bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2297: Anti-labyrinthin monoclonal antibody reduces human adenocarcinoma circulating tumor cells in the blood of patient-derived xenograft models and inhibits the growth of adenocarcinoma cell cultures
Authors: Saleev Natalia , Blondheim-Shraga Netta R. , Solomonov Evgeny , Shapira Shiran , Haviv Izhak , Stemmer Solomon M. , Slor Hanoch 
Published: August 2019

Abstract
Labyrinthin is a 255-amino acid protein antigen that is expressed on the cell-surface of most adenocarcinoma tumors and is not expressed on the surface of most normal cells, which makes it an attractive candidate for targeted therapy. Originally, labyrinthin had been deduced to be a product of a large deletion in the gene coding for junctate. We found that the junctate gene in labyrinthin-expressing adenocarcinoma cells does not have any deletion, and we propose that the labyrinthin protein is a splice variant of the junctate gene. This study aimed to determine the effects of an anti-labyrinthin monoclonal antibody, on adenocarcinoma cells in vitro and on patient-derived xenograft (PDX) models in vivo. Lung, breast and colorectal adenocarcinoma cell lines, as well as a primary-cell culture of a colorectal adenocarcinoma patient, were assessed for cell surface expression of labyrinthin. The cells were then incubated in the presence of the anti-labyrinthin antibody and growth rate was monitored by live imaging methods. Untreated primary-cell cultures of the colorectal adenocarcinoma patient were also grafted to immunodeficient mice to produce PDX tumors. When establishment of palpable tumors was observed, the mice were injected with the antibody. Peripheral blood was sampled from the mice and circulating tumor cells (CTCs) were quantified by flow cytometry. A significant reduction of approximately 60% was detected in the number of CTCs in the peripheral blood of the antibody-treated PDX mice compared to untreated control PDX mice. Additionally, a significant reduction was measured in the growth-rate of cultured primary cells and in lung, breast and colorectal adenocarcinoma cell lines in the presence of the antibody. We conclude that the anti-labyrinthin antibody has an inhibitory effect on the formation of adenocarcinoma CTCs in vivo as well as on the growth rate of cultured adenocarcinoma tumor cells.
Citation Format: Natalia Saleev, Netta R. Blondheim-Shraga, Evgeny Solomonov, Shiran Shapira, Izhak Haviv, Solomon M. Stemmer, Hanoch Slor. Anti-labyrinthin monoclonal antibody reduces human adenocarcinoma circulating tumor cells in the blood of patient-derived xenograft models and inhibits the growth of adenocarcinoma cell cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2297.
Abstract 2311: Analysis of glypican 3-targeted chimeric antigen receptor T cells in hepatocellular carcinoma cell and mouse models
Authors: Li Dan , Li Nan , Zhang Yifan , Fu Haiying , Duan Zhijian , Hummer Alissa , Yang Hongjia , Torres Madeline B. , Luo Xiaoling , Su Ling , Zhu Hu , Kramer Josh , Chen Jinqiu , Wu Xiaolin , Hall Matthew , Wang Qun , Hewitt Stephen , Greten Tim , Ho Mitchell 
Published: August 2019

