bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4873: ImmTACs re-direct the immune system efficiently to eradicate cancer
Authors: Bossi Giovanna , Kenefeck Rupert , Caroline Boudousquie Caroline , Harper Jane , Dukes Joseph , Liddy Nathaniel , Paston Samantha , Mahon Tara , Molloy Peter , Sami Malkit , Baston Emma , Cameron Brian , Vuidepot Annelise , Hassan Namir , Jakobsen Bent K. 
Published: July 2016

Abstract
Immunotherapy strategies that are able to induce T cell infiltration into tumors and activate a cytotoxic T cell response have the potential to destroy the tumor. Although T cells can mediate clearance of a tumor, thymic selection and the suppressive microenvironment limit their effectiveness. To overcome poor tumor immunogenicity, we have developed a unique platform that enables the generation of ImmTACs (Immune-mobilising monoclonal TCRs Against Cancer); these are comprised of an affinity enhanced TCR specific for a cancer antigen fused to an anti-CD3 scFv. The TCR end targets and binds MHC class I/peptide complex displayed on cancerous cells while the anti-CD3 scFv end engages polyclonal T cells to mediate a potent anti-tumor response.
The most advanced ImmTAC, IMCgp100, targets the HLA-A2/gp100280-288 epitope presented by melanoma cells. IMCgp100 is currently in a Phase I/IIa clinical trial for advance malignant melanoma and is showing promising clinical efficacy in some patients. Here we report a series of in vitro experiments evaluating IMCgp100 mechanism of action. IMCgp100 is able to redirect T cells from healthy donors or from melanoma patients to destroy cancer cells and secrete a range of inflammatory cytokines and chemokines associated with T cell trafficking into tumors; some of these cytokines also induce upregulation of inhibitory pathway molecules. We show that effector memory cells in the CD8+ and CD4+ T cell compartments are very efficient in eliminating melanoma cells and in expanding upon IMCgp100 engagement. The effects of combining IMCgp100 with agents that relieve the suppression imposed by immune check-point molecules have also been investigated.
Citation Format: Giovanna Bossi, Rupert Kenefeck, Caroline Caroline Boudousquie, Jane Harper, Joseph Dukes, Nathaniel Liddy, Samantha Paston, Tara Mahon, Peter Molloy, Malkit Sami, Emma Baston, Brian Cameron, Annelise Vuidepot, Namir Hassan, Bent K. Jakobsen. ImmTACs re-direct the immune system efficiently to eradicate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4873.
Abstract 4877: Discovery of novel and potent inhibitors of indoleamine-2,3-dioxygenase (IDO1) for cancer immunotherapy
Authors: Liu Shengyang , Tao Taoliangshan , Liang Yue , Guo Hongli , Ye Xiaogang , Wu Zhiheng , Bao Fang , Yang Heping , Cai Yaxian , Yang Gangjing , Wang Longsheng , Liu Fang , Fu Guangliang , Liu Xiaolei , Du Jiangang , Qin Ping , Ma Yuanfei , Zhu Panhu , Yu Yajun , Ma Chen , Wang Pei , Zhao Liping , Wang Yuxun , Gao Daxin , Li Qun 
Published: July 2016

