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Pancreatic Neoplasms: HELP
Articles from Miscellaneous institutions in Gaithersburg
Based on 6 articles published since 2008

These are the 6 published articles about Pancreatic Neoplasms that originated from Miscellaneous institutions in Gaithersburg during 2008-2019.
+ Citations + Abstracts
1 Article Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model. 2016

Luheshi, Nadia M / Coates-Ulrichsen, Jane / Harper, James / Mullins, Stefanie / Sulikowski, Michal G / Martin, Philip / Brown, Lee / Lewis, Arthur / Davies, Gareth / Morrow, Michelle / Wilkinson, Robert W. ·MedImmune Ltd., Cambridge CB21 6GH, UK. · MedImmune LLC., Gaithersburg, MD 20878, USA. ·Oncotarget · Pubmed #26918344.

ABSTRACT: Despite the availability of recently developed chemotherapy regimens, survival times for pancreatic cancer patients remain poor. These patients also respond poorly to immune checkpoint blockade therapies (anti-CTLA-4, anti-PD-L1, anti-PD-1), which suggests the presence of additional immunosuppressive mechanisms in the pancreatic tumour microenvironment (TME). CD40 agonist antibodies (αCD40) promote antigen presenting cell (APC) maturation and enhance macrophage tumouricidal activity, and may therefore alter the pancreatic TME to increase sensitivity to immune checkpoint blockade. Here, we test whether αCD40 transforms the TME in a mouse syngeneic orthotopic model of pancreatic cancer, to increase sensitivity to PD-L1 blockade. We found that whilst mice bearing orthotopic Pan02 tumours responded poorly to PD-L1 blockade, αCD40 improved overall survival. αCD40 transformed the TME, upregulating Th1 chemokines, increasing cytotoxic T cell infiltration and promoting formation of an immune cell-rich capsule separating the tumour from the normal pancreas. Furthermore, αCD40 drove systemic APC maturation, memory T cell expansion, and upregulated tumour and systemic PD-L1 expression. Combining αCD40 with PD-L1 blockade enhanced anti-tumour immunity and improved overall survival versus either monotherapy. These data provide further support for the potential of combining αCD40 with immune checkpoint blockade to promote anti-tumour immunity in pancreatic cancer.

2 Article Development of a Trispecific Antibody Designed to Simultaneously and Efficiently Target Three Different Antigens on Tumor Cells. 2015

Dimasi, Nazzareno / Fleming, Ryan / Hay, Carl / Woods, Rob / Xu, Linda / Wu, Herren / Gao, Changshou. ·Antibody Discovery and Protein Engineering and ‡Oncology Research, MedImmune , Gaithersburg, Maryland 20878, United States. ·Mol Pharm · Pubmed #26176328.

ABSTRACT: Targeting Eph (erythropoietin producing hepatoma) receptors with monoclonal antibodies is being explored as therapy for several types of cancer. To test whether simultaneous targeting of EphA2, EphA4, and EphB4 would be an effective approach to cancer therapy, we generated a recombinant trispecific antibody using the variable domain genes of anti-EphA2, anti-EphA4, and anti-EphB4 monoclonal antibodies. A multidisciplinary approach combining biochemical, biophysical, and cellular-based assays was used to characterize the trispecific antibody in vitro and in vivo. Here we demonstrate that the trispecific antibody is expressed at high levels by mammalian cells, monodispersed in solution, thermostable, capable of simultaneously binding the three receptors, and able to activate the three targets effectively as evidenced by receptor internalization and degradation both in vitro and in vivo. Furthermore, pharmacokinetic analysis using tumor-bearing nude mice showed that the trispecific antibody remains in the circulation similarly to its respective parental antibodies. These results indicate that simultaneous blockade of EphA2, EphA4, and EphB4 could be an attractive approach to cancer therapy.

3 Article In Vivo Loss of Function Screening Reveals Carbonic Anhydrase IX as a Key Modulator of Tumor Initiating Potential in Primary Pancreatic Tumors. 2015

Pore, Nabendu / Jalla, Sanjoo / Liu, Zheng / Higgs, Brandon / Sorio, Claudio / Scarpa, Aldo / Hollingsworth, Robert / Tice, David A / Michelotti, Emil. ·MedImmune, LLC, Gaithersburg, MD, USA. Electronic address: poren@medimmune.com. · MedImmune, LLC, Gaithersburg, MD, USA. · ARC-NET Research Centre and Department of Pathology and Diagnostics, University of Verona Medical School, Verona, Italy. · MedImmune, LLC, Gaithersburg, MD, USA. Electronic address: Michelottie@medimmune.com. ·Neoplasia · Pubmed #26152355.

ABSTRACT: Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs) targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX), monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT) were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model.