Abstract
Background: Glypican-3 (GPC3) is a cell surface protein that is highly expressed in hepatocellular carcinoma (HCC).
Methods and Results: In this report, we analyzed two chimeric antigen receptors (CARs) targeting GPC3, CAR (HN3) recognizes the N-lobe of GPC3 while CAR (hYP7) targets the C-lobe that is close to the cell surface. In a real-time cell cytolytic assay, we found that CAR (hYP7) T cells showed higher cytolytic activity than CAR(HN3) T cells at an E:T ratio of 2:1 when co-cultured with HepG2 cells for up to 140 hours. The Luminex analysis showed that CAR (hYP7) T cells produced significantly more Th1/Th2 cytokines and chemokines than CAR (HN3) T cells following exposure to Hep3B and HepG2 cells. In the Hep3B peritoneal dissemination xenograft mouse model, a single intraperitoneal infusion of CAR (hYP7) cells exhibited sustainable antitumor efficacy, and all of the mice survived without recurrence 10 weeks post treatment. Strikingly, we demonstrated that single injection of CAR (hYP7) T cells derived from either healthy donor or HCC patient significantly regressed tumor growth in the orthotopic HCC mouse model. Using a highly sensitive droplet digital PCR (ddPCR), we detected high frequencies of CAR T cells in the spleen and tumor microenvironment of mice in the CAR (hYP7) group. By contrast, CD19 CAR T cells showed no sign of gene integration in either tissue. More importantly, we found that CD8+ CAR (hYP7) T cells recovered from mouse spleens exhibited much higher lytic activity against HCC cells than CD4+ CAR (hYP7) T cells. Finally, we found that the GPC3-targeted CAR T cells downregulated the Wnt signaling in HCC cells.
Conclusion: The hYP7 antibody-derived GPC3-specific CAR is a promising therapeutic that could be tested for the treatment of advanced stage liver cancer.
Citation Format: Dan Li, Nan Li, Yifan Zhang, Haiying Fu, Zhijian Duan, Alissa Hummer, Hongjia Yang, Madeline B. Torres, Xiaoling Luo, Ling Su, Hu Zhu, Josh Kramer, Jinqiu Chen, Xiaolin Wu, Matthew Hall, Qun Wang, Stephen Hewitt, Tim Greten, Mitchell Ho. Analysis of glypican 3-targeted chimeric antigen receptor T cells in hepatocellular carcinoma cell and mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2311.
Abstract 2335: Breast cancer cell-derived DNA activates STING pathway in macrophages
Authors: LIM GaYoung , Ka Na-Lee , Lee Mi-Ock 
Published: August 2019

Abstract
Cell-free DNA (cfDNA) has been studied to be a diagnostic and prognosic marker. In breast cancer, however, there have been few studies on the biological role of cfDNA in the tumor microenvironment. Thus, investigating a role of cfDNA released from cancer cells to the tumor microenvironment is important in order to understand cancer biology. In this study, we showed that free DNA was a mediator that elicited inflammation and activated stimulator of interferon genes (STING) signaling, an essential pathway in cytosolic DNA-associated innate immune reponses in breast cancer. First, we found that mRNA levels of pro-inflammatory cytokines were increased in THP-1 macrophage cells co-cultured with MDA-MB-231 breast cancer cells. Second, the amount of free double strand DNA derived from MDA-MB-231 cells culture media was much more than THP-1 cells. Third, there was little induction of STING pathway in response to exogenous DNA in MDA-MB-231 cells, suggesting that cancer cells may not be sensitive to exogenous DNA for activating STING pathway. In contrast, STING pathway was activated in response to exogenous DNA in THP-1 cells. Taken together, cancer cell-derived DNA could be a factor to induce inflammation through activating STING pathway in tumor-associated macrophages.
Citation Format: GaYoung LIM, Na-Lee Ka, Mi-Ock Lee. Breast cancer cell-derived DNA activates STING pathway in macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2335.
Abstract 2336: Clinical-pathological characterization of the immunomodulator subgroup of triple negative breast cancer as a promising step in the selection of patients in personalized immunotherapies
Authors: Bautista Ruben R. , Rodríguez Oscar Gerardo A. , Miranda Alfredo H. , Dehesa Alejandro Z. 
Published: August 2019

