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Pancreatic cancer immunotherapy

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https://www.readbyqxmd.com/read/29668571/evaluating-for-pseudoprogression-in-colorectal-and-pancreatic-tumors-treated-with-immunotherapy
#1
Christine M Parseghian, Madhavi Patnana, Priya Bhosale, Kenneth R Hess, Ya-Chen Tina Shih, Bumyang Kim, Scott Kopetz, Michael J Overman, Gauri R Varadhachary, Milind Javle, Aung Naing, Sarina Piha-Paul, David Hong, Hung Le, Vivek Subbiah, Shubham Pant
Pseudoprogression has been observed in patients with various tumor types treated with immunotherapy. However, the frequency of pseudoprogression is unknown in gastrointestinal malignancies. Metastatic colorectal cancer (mCRC) and advanced pancreatic ductal adenocarcinoma (PDAC) patients who progressed on treatment with immunotherapy beyond RECIST version 1.1 criteria were analyzed. Degree of progression, tumor markers, time to progression, overall survival, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and costs were analyzed for patients treated beyond progression (TBP) and not treated beyond progression...
April 17, 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29661773/integrated-genomic-and-immunophenotypic-classification-of-pancreatic-cancer-reveals-three-distinct-subtypes-with-prognostic-predictive-significance
#2
Martin Wartenberg, Silvia Cibin, Inti Zlobec, Erik Vassella, Serenella M M Eppenberger-Castori, Luigi Terracciano, Micha Eichmann, Mathias Worni, Beat Gloor, Aurel Perren, Eva Karamitopoulou
PURPOSE: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC-cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. EXPERIMENTAL DESIGN: A well-characterized PDAC-cohort (n=110) underwent next-generation sequencing with a hotspot cancer panel, while Next-generation Tissue-Microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM) and DNA mismatch-repair proteins...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29660367/natural-killer-cells-and-their-therapeutic-role-in-pancreatic-cancer-a-systematic-review
#3
REVIEW
Jonas R M Van Audenaerde, Geert Roeyen, Phillip K Darcy, Michael H Kershaw, M Peeters, Evelien L J Smits
Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies...
April 13, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29623227/fulminant-diabetes-in-a-patient-with-advanced-melanoma-on-nivolumab
#4
Nora Chokr, Hafsa Farooq, Elizabeth Guadalupe
Background: Anti-PD-1 agents were approved for advanced melanoma after the landmark trial Checkmate-037. Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells in genetically predisposed people. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case: A 61-year-old male with advanced melanoma presented with a three-day history of nausea, vomiting, and malaise...
2018: Case Reports in Oncological Medicine
https://www.readbyqxmd.com/read/29617184/targeting-interleukin-22-for-cancer-therapy
#5
Anamarija Markota, Stefan Endres, Sebastian Kobold
Interleukin-22 (IL-22) is a member of IL-10 family of cytokines. IL-22 induces proliferative and anti-apoptotic signaling pathways and production of anti-microbial molecules that enhance tissue regeneration and host defense. IL-22 has also been identified as a cancer-promoting cytokine since deregulation of the IL-22-IL-22R1 system is linked to different cancer entities including lung, breast, gastric, pancreatic and colon cancers. T cells and innate lymphoid cells are the main cellular sources of IL-22. Expression of its specific receptor IL-22R1 is restricted to the non-hematopoietic cells which makes the IL-22-IL-22R1 pathway an attractive target for anti-cancer therapy...
April 4, 2018: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29615613/multi-omics-analysis-reveals-neoantigen-independent-immune-cell-infiltration-in-copy-number-driven-cancers
#6
Daniel J McGrail, Lorenzo Federico, Yongsheng Li, Hui Dai, Yiling Lu, Gordon B Mills, Song Yi, Shiaw-Yih Lin, Nidhi Sahni
To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration...
April 3, 2018: Nature Communications
https://www.readbyqxmd.com/read/29610286/immunotherapy-for-pancreatic-cancer-more-than-just-a-gut-feeling
#7
Erick Riquelme, Anirban Maitra, Florencia McAllister
<b/> Development of pancreatic cancer in spontaneous murine models is associated with enrichment of specific strains of gut and intratumoral bacteria that induce a tolerogenic immunosuppressive microenvironment favoring cancer progression and resistance to immunotherapies. Ablation of the microbiome with antibiotics reshapes the tumor microenvironment, inducing T-cell activation, improving immune surveillance, and increasing sensitivity to immunotherapy in established tumors. Cancer Discov; 8(4); 386-8...