Abstract
Indoleamine-2,3-dioxygenase (IDO1) is an immune regulatory enzyme that oxidizes tryptophan to kynurenine. IDO1 is overexpressed in numerous tumor cells that block T-cell activation, induce T-cell apoptosis and increase regulatory T cells, which create an environment in which tumor-specific cytotoxic T lymphocytes are no longer able to attack a patient's cancer cells. IDO1 inhibition reverses the immune suppression at the tumor site and allows the generation of an effective anticancer immune response. Preclinical and clinical studies have shown that IDO1 inhibitors increase the anticancer immune response and dramatically increase the efficacy of various therapeutic agents especially the immune checkpoint antibodies targeting PD-1, PD-L1 and CTLA-4.
Via structure-based design, we have discovered a series of novel and potent IDO1 inhibitors that demonstrate strong IDO1 on-target activity with IC50 values ranging from 10 nM to 50 nM against human IDO1 enzyme. These compounds potently inhibit IDO1 in tumor-bearing mice as well as in Hela cells with lower single-digit to lower double digit nM IC50. The lead compound selected for clinical development shows good ADME profile, low serum binding, and good efficacy in various murine animal models when dosed orally and subcutaneously alone or in combination with immune checkpoint inhibitors. Preclinical evaluation of the compound will be presented in details.
Citation Format: Shengyang Liu, Taoliangshan Tao, Yue Liang, Hongli Guo, Xiaogang Ye, Zhiheng Wu, Fang Bao, Heping Yang, Yaxian Cai, Gangjing Yang, Longsheng Wang, Fang Liu, Guangliang Fu, Xiaolei Liu, Jiangang Du, Ping Qin, Yuanfei Ma, Panhu Zhu, Yajun Yu, Chen Ma, Pei Wang, Liping Zhao, Yuxun Wang, Daxin Gao, Qun Li. Discovery of novel and potent inhibitors of indoleamine-2,3-dioxygenase (IDO1) for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4877.
Abstract 4879: Cancer cell-mediated signaling of TLR 2, 4, and 9 causes activation of PI3K/Akt/mTOR pathway and induces tumor cell proliferation in pancreatic cancer
Authors: Kreckel Jennifer , Grimmig Tanja , Moench Romana , Germer Christoph T. , Gasser Martin , Waaga-Gasser Ana Maria 
Published: July 2016

Abstract
Background: Toll like receptor (TLR) ligands are in clinical use for the immunotherapy of different cancers. They are supposed to induce an inflammatory immune response against the tumor. Interestingly, several studies showed that TLRs were expressed by cancer cells in different tumor entities and that their activation can contribute to an inflammatory microenvironment. Yet, for pancreatic cancer, TLR expression and its impact in tumor cells is only poorly understood. Therefore this study analyzed the influence of TLR2, 4, and 9 expression and activation on tumor cell signaling and proliferation in pancreatic cancer.
Methods: The expression of TLR 2, 4, and 9 was analyzed in vitro in several established as well as primary human pancreatic cancer cell lines by qRT-PCR and Western Blot. TLR stimulation was then performed in BxPC-3, MIA Paca2, and PacaDD135 cells using the TLR ligands oligodeoxyribonucleotide2006 (ODN2006), lipoteichonic acid of Staphylococcus aureus (LTA-SA) and High-Mobility Group Box 1 (HMGB1). Expression of MyD88 and pAkt was then analyzed by Western Blot. Functional analysis on proliferation (ATP assay) and cytokine expression (Luminex) was additionally performed.
Results: Expression of TLR2, 4 and/or 9 was demonstrated in all investigated human pancreatic cancer cell lines. Receptor activation by single or combined use of TLR ligands resulted in increased MyD88 and pAkt (Ser473) expression. Additionally, up-regulated anti-apoptotic protein Bcl-2 expression was found in stimulated cells, but not in the unstimulated cells. Furthermore, TLR activation resulted in the production of the interleukin(IL)-6, IL-8 and tumor necrosis factor á (TNF-á). Interestingly, tumor cell proliferation was increased within 24 and 48 hours of stimulation.
Conclusion: Our results demonstrate TLR2, 4 and/or 9 expression in all human pancreatic cancer cell lines. Additionally, our findings on TLR activation suggest chronic inflammation-mediated TLR signaling to negatively influence tumor cell apoptosis and to shift the cytokine release in pancreatic cancer towards an inflammatory microenvironment. These findings emphasize the particular role of TLR2, 4 and 9 and their activation in pancreatic cancer, outlining their relevance as potential targets for cancer therapy.
Citation Format: Jennifer Kreckel, Tanja Grimmig, Romana Moench, Christoph T. Germer, Martin Gasser, Ana Maria Waaga-Gasser. Cancer cell-mediated signaling of TLR 2, 4, and 9 causes activation of PI3K/Akt/mTOR pathway and induces tumor cell proliferation in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4879.
Abstract 4880: A high-throughput siRNA screen identifies Nucleoside Diphosphate Kinase (NME3) as a novel host regulator of NF-êB signaling in response to Salmonella-induced activation of TLR-5
Authors: Gonzalez Caleb , Flentie Kelly , Kocher Brandon , Jayne Marasa Jayne , Piwnica-Worms David 
Published: July 2016