Abstract
Introduction: Triple Negative Breast Cancer (CMTN) represents 23.1% of breast cancer cases in Mexico, is defined as a tumor that is absent of hormone receptors (estrogen and progesterone) and low HER2 overexpression and clinically is characterized by its agressive tumoral behavior.
Lehmann et al. described an immunomodulatory (IM) group which is composed of genes for immune antigens and transduction pathways of immune signals and cytokines. Recent studies have shown that patients with the IM phenotype have a better prognosis. So it is important to continue with the description of this subgroup as the first step for personalized therapies in this heterogeneous tumor.
Methodology: Retrospective clinical study, patients with diagnosis of CMTN, attended at the National Cancer Institute of Mexico (Total: 69 patients) were included. Following, the extraction of RNA from the primary tumor tissue of CMTN paraffin blocks was performed to subsequently generate labeled cDNA for hybridization in Affymetrix® Human Gene 2.0 microarrays, to later carry out the scanning and analysis of the data. For the analysis of microarrays we used the free software R and Bioconductor.65. And then the classification of patients using the platform "TNBCtype (http://cbc.mc.vanderbilt.edu/tnbc/)". And finally the analysis of survival, univariate and multivariate through SPSS.
Results: We observed some clinical variables with statistical difference such as radiotherapy (p&lt;0.001), metastasis to lung (p=0.009), liver (p=0.013), and central nervous system (p=0.0029), as well as the Lehmann classifier showed significant difference between patients classified as IM vs. No IM (p=0.04).
Conclusions: the IM classifier could not only serve as an excellent prognostic classification in CMTN but as a predictor of immunological treatments.
Citation Format: Ruben R. Bautista, Oscar Gerardo A. Rodríguez, Alfredo H. Miranda, Alejandro Z. Dehesa. Clinical-pathological characterization of the immunomodulator subgroup of triple negative breast cancer as a promising step in the selection of patients in personalized immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2336.
Abstract 2340: Differentiation of pro- and anti-inflammatory features of monocyte-derived dendritic cells
Authors: Bakke Ragnhild Maukon , Azeem Waqas , Appel Silke , Kalland Karl-Henning , Oyan Anne Margrete 
Published: August 2019

Abstract
Background: Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system and are consequently exploited in cancer immunotherapy in order to present tumor-associated antigens to lymphocytes. The ability of tumor cells to induce tolerogenic DCs and avoid the immune system challenges DC-based immunotherapies. Utilizing buffycoats of healthy blood donors we have investigated the activation of gene expression programs conventionally associated with either pro- or anti-inflammatory features of monocyte-derived DCs.
Methodology: Following isolation of monocytes from buffycoats, various culture conditions were tested to generate immature DCs and to mature and activate them in vitro. Genome-wide gene expression, secretion of cytokines and tryptophan metabolites, surface expression of maturation and activation markers, and functional abilities were analyzed. Specifically, beta-catenin and indoleamine 2,3-dioxigenase 1 (IDO-1) activation were examined using both agonists and inhibitors of those pathways.
Results: A considerable variability among buffycoats of different healthy blood donors was observed regarding DC yield and cytokine secretion. Induction time to generate immature DCs with interleukin-4 and granulocyte-macrophage colony-stimulating factor affected DC differentiation. Several maturation conditions induced strong IDO-1 expression. Activation of beta-catenin during DC maturation induced anti-inflammatory features that could be competed by adding beta-catenin inhibitors during cultivation of the cells. Pro- and anti-inflammatory features often co-existed in mature DCs.
Conclusions: Beta-catenin and IDO-1 activation are prevalent according to different conditions of monocyte-derived DC maturation and associated with anti-inflammatory features. Both pathways can be inhibited by specific antagonists. More robust pro-inflammatory DC generation is desirable for more effective cancer immunotherapy.
Citation Format: Ragnhild Maukon Bakke, Waqas Azeem, Silke Appel, Karl-Henning Kalland, Anne Margrete Oyan. Differentiation of pro- and anti-inflammatory features of monocyte-derived dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2340.
Abstract 2347: NOD-like receptor NLRP12 suppresses hepatocellular carcinoma via regulation of JNK signaling
Authors: Zaki Hasan 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12, a member of NOD-like receptor, has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN) or DEN plus hepatotoxin carbon tetrachloride (CCl4). Livers collected from wild-type and Nlrp12-/- mice at 10 and 5.5 months following DEN or DEN plus CCl4 treatment, respectively, were examined for tumor burden, histopathological changes, expression of inflammatory and tumor-promoting genes, and activation of signaling pathways. Primary hepatocytes from healthy mice were isolated, cultured, and used to assess cell signaling, apoptosis, and proliferation. Cancer genomics database analysis showed that NLRP12 expression is significantly reduced in human HCC and 2-3% HCC patients carry mutations in NLRP12. Nlrp12-/- mice were highly susceptible to DEN or DEN plus CCl4-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling pathway analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. Inhibition of JNK activation or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, this study demonstrated for the first time that NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.
Citation Format: Hasan Zaki. NOD-like receptor NLRP12 suppresses hepatocellular carcinoma via regulation of JNK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2347.
Abstract 2362: NF-κB (p65) mediates interleukin-1 (IL-1) repression of androgen receptor (AR) in AR+prostate cancer (PCa) cell lines
Authors: Thomas-Jardin Shayna Elizabeth , Dahl Haley , Bautista Monica , Ha Freedom , Jacob Joan , Nawas Afshan Fathima , Kanshwala Mohammed , Xing Chao , Delk Nikki 
Published: August 2019

