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Pancreatic cancer and immune checkpoint

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https://www.readbyqxmd.com/read/28404866/combined-antiangiogenic-and-anti-pd-l1-therapy-stimulates-tumor-immunity-through-hev-formation
#1
Elizabeth Allen, Arnaud Jabouille, Lee B Rivera, Inge Lodewijckx, Rindert Missiaen, Veronica Steri, Kevin Feyen, Jaime Tawney, Douglas Hanahan, Iacovos P Michael, Gabriele Bergers
Inhibitors of VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) are commonly used in the clinic, but their beneficial effects are only observed in a subset of patients and limited by induction of diverse relapse mechanisms. We describe the up-regulation of an adaptive immunosuppressive pathway during antiangiogenic therapy, by which PD-L1 (programmed cell death ligand 1), the ligand of the negative immune checkpoint regulator PD-1 (programmed cell death protein 1), is enhanced by interferon-γ-expressing T cells in distinct intratumoral cell types in refractory pancreatic, breast, and brain tumor mouse models...
April 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28404865/dual-angiopoietin-2-and-vegfa-inhibition-elicits-antitumor-immunity-that-is-enhanced-by-pd-1-checkpoint-blockade
#2
Martina Schmittnaegel, Nicolò Rigamonti, Ece Kadioglu, Antonino Cassará, Céline Wyser Rmili, Anna Kiialainen, Yvonne Kienast, Hans-Joachim Mueller, Chia-Huey Ooi, Damya Laoui, Michele De Palma
Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma...
April 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28348045/stratification-of-pancreatic-ductal-adenocarcinoma-combinatorial-genetic-stromal-and-immunological-markers
#3
Erik Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W Botros, Vladimir Makarov, Nadeem Riaz, Vinod P Balachandran, Steven D Leach, Debrah M Thompson, Timothy A Chan, Agnieszka K Witkiewicz
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunological features of PDAC to delineate impact on prognosis and to more effectively employ immunotherapy. EXPERIMENTAL DESIGN: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunological subtypes of PDAC that were confirmed in the Cancer Genome Atlas data set...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28346697/car-t-cell-therapy-for-pancreatic-cancer
#4
REVIEW
Carl J DeSelm, Zachary E Tano, Anna M Varghese, Prasad S Adusumilli
Chimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted investigating this approach in solid tumors such as pancreatic cancer. The complex tumor microenvironment, stromal hindrance in limiting immune response, and expression of checkpoint blockade on T cells pose hurdles. Herein, we summarize the opportunities, challenges, and state of knowledge in targeting pancreatic cancer with CAR T-cell therapy...
March 27, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28255028/gene-signature-driving-invasive-mucinous-adenocarcinoma-of-the-lung
#5
Minzhe Guo, Koichi Tomoshige, Michael Meister, Thomas Muley, Takuya Fukazawa, Tomoshi Tsuchiya, Rebekah Karns, Arne Warth, Iris M Fink-Baldauf, Takeshi Nagayasu, Yoshio Naomoto, Yan Xu, Marcus A Mall, Yutaka Maeda
Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung Tumor Signature of 143 genes, which was unexpectedly enriched in mucin-producing gastrointestinal, pancreatic, and breast cancers. The signature genes included transcription factors FOXA3, SPDEF, HNF4A, mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1/B7-H4 (but not PD-L1/B7-H1)...
April 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28253833/emerging-antibodies-for-the-treatment-of-pancreatic-cancer
#6
Kalliopi Andrikou, Chiara Peterle, Stefania Pipitone, Massimiliano Salati, Stefano Cascinu
Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC. Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment...
March 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/28239470/fak-inhibition-opens-the-door-to-checkpoint-immunotherapy-in-pancreatic-cancer
#7
EDITORIAL
Stefan N Symeonides, Stephen M Anderton, Alan Serrels
Immunotherapy has had remarkable success in the treatment of some cancer types. However, pancreatic cancer has remained largely refractory to immunotherapy, including immune checkpoint inhibitors. Recently, Jiang and colleagues identified a key role for FAK in regulating the composition of the fibrotic and immuno-suppressive pancreatic tumour niche, and showed that FAK inhibitors can be used in combination with immune checkpoint blockade and gemcitabine chemotherapy to significantly delay pancreatic tumour progression...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28131992/the-mll1-h3k4me3-axis-mediated-pd-l1-expression-and-pancreatic-cancer-immune-evasion
#8
Chunwan Lu, Amy V Paschall, Huidong Shi, Natasha Savage, Jennifer L Waller, Maria E Sabbatini, Nicholas H Oberlies, Cedric Pearce, Kebin Liu
BACKGROUND: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. METHODS: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion...