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29605510/immunotherapy-for-pancreatic-cancer-a-long-and-hopeful-journey
#8
Jian-Wei Xu, Lei Wang, Yu-Gang Cheng, Guang-Yong Zhang, San-Yuan Hu, Bin Zhou, Han-Xiang Zhan
Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials...
March 29, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29599906/dynamic-changes-during-the-treatment-of-pancreatic-cancer
#9
Robert A Wolff, Andrea Wang-Gillam, Hector Alvarez, Hervé Tiriac, Dannielle Engle, Shurong Hou, Abigail F Groff, Anthony San Lucas, Vincent Bernard, Kelvin Allenson, Jonathan Castillo, Dong Kim, Feven Mulu, Jonathan Huang, Bret Stephens, Ignacio I Wistuba, Matthew Katz, Gauri Varadhachary, YoungKyu Park, James Hicks, Arul Chinnaiyan, Louis Scampavia, Timothy Spicer, Chiara Gerhardinger, Anirban Maitra, David Tuveson, John Rinn, Gregory Lizee, Cassian Yee, Arnold J Levine
This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments...
March 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29576277/the-clinicopathological-and-prognostic-significance-of-pd-l1-expression-in-pancreatic-cancer-a-meta-analysis
#10
He-Li Gao, Liang Liu, Zi-Hao Qi, Hua-Xiang Xu, Wen-Quan Wang, Chun-Tao Wu, Shi-Rong Zhang, Jin-Zhi Xu, Quan-Xing Ni, Xian-Jun Yu
BACKGROUND: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC. DATA SOURCES: Electronic search of the PubMed, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis...
March 13, 2018: Hepatobiliary & Pancreatic Diseases International: HBPD INT
https://www.readbyqxmd.com/read/29568387/engineered-t-lymphocytes-eliminate-lung-metastases-in-models-of-pancreatic-cancer
#11
Qiang Sun, Shixin Zhou, Jingjing Zhao, Changwen Deng, Ruidi Teng, Yiding Zhao, Jiajia Chen, Jiebin Dong, Ming Yin, Yun Bai, Hongkui Deng, Jinhua Wen
Pancreatic cancer is known as one of the most lethal cancers in the world. A majority of advanced stage pancreatic cancer patients are diagnosed with distant metastasis and given poor prognoses, calling for a better therapeutic option. Mesothelin, which is overexpressed in pancreatic cancer and other solid tumors, is a potential target for pancreatic cancer immunotherapy. Adoptive transfer of T cells engineered with chimeric antigen receptors (CART cells) was effective for treating CD19-positive leukemia, but it is more difficult for CART cells to eliminate solid tumors...
March 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29567829/the-pancreatic-cancer-microbiome-promotes-oncogenesis-by-induction-of-innate-and-adaptive-immune-suppression
#12
Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, Constantinos P Zambirinis, Emma Kurz, Ankita Mishra, Navyatha Mohan, Berk Aykut, Mykhaylo Usyk, Luisana E Torres, Gregor Werba, Kevin Zhang, Yuqi Guo, Qianhao Li, Neha Akkad, Sarah Lall, Benjamin Wadowski, Johana Gutierrez, Juan Andres Kochen Rossi, Jeremy W Herzog, Brian Diskin, Alejandro Torres-Hernandez, Josh Leinwand, Wei Wang, Pardeep S Taunk, Shivraj Savadkar, Malvin Janal, Anjana Saxena, Xin Li, Deirdre Cohen, R Balfour Sartor, Deepak Saxena, George Miller
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation...
March 22, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29564181/immunotherapy-in-pancreatic-adenocarcinoma-overcoming-barriers-to-response
#13
REVIEW
Ari Rosenberg, Devalingam Mahalingam
Pancreatic adenocarcinoma (PAC) remains one of the leading causes of cancer-related death. Despite multiple advances in targeted and immune therapies, the 5-year survival in advanced PAC remains poor. In this review, we discuss some of the unique aspects of the tumor microenvironment (TME) in PAC that may contribute to its resistance to immune therapies, as well as opportunities to potentially overcome some of these inherent barriers. Furthermore, we discuss strategies to enable immune therapies in PAC such as cytotoxic chemotherapy and radiation therapy, cancer vaccines, cytokine based therapy, oncolytic viruses, and adoptive T-cell therapy...