4 Article Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody. 2015

Stewart, Ross / Morrow, Michelle / Hammond, Scott A / Mulgrew, Kathy / Marcus, Danielle / Poon, Edmund / Watkins, Amanda / Mullins, Stefanie / Chodorge, Matthieu / Andrews, John / Bannister, David / Dick, Emily / Crawford, Nicola / Parmentier, Julie / Alimzhanov, Marat / Babcook, John S / Foltz, Ian N / Buchanan, Andrew / Bedian, Vahe / Wilkinson, Robert W / McCourt, Matthew. ·MedImmune Ltd, Cambridge, United Kingdom. StewartR@medimmune.com. · MedImmune Ltd, Cambridge, United Kingdom. · MedImmune LLC, Gaithersburg, Maryland. · Abbvie Inc, Worcester, Massachusetts. Previously AstraZeneca Ltd. · Acceleron Pharma, Inc, Cambridge, Massachusetts. Previously Astrazeneca Ltd. · CDRD, University of British Columbia, Vancouver, British Columbia, Canada. Previously Amgen Inc. · Amgen Inc, Burnaby, British Columbia, Canada. · AstraZeneca Ltd, Waltham, Massachusetts. · Kymab Ltd, The Bennet Building, Babraham Research Campus, Cambridge, United Kingdom. Previously MedImmune Ltd. ·Cancer Immunol Res · Pubmed #25943534.

ABSTRACT: Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.

5 Article Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. 2014

Rigamonti, Nicolò / Kadioglu, Ece / Keklikoglou, Ioanna / Wyser Rmili, Céline / Leow, Ching Ching / De Palma, Michele. ·Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. · Translational Medicine Oncology, MedImmune, Gaithersburg, MD 20878, USA. · Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: michele.depalma@epfl.ch. ·Cell Rep · Pubmed #25088418.

ABSTRACT: Angiopoietin-2 (ANG2/ANGPT2) is a context-dependent TIE2 receptor agonist/antagonist and proangiogenic factor. Although ANG2 neutralization improves tumor angiogenesis and growth inhibition by vascular endothelial growth factor (VEGF)-A signaling blockade, the mechanistic underpinnings of such therapeutic benefits remain poorly explored. We employed late-stage RIP1-Tag2 pancreatic neuroendocrine tumors (PNETs) and MMTV-PyMT mammary adenocarcinomas, which develop resistance to VEGF receptor 2 (VEGFR2) blockade. We found that VEGFR2 inhibition upregulated ANG2 and vascular TIE2 and enhanced infiltration by TIE2-expressing macrophages in the PNETs. Dual ANG2/VEGFR2 blockade suppressed revascularization and progression in most of the PNETs, whereas it had only minor additive effects in the mammary tumors, which did not upregulate ANG2 upon VEGFR2 inhibition. ANG2/VEGFR2 blockade did not elicit increased PNET invasion and metastasis, although it exacerbated tumor hypoxia and hematopoietic cell infiltration. These findings suggest that evasive tumor resistance to anti-VEGFA therapy may involve the adaptive enforcement of ANG2-TIE2 signaling, which can be reversed by ANG2 neutralization.

6 Article Combination of human tumor necrosis factor-alpha (hTNF-alpha) gene delivery with gemcitabine is effective in models of pancreatic cancer. 2009

Murugesan, S R / King, C R / Osborn, R / Fairweather, W R / O'Reilly, E M / Thornton, M O / Wei, L L. ·Department of Research, GenVec Inc, Gaithersburg, MD 20878, USA. ·Cancer Gene Ther · Pubmed #19444305.

ABSTRACT: Pancreatic adenocarcinoma is an aggressive and highly lethal malignancy. Currently, gemcitabine is commonly used in patients with pancreatic cancer. However, the life expectancy of pancreatic cancer patients remains poor. We explored the possibility of increased anti-tumor activity by combining human tumor necrosis factor-alpha (hTNF-alpha) with current front-line therapy. Human TNF-alpha displays potent anti-tumor activity, but its use is limited by the toxicity of systemic administration. We developed a gene delivery approach using intratumoral injections of an adenoviral vector expressing hTNF-alpha, AdEgr.TNF.11D (TNFerade), to increase local concentrations of hTNF-alpha within the tumor, thereby maximizing local anti-tumor activity and yet minimizing the systemic toxicities. An ongoing phase III clinical trial is testing the efficacy of AdEgr.TNF.11D-injected intratumorally and combining with chemotherapy in locally advanced pancreatic cancer. In this study, we show that treatment with AdEgr.TNF.11D and gemcitabine results in a high level of hTNF-alpha expression in human pancreatic cancer cell lines. The combined treatment was well tolerated, highly active and produced marked delays in the growth of human pancreatic xenograft tumors relative to either agent alone. Our results strongly suggest that combination of AdEgr.TNF.11D and gemcitabine may be a potentially useful therapeutic approach for the improved treatment of pancreatic cancer.