January 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28121247/targeting-inos-to-increase-efficacy-of-immunotherapies
#9
Suhendan Ekmekcioglu, Elizabeth A Grimm, Jason Roszik
Inducible NO synthase (iNOS/NOS2) protein expression is a well-studied predictor of poor outcome in multiple cancers, and it has also been associated with inflammatory and immunosuppressive processes in the tumor microenvironment. Immunotherapies are becoming increasingly key components in cancer treatment, and iNOS is receiving more attention as a potential regulator of treatment resistance. As we have reported in pancreatic cancer, by modulation of effector T-cell activity, iNOS overexpression may allow the tumor to escape the immune response through creating a microenvironment which causes recalcitrance to immunotherapy...
January 25, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28007776/immune-cytolytic-activity-stratifies-molecular-subsets-of-human-pancreatic-cancer
#10
David Balli, Andrew J Rech, Ben Z Stanger, Robert H Vonderheide
PURPOSE: Immunotherapy has the potential to improve the dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials - including those with single-agent PD-1/PD-L1 inhibition - have been disappointing. Our aim was to examine the immune landscape of PDA as it relates to aspects of tumor biology, including neoepitope burden. EXPERIMENTAL DESIGN: We used publically available expression data from 134 primary resection PDA samples from The Cancer Genome Atlas to stratify patients according to a cytolytic T-cell activity expression index...
December 22, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27993090/wilms-tumor-1-wt1-targeted-cancer-vaccines-to-extend-survival-for-patients-with-pancreatic-cancer
#11
Shigeo Koido, Masato Okamoto, Shigetaka Shimodaira, Haruo Sugiyama
Despite novel chemotherapy treatments, pancreatic ductal adenocarcinoma (PDA) remains a lethal disease. New targeted cancer vaccines may represent a viable option for patients with PDA. The Wilms' tumor 1 (WT1) antigen is one of the most widely expressed tumor-associated antigens in various types of tumors, including PDA. Recent reports have indicated that WT1-targeted cancer vaccines for patients with PDA mediated a potent antitumor effect when combined with chemotherapy in preclinical and clinical studies...
November 2016: Immunotherapy
https://www.readbyqxmd.com/read/27939096/focal-adhesion-kinase-a-promising-therapeutic-target-in-pancreatic-adenocarcinoma
#12
Emilie Decaup, Julia Rochotte, Stéphane Pyronnet, Corinne Bousquet, Christine Jean
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly cancer, characterized by a uniquely immunosuppressive and fibrotic microenvironment responsible for its high chemoresistance. Jiang et al. identify FAK (focal adhesion kinase) activity as an interesting therapeutic target, the inhibition of which drastically reduces PDAC microenvironment deleterious features. In combination with gemcitabine and immune-checkpoint therapy, FAK inhibitor promotes long-term tumor stasis with extended survival in PDAC mouse models...
December 6, 2016: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/27930550/role-of-immune-cells-in-pancreatic-cancer-from-bench-to-clinical-application-an-updated-review
#13
REVIEW
Jae Hyuck Chang, Yongjian Jiang, Venu G Pillarisetty
BACKGROUND: Pancreatic cancer (PC) remains difficult to treat, despite the recent advances in various anticancer therapies. Immuno-inflammatory response is considered to be a major risk factor for the development of PC in addition to a combination of genetic background and environmental factors. Although patients with PC exhibit evidence of systemic immune dysfunction, the PC microenvironment is replete with immune cells. METHODS: We searched PubMed for all relevant English language articles published up to March 2016...
December 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27920468/immune-checkpoint-therapy-for-pancreatic-cancer
#14
REVIEW
Henrik Johansson, Roland Andersson, Monika Bauden, Sarah Hammes, Stefan Holdenrieder, Daniel Ansari
Novel treatment modalities are necessary for pancreatic cancer. Immunotherapy with immune checkpoint inhibition has shown effect in other solid tumors, and could have a place in pancreatic cancer treatment. Most available clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, there have been findings of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy...