February 2018: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/29561217/immunological-mutational-signature-in-adenosquamous-cancer-of-pancreas-an-exploratory-study-of-potentially-therapeutic-targets
#14
Nicola Silvestris, Oronzo Brunetti, Rosamaria Pinto, Daniela Petriella, Antonella Argentiero, Livia Fucci, Stefania Tommasi, Katia Danza, Simona De Summa
OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP...
March 27, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29547556/update-in-systemic-and-targeted-therapies-in-gastrointestinal-oncology
#15
Nelson S Yee
Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented...
March 16, 2018: Biomedicines
https://www.readbyqxmd.com/read/29526540/dendritic-cell-based-cancer-immunotherapy-for-pancreatic-cancer
#16
REVIEW
Wei Li, Xiujun Song, Huijie Yu, Manze Zhang, Fengsheng Li, Cheng Cao, Qisheng Jiang
Pancreatic cancer (PC) is a lethal disease and remains one of the most resistant cancers to traditional therapies. New therapeutic modalities are urgently needed, particularly immunotherapy, which has shown promise in numerous animal model studies. Dendritic cell (DC)-based immunotherapy has been used in clinical trials for various cancers, including PC, because DCs are the most potent antigen-presenting cell (APC), which are capable of priming naive T cells and stimulating memory T cells to generate antigen-specific responses...
March 8, 2018: Arab Journal of Gastroenterology: the Official Publication of the Pan-Arab Association of Gastroenterology
https://www.readbyqxmd.com/read/29523759/landscape-of-tumor-mutation-load-mismatch-repair-deficiency-and-pd-l1-expression-in-a-large-patient-cohort-of-gastrointestinal-cancers
#17
Mohamed E Salem, Alberto Puccini, Axel Grothey, Derek Raghavan, Richard M Goldberg, Joanne Xiu, W Michael Korn, Benjamin A Weinberg, Jimmy J Hwang, Anthony F Shields, John L Marshall, Philip A Philip, Heinz-Josef Lenz
The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing (NGS) was performed on genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens using the NextSeq platform...
March 9, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29467893/ifn-%C3%AE-induces-the-upregulation-of-rfxap-via-inhibition-of-mir-212-3p-in-pancreatic-cancer-cells-a-novel-mechanism-for-ifn-%C3%AE-response
#18
Guoping Ding, Liangjing Zhou, Tao Shen, Liping Cao
Previous studies have demonstrated that pancreatic cancer-derived microRNA (miR)-212-3p can inhibit the expression of regulatory factor X-associated protein (RFXAP), an important transcription factor for major histocompatibility complex (MHC) class II, and thereby lead to downregulation of MHC class II in dendritic cells. It has also been established that interferon (IFN)-γ can increase the expression of MHC class II in immune cells. It was therefore hypothesized that IFN-γ can inhibit miR-212-3p expression in pancreatic cancer, leading to the upregulation of RFXAP and MHC class II expression...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29462900/next-generation-immunotherapy-for-pancreatic-cancer-dna-vaccination-is-seeking-new-combo-partners
#19
REVIEW
Paola Cappello, Claudia Curcio, Giorgia Mandili, Cecilia Roux, Sara Bulfamante, Francesco Novelli
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor...
February 16, 2018: Cancers
https://www.readbyqxmd.com/read/29459478/targeting-cytokine-therapy-to-the-pancreatic-tumor-microenvironment-using-pd-l1-specific-vhhs
#20
Michael Dougan, Jessica R Ingram, Hee-Jin Jeong, Munir M Mosaheb, Patrick T Bruck, Lestat Ali, Novalia Pishesha, Olga Blomberg, Paul M Tyler, Mariah M Servos, Mohammad Rashidian, Quang-De Nguyen, Ulrich H von Andrian, Hidde L Ploegh, Stephanie K Dougan
Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect...
February 19, 2018: Cancer Immunology Research
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