Abstract
Bacterial flagellin is a potent activator of NF-êB signaling, inflammation and host innate immunity. In comparison to TNFá, perhaps the most studied NF-êB-inducing ligand, flagellin elicits an overlapping, yet unique downstream transcriptional response by host cells. In contrast to the pro-oncogenic functions of TNFá, recent data indicate that flagellin may represent a novel anti-tumor ligand that acts through TLR5 and the NF-êB pathway to induce host immunity and to aid in the clearance of tumor xenografts. To begin to characterize the molecular basis for the anti-tumor effect of flagellin and to identify downstream innate signaling components of NF-êB that are responsible for the pro-inflammatory program necessary for these anti-tumor effects, we employed a high throughput screen. Utilizing HCT116 colon carcinoma cells expressing a dynamic NF-êB bioluminescent reporter and Salmonella typhimurium expressing flagellin, we performed a live cell screen of a siRNA library targeting 691 known and predicted human kinases to identify novel modulators of flagellin-induced NF-êB activation. This screen uncovered nucleoside diphosphate kinase (NME3) as a previously unrecognized, positive regulator of NF-êB signaling in response to flagellin. Targeted knockdown and overexpression assays confirmed the regulatory contribution of NME3. Furthermore, Kaplan-Meier survival analysis for breast, lung and ovarian cancer patients showed that high level expression of NME3 correlated with increased overall survival. Together, these data identify a novel pro-inflammatory role for NME3 in NF-êB signaling that may potentially be exploited to optimize cancer immunotherapy.
Citation Format: Caleb Gonzalez, Kelly Flentie, Brandon Kocher, Jayne Jayne Marasa, David Piwnica-Worms. A high-throughput siRNA screen identifies Nucleoside Diphosphate Kinase (NME3) as a novel host regulator of NF-êB signaling in response to Salmonella-induced activation of TLR-5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4880.
Abstract 4899: The regulation by kinases of the expression of human major histocompatibility class I molecules
Authors: Brea Elliott J. , Oh Claire , Manchado Eusebio , Gejman Ron , Mo George , Mondello Patrizia , Garippa Ralph , Rosen Neal , Scheinberg David A. 
Published: July 2016

Abstract
The major histocompatability complex (MHC) is a central receptor in the adaptive immune response and is the underlying target of several effective therapies for cancer. Druggable kinases may provide the opportunity to modulate the immune response toward MHC. However, the regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. The entire human kinome was screened using a pooled shRNA interference-based approach in a human mesothelioma cell line to uncover kinase regulators of MHC-I. Negative and positive regulators of cell surface HLA levels were discovered. A subset of highly scoring positive and negative kinase hits were subsequently validated by additional RNAi, and pharmacologic inhibitors when available. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of HLA expression in multiple cancer types. We mapped the pathways responsible for increased HLA upon kinase inhibition. Interestingly, inhibition of the MAP Kinase pathway broadly influenced expression of other components of the antigen presentation machinery. Moreover, DDR2 and MINK1 were shown to positively regulate HLA-A*02:01. This had therapeutic relevance, as shown with a therapeutic TCR mimic antibody to a MHC/peptide complex. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases.
Citation Format: Elliott J. Brea, Claire Oh, Eusebio Manchado, Ron Gejman, George Mo, Patrizia Mondello, Ralph Garippa, Neal Rosen, David A. Scheinberg. The regulation by kinases of the expression of human major histocompatibility class I molecules. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4899.
Abstract 490: High-throughput mutational analysis in cell-free DNA by targeted next-generation sequencing
Authors: Tam Nga wan Rachel , Shames David , Darbonne Walter 
Published: July 2016