November 21, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27910859/t-cell-programming-in-pancreatic-adenocarcinoma-a-review
#15
REVIEW
Y D Seo, V G Pillarisetty
Despite recent advancements in multimodal therapy, pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. In the era of burgeoning immune therapies against previously difficult-to-treat malignancies, there has been growing interest in activating the immune system against PDA; however, unlike in other cancers such as melanoma and lymphoma, immunotherapy has not yielded many clinically significant results. To harness these mechanisms for therapeutic use, an in-depth understanding of T-cell programming in the immune microenvironment of PDA must be achieved...
March 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/27865460/current-and-emerging-targeting-strategies-for-treatment-of-pancreatic-cancer
#16
A T Baines, P M Martin, C J Rorie
With a dismal 5-year survival rate of only 8%, pancreatic cancer still remains a very lethal disease. As with most cancers, pancreatic cancer is treated with different combinations of chemotherapeutic drugs which result in side effects and potential drug resistance leading in many cases to the unfortunate demise of the patient. Over recent years, a number of therapies have been developed against numerous molecular targets in cancers. Kinase inhibitors and monoclonal antibodies have been shown to target numerous kinases, growth factor receptors, and cell signaling pathways...
2016: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/27863199/mesothelin-immunotherapy-for-cancer-ready-for-prime-time
#17
Raffit Hassan, Anish Thomas, Christine Alewine, Dung T Le, Elizabeth M Jaffee, Ira Pastan
Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27856273/hypermutation-in-pancreatic-cancer
#18
Jeremy L Humphris, Ann-Marie Patch, Katia Nones, Peter J Bailey, Amber L Johns, Skye McKay, David K Chang, David K Miller, Marina Pajic, Karin S Kassahn, Michael C J Quinn, Timothy J C Bruxner, Angelika N Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Andrew Stone, Peter J Wilson, Matthew Anderson, J Lynn Fink, Oliver Holmes, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Nick Waddell, Scott Wood, Ronald S Mead, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J Cowley, Marc D Jones, Adnan M Nagrial, Venessa T Chin, Lorraine A Chantrill, Amanda Mawson, Angela Chou, Christopher J Scarlett, Andreia V Pinho, Ilse Rooman, Marc Giry-Laterriere, Jaswinder S Samra, James G Kench, Neil D Merrett, Christopher W Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B Jamieson, Colin J McKay, C Ross Carter, Euan J Dickson, Janet S Graham, Fraser Duthie, Karin Oien, Jane Hair, Jennifer P Morton, Owen J Sansom, Robert Grützmann, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Richard D Schulick, Christopher L Wolfgang, Richard A Morgan, Rita T Lawlor, Borislav Rusev, Vincenzo Corbo, Roberto Salvia, Ivana Cataldo, Giampaolo Tortora, Margaret A Tempero, Oliver Hofmann, James R Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A Musgrove, Anthony J Gill, John V Pearson, Sean M Grimmond, Nicola Waddell, Andrew V Biankin
Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2...
January 2017: Gastroenterology
https://www.readbyqxmd.com/read/27797936/il-6-and-pd-l1-antibody-blockade-combination-therapy-reduces-tumour-progression-in-murine-models-of-pancreatic-cancer
#19
Thomas A Mace, Reena Shakya, Jason R Pitarresi, Benjamin Swanson, Christopher W McQuinn, Shannon Loftus, Emily Nordquist, Zobeida Cruz-Monserrate, Lianbo Yu, Gregory Young, Xiaoling Zhong, Teresa A Zimmers, Michael C Ostrowski, Thomas Ludwig, Mark Bloomston, Tanios Bekaii-Saab, Gregory B Lesinski
OBJECTIVE: Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy. DESIGN: Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively...
October 21, 2016: Gut
https://www.readbyqxmd.com/read/27760957/-administration-of-immune-checkpoint-inhibitor-for-cancer-except-for-melanoma-and-lung-cancer
#20
Tsutomu Takeda, Nobuaki Hattori, Takashi Takeda, Takehiro Noda, Hiroko Takeda
We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses. Three remarkably effective responses were seen in cases of pancreatic cancer, esophageal cancer, and brain malignant lymphoma. In every effective case, dendritic cell therapy was administered prior to nivolumab...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
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