC-θ signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKζ, Cbl-b, or both (double knockout, DKO) in T cells, and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model...
April 1, 2018: ImmunoHorizons
Mayura V Wagle, Julia M Marchingo, Jason Howitt, Seong-Seng Tan, Christopher C Goodnow, Ian A Parish
Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice...
July 17, 2018: Cell Reports
Brendan Horton, Stefani Spranger
Pancreatic adenocarcinoma (PDAC) is mostly refractory to immunotherapies. In this issue of Immunity, Li et al. (2018) generate a library of clonal PDAC tumors to examine the tumor-intrinsic features shaping the anti-tumor immune response and find that tumor cell-derived CXCL1 directly blunts T cell infiltration and reduces responsiveness to immunotherapy.
July 17, 2018: Immunity
Walter Alexander
We report on sessions on immunotherapies for non-small-cell lung cancer and pancreatic cancer from AACR and on endometriosis, hypoactive sexual desire disorder, neonatal abstinence syndrome, and more from ACOG.
July 2018: P & T: a Peer-reviewed Journal for Formulary Management
Robert J Torphy, Yuwen Zhu, Richard D Schulick
Immunotherapy is a rapidly growing field and represents a paradigm shift in the treatment of malignancies as it offers a new therapeutic approach beyond surgery, conventional chemotherapy, and radiation treatment. Targeting immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 and programmed death 1/programmed death ligand 1 has had immense clinical success resulting in sustained treatment response for a subset of patients with certain malignancies such as melanoma, non-small-cell lung cancer, urothelial carcinoma, squamous cell carcinoma of the head and neck, renal cell cancer, hepatocellular cancer, and metastatic colorectal cancer...
July 2018: Annals of gastroenterological surgery
Livia Archibugi, Marianna Signoretti, Gabriele Capurso
Many risk factors for pancreatic cancer are related with microbiome alteration. In the past few years, the human microbiome and its relation with the immune system have been linked with carcinogenesis of different organs distant from the gut, including the pancreas. Patterns of oral microbiome associated with periodontitis are associated with an increased risk of pancreatic cancer, possibly because of the increased systemic inflammatory response, or to the capacity of some specific bacteria to alter the host immune response, making it more favorable to cancer cells...
July 11, 2018: Journal of Clinical Gastroenterology
Alexander C Hopkins, Mark Yarchoan, Jennifer N Durham, Erik C Yusko, Julie A Rytlewski, Harlan S Robins, Daniel A Laheru, Dung T Le, Eric R Lutz, Elizabeth M Jaffee
BACKGROUND: Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes. METHODS: We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab...
July 12, 2018: JCI Insight
Bhalchandra Mirlekar, Daniel Michaud, Ryan Searcy, Kevin Greene, Yuliya Pylayeva-Gupta
Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced...
July 6, 2018: Cancer Immunology Research
Christopher Kopan, Tori Tucker, Michael Alexander, M Rezaa Mohammadi, Egest J Pone, Jonathan Robert Todd Lakey
Recent advances on using immune and stem cells as two-pronged approaches for type 1 diabetes mellitus (T1DM) treatment show promise for advancement into clinical practice. As T1DM is thought to arise from autoimmune attack destroying pancreatic β-cells, increasing treatments that use biologics and cells to manipulate the immune system are achieving better results in pre-clinical and clinical studies. Increasingly, focus has shifted from small molecule drugs that suppress the immune system nonspecifically to more complex biologics that show enhanced efficacy due to their selectivity for specific types of immune cells...
2018: Frontiers in Immunology
Jinyang Li, Katelyn T Byrne, Fangxue Yan, Taiji Yamazoe, Zeyu Chen, Timour Baslan, Lee P Richman, Jeffrey H Lin, Yu H Sun, Andrew J Rech, David Balli, Ceire A Hay, Yogev Sela, Allyson J Merrell, Shannon M Liudahl, Naomi Gordon, Robert J Norgard, Salina Yuan, Sixiang Yu, Timothy Chao, Shuai Ye, T S Karin Eisinger-Mathason, Robert B Faryabi, John W Tobias, Scott W Lowe, Lisa M Coussens, E John Wherry, Robert H Vonderheide, Ben Z Stanger
The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets...
July 17, 2018: Immunity
Bharti Garg, Bhuwan Giri, Shrey Modi, Vrishketan Sethi, Iris Castro, Oliver Umland, Yuguang Ban, Shweta Lavania, Rajinder Dawra, Sulagna Banerjee, Selwyn Vickers, Nipun B Merchant, Steven Xi Chen, Eli Gilboa, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja
BACKGROUND & AIMS: Immunotherapies are ineffective against pancreatic cancer. We investigated whether the activity of nuclear factor (NF)κB in pancreatic stromal cells contributes to an environment that suppresses antitumor immune response. METHODS: Pancreata of C57BL/6 or Rag1-/- mice were given pancreatic injections of a combination of KrasG12D/+ ; Trp53 R172H/+ ; Pdx-1cre (KPC) pancreatic cancer cells and pancreatic stellate cells (PSCs) extracted from C57BL/6 (control) or mice with disruption of the gene encoding the NFκB p50 subunit (Nfkb1 or p50-/- mice)...
July 28, 2018: Gastroenterology
Brooke N McKnight, Akhila N W Kuda-Wedagedara, Kuntal K Sevak, Dalya Abdel-Atti, Wendy N Wiesend, Anson Ku, Dakshnamurthy Selvakumar, Sean D Carlin, Jason S Lewis, Nerissa T Viola-Villegas
Tumor resistance to treatment paved the way toward the development of single agent drugs that target multiple molecular signatures amplified within the malignancy. The discovered crosstalk between EGFR and HER3 as well as the role of HER3 in mediating EGFR resistance made these two receptor tyrosine kinases attractive targets. MEHD7945A or duligotuzumab is a single immunotherapy agent that dually targets both molecular signatures. In this study, a positron emission tomography (PET) companion diagnostic to MEHD7945A is reported and evaluated in pancreatic cancer...
June 13, 2018: Scientific Reports
Adrian M J Pokorny, Venessa T Chin, Adnan M Nagrial, Desmond Yip, Lorraine A Chantrill
Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5-year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental...
June 2018: Internal Medicine Journal
Andrea Boni, Giovanni Cochetti, Stefano Ascani, Michele Del Zingaro, Francesca Quadrini, Alessio Paladini, Diego Cocca, Ettore Mearini
BACKGROUND: The management of metastatic Renal Cell Carcinoma (RCC) has changed dramatically in the last 20 years, and the role of surgery in the immunotherapy's era is under debate. Metastatic lesions interesting pancreas are infrequent, but those harbouring from RCC have an high incidence. If metachronous resections are not rare, synchronous resection of primary RCC and its pancreatic metastasis is uncommonly reported, and accounts for a bad prognosis. CASE PRESENTATION: We report the case of a 68 years old woman, who presented hematuria at hospital incoming, with radiological appearance of a 13 cm left renal mass, with a 2...
June 13, 2018: BMC Surgery
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