Abstract
Inflammation promotes cancer initiation and progression. The Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NF-κB) family of transcription factor proteins, p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1), and p100/52 (NF-κB2), form homo- and heterodimeric complexes that mediate inflammatory cytokine signaling. We previously reported that the inflammatory cytokines, interleukin-1 alpha (IL-1α) and IL-1 beta (IL-1β), repress androgen receptor (AR) levels and activity in AR+ prostate cancer (PCa) cell lines. AR drives PCa tumorigenicity and, thus, AR is a therapeutic target. Our data suggests that IL-1 selects for ARlow/-PCa cell subpopulations that can evade AR-targeting therapy. Using RNA sequencing, we identified an IL-1-regulated gene signature predicted to supported AR-independent tumorigenicity in PCa cells. Pathway analysis of the RNA sequencing data predicted that AR is a target molecule of p65 (RELA). p50:p65 heterodimers are known to mediate IL-1 signaling, therefore, we investigated if NF-κB (p50:p65) signaling mediates IL-1 repression of AR. We found that siRNA silencing of p65 is sufficient to attenuate IL-1 repression of AR mRNA and protein levels and AR activity in AR+ PCa cell lines, while siRNA silencing of p50 had no effect on IL-1 repression of AR. Our data suggests that p65 represses AR levels, directly or indirectly, in response to IL-1. Thus, therapeutic inhibition of p65 activity could prevent the accumulation of inflammation-induced treatment-resistance ARlow/- PCa cell subpopulations.
Citation Format: Shayna Elizabeth Thomas-Jardin, Haley Dahl, Monica Bautista, Freedom Ha, Joan Jacob, Afshan Fathima Nawas, Mohammed Kanshwala, Chao Xing, Nikki Delk. NF-κB (p65) mediates interleukin-1 (IL-1) repression of androgen receptor (AR) in AR+prostate cancer (PCa) cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2362.
Abstract 2365: Selective Stat3 inhibition in the tumor microenvironment restricts gastrointestinal tumor growth
Authors: Alorro Mariah Grace , Masson Frederick , Eissmann Moritz , Ernst Matthias 
Published: August 2019

Abstract
The transcription factor Stat3 plays essential roles in biological processes involving development, immunity and inflammation. Stat3 is known to regulate the expression of a large repertoire of genes which when deregulated, as in the context of tumorigenesis, can lead to the development of some of the well-known hallmarks of cancer, such as resistance to cell death and sustained proliferation. Indeed the aberrant activation of Stat3 has been characterized across a number of different cancers including gastrointestinal cancers, presenting Stat3 and its signalling pathway a promising therapeutic target. Although intrinsic Stat3 signalling in tumor cells is well characterized, the effect(s) of Stat3 signalling among the infiltrating cells of the tumor microenvironment is still poorly understood. With this project we aim to elucidate the role of Stat3 in the non-tumoral compartment, and explore the therapeutic value of Stat3 inhibition for gastric and colon cancer.
We generated the CAGsrtTA3;STAT3.1348 (shStat3) mouse that utilizes short-hairpin RNAi technology allowing for conditional and reversible Stat3 reduction. To study the effects of systemic Stat3 inhibition, the shStat3 was crossed with the gp130F/F mutant mouse that spontaneously develops gastric cancer. To assess the effects of Stat3 suppression in the non-tumoral compartment alone, the shStat3 mice were sub-cutaneously injected with MC38 murine colon cancer cells. Tumors and other tissues of these mice were excised and analysed.
We found that shStat3-mediated systemic Stat3 suppression resulted in significant tumor reduction in the gp130F/F gastric cancer mice. Similarly, isolated Stat3 reduction in the non-tumoral compartment of the shStat3 mice, restricted the growth of Stat3-proficient MC38 tumor allografts. Immunophenotyping of excised tumors highlighted an increase of a monocytic Ly6C+Ly6G- myeloid population.
Our data provides evidence for the therapeutic value of specific Stat3 targeting in gastrointestinal cancers. Interestingly, we have shown that Stat3 suppression in the non-tumoral compartment alone was enough to result in significant tumor reduction, indicating a prominent role of Stat3 in creating a pro-tumorigenic microenvironment. We have also identified a monocytic population as candidate cell type that drives this Stat3 suppression mediated anti-tumor effect.
Citation Format: Mariah Grace Alorro, Frederick Masson, Moritz Eissmann, Matthias Ernst. Selective Stat3 inhibition in the tumor microenvironment restricts gastrointestinal tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2365.
Abstract 2375: Developing double knock-in models of human immune checkpoint targets (dKI HuGEMM) for efficacy assessment of combinatorial therapeutic antibodies
Authors: Zheng Lei , He Daniel Xianfei , Sun Ruilin , An Annie Xiaoyu , Fei Jian , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: August 2019