Abstract
Circulating cell-free DNA (cfDNA) in plasma offers a non-invasive approach to monitor tumor molecular profiling in real-time at multiple time-points, detection of emerging genomic alterations associated with drug resistance and clarifying cancer prognosis and diagnosis of cancer recurrence or progression. We developed a robust, multiplexed and PCR-based targeted next-generation sequencing approach to detect actionable mutations in cfDNA with low DNA input (1-5 ng). We employed the latest Ion TorrentTM S5/XL bench-top sequencer with Ion ChefTM Automation System and successfully automated the entire 2-day workflow from libraries preparation to semi-conducting chip sequencing. The hands-on time has been reduced to only 30 min.
We will present data showing validation of this NGS platform using commercially available DNA control, archival FFPE tissue and cfDNA matched samples and demonstrate robust sensitivity and specificity by using the off-the-shelf Ion AmpliSeq Cancer Hotspot Panel v2 that covers 50 oncogenes. We also compared this approach to other orthogonal technologies, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR) and achieved 100% concordance across these platforms. NGS can detect mutations down to 1% allelic frequency with 100% sensitivity and specificity.
This robust and automated NGS platform is being routinely used in our lab to analyze cell-free DNA samples from multiple clinical trials. These efforts enable the development of a non-invasive method to overcome existing challenges to provide molecular understanding of patient's tumor evolution in real time, and aid in the development of personalized therapies for cancer patients.
Citation Format: Nga wan Rachel Tam, David Shames, Walter Darbonne. High-throughput mutational analysis in cell-free DNA by targeted next-generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 490.
Abstract 491: Salvage MET amplification detection and therapy through cell-free DNA NGS in a progressing lung cancer patient
Authors: Peled Nir , Belilovski Anna , Soussan-Gutman Lior , Lanman Richard B. , Talasaz AmirAli 
Published: July 2016

Abstract
Background: Mutational analysis has become standard of care in lung cancer. However, many patients do not have tissue available due to lack of tissue, or more commonly due to tissue exhaustion by previous tissue analysis. Next generation sequencing of circulating cell-free DNA (cfDNA) provides a non-invasive alternative. EGFR point mutations and indels are well reported in this manner, however gene copy number amplification is more challenging. Here we present a cases where MET amplification has been detected and guided highly efficient therapy in advanced lung cancer patient.
Methods: Guardant360TM is a targeted cfDNA NGS panel using hybrid capture and complete exon sequencing exons for single nucleotide variant detection in 68 genes, copy number amplifications (CNA) in 16 genes, and selected indels and fusions. CNA has been validated against cell lines with known amplifications.
Results: A 70 y old former light smoker (15 PY) with pulmonary fibrosis and moderate pulmonary hypertension was diagnosed with a 30 mm RMB lung adenocarcinoma that was treated by stereotactic beam radiotherapy due to poor pulmonary reserve. After 5 months, mediastinal, liver and multiple bone metastases were diagnosed. Genomic analysis of the primary tissue biopsy yielded a rare EGFR mutation (I744F) and afatinib therapy was started to cover uncommon EGFR mutations. However, 2 months later, a significant progression has occurred and the patient had severe local progression with respiratory near-failure. The patient was not a candidate for chemotherapy and there was no further tissue available for molecular testing. Therefore cfDNA testing was performed finding no residual EGFR mutation in the blood but a MET amplification reported above the 90th percentile for the Guardant Health laboratory with copy number of 53.6 in the blood.
Upon this result, crizotinib 250 mg BID was started with immediate clinical improvement, followed with a dramatic imaging response on CT/PET scans. Currently, the patient is in PS-0 and free of any symptoms, 3 months since treatment has been started.
Conclusion: cfDNA detection of MET amplification as a key resistance mechanism after EGFR TKI therapy is feasible in patients where tissue is not accessible or was undergenotyped and may be accompanied by a fast and dramatic clinical improvement.
Citation Format: Nir Peled, Anna Belilovski, Lior Soussan-Gutman, Richard B. Lanman, AmirAli Talasaz. Salvage MET amplification detection and therapy through cell-free DNA NGS in a progressing lung cancer patient. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 491.
Abstract 492: Automated circulating cell-free DNA purification from large volume draws
Authors: Ray Robert , Bratz Mark , Wieczorek Doug , White Douglas , Horejsh Douglas , Vincent Eric , Schagat Trista 
Published: July 2016

Abstract
Circulating, cell-free DNA (ccfDNA) has emerged as an important tool in molecular oncology research. Because it is highly fragmented, present in small quantities, and highly susceptible to degradation, purification of ccfDNA poses unique challenges to researchers. While plasma is the main focus of many researchers for ccfDNA, recent work has shown that it is present in other biological fluids.
Promega has developed a unique chemistry to selectively purify ccfDNA from plasma. The Maxwell RSC ccfDNA Plasma system is a completely automated system that allows purification of ccfDNA from 1ml of plasma. To add flexibility, we adapted the chemistry to automated platforms in 24-well configurations. These platforms include the Hamilton Microlab STAR series and the KingFisher Flex Processor. Because the biomarkers in ccfDNA can be of very low frequency, many researchers prefer to process volumes of samples &gt;1ml which can exceed the capacity of many purification systems. Using a sequential bind strategy, we demonstrate that ccf DNA can be purified from at least 8ml sample draw using a fully automated method. Liquid draws tested include plasma and urine. DNA quantity was assessed by qPCR using an autosomal target, and quality was assessed using an internal PCR control.
This study shows the flexibility and robustness of the Maxwell RSC ccfDNA chemistry. We successfully adapted it for purification from relatively large volume liquids in a fully automated manner making this a convenient option for early biomarker research.
Citation Format: Robert Ray, Mark Bratz, Doug Wieczorek, Douglas White, Douglas Horejsh, Eric Vincent, Trista Schagat. Automated circulating cell-free DNA purification from large volume draws. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 492.
Abstract 4929: UbcH10 may represent a potential marker of gastric carcinoma
Authors: Yang Mengxuan , Qu Yingying , Hu Gang , Tu Shiwei , Shi RL , Wu XB , Hu ZQ , Zhang QM , Liu SQ , Pan GF , Zhang Ziping , Zhou He 
Published: July 2016

Abstract
Gastric cancer is a fatal disease with limited early diagnostic methods available. There is an urgent need to find more effective targets for early diagnosis and therapeutics. UbcH10 is an ubiquitin-conjugating enzyme with a high expression reported in some cancers. Several gastric tumor cell lines with high or low expression of UbcH10 were exploited to study the role of UbcH10 in gastric cancer. Knocking down of UbcH10 expression using siRNA in high expressing gastric cancer cell lines resulted in reduced proliferation, increased cisplatin-induced apoptosis and reduced serum-induced ERK, Akt and p38 phosphorylation signaling. In agreement, overexpression of UbcH10 expression in low-expression gastric cancer cell lines led to enhanced cell proliferation, resistance to cisplatin-induced apoptosis. Most importantly, IHC analyses showed that the UbcH10 protein expressed at a high level in patient gastric cancer tissues, but not in adjacent mesenchyme tissues. These data suggest that UbcH10 may promote gastric cancer growth and can serve as a biomarker for diagnosis or target for new therapeutics in gastric cancer.
Citation Format: Mengxuan Yang, Yingying Qu, Gang Hu, Shiwei Tu, RL Shi, XB Wu, ZQ Hu, QM Zhang, SQ Liu, GF Pan, Ziping Zhang, He Zhou. UbcH10 may represent a potential marker of gastric carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4929.