Abstract
Immune checkpoint inhibitors (ICIs), i.e. PD1, PDL1 and CTLA4 therapeutic antibodies, have led to long-term survival in many late stage solid tumor patients. Despite their revolutionary clinical impact, the overall response rate is still low. One major roadblock is that compensatory immune inhibitory pathways are turned on to protect tumor cells from being attacked by T cells. Various combinatory ICI treatments have now been investigated in clinical trials to tackle this challenge. We have previously reported the development of immune checkpoint target humanized mice (HuGEMM) through CRISPR-Cas9 knock-in. We have generated PD1 and CTLA4 HuGEMM mice and used them for efficacy assessment of corresponding therapeutic antibodies. We have also generated human PDL1 expressing MC38 cells and PDL1 HuGEMM, and demonstrated robust efficacy of several PDL1 therapeutic antibodies. Here we report the establishment of double knock-in (dKI) mice of ICI targets, i.e., PD1/PDL1 and PD1/CTLA4 dKI HuGEMM, and use them as tools to test immunotherapies with PD1/PDL1 and PD1/CTLA4 combos. Similar to clinical benefit of PD1 and CTLA4 combo shown in the melanoma and NSCLC patients, we found combined treatment of Nivolumab and Ipilimumab antibody leads to 103% TGI in the corresponding PD1/CTLA4 dKI-HuGEMM, with complete tumor remission in 80% of treated mice. These mice remained disease free throughout a tumor re-challenge study for over 40 days. We have also developed PD1/PDL1 dKI HuGEMM and tested combined treatment of Atezolizumab and Nivolumab. Interestingly, we observed improved efficacy in the combo treatment group despite the two ICIs are thought to target the same PD1/PDL1 axis. Monotherapies may not fully release the PD1/PDL1 blockade due to complicity of multiple compatible ligands & receptors, including PDL2 and B7-1. We have also tested PD1/OX40 combo treatment with dKI HuGEMM, which is reported separately. Taken together, Our dKI HuGEMM models offer robust tests on ICI combinations, as well as combos of ICIs with other anti-tumor therapeutic modalities.
Citation Format: Lei Zheng, Daniel Xianfei He, Ruilin Sun, Annie Xiaoyu An, Jian Fei, Henry Qixiang Li, Davy Xuesong Ouyang. Developing double knock-in models of human immune checkpoint targets (dKI HuGEMM) for efficacy assessment of combinatorial therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2375.
Abstract 2393: Bridging MOA-based reporter bioassays with PBMC based ADCC for immunotherapy drug development
Authors: Cong Mei , Stecha Pete , paguio Aileen , binkowski brock , Cheng Zhi-Jie , Fan Frank 
Published: August 2019

Abstract
Having a functional bioassay that is MOA-based, accurate, precise, robust and reproducible is critical for the development of antibody-based biologics. We have developed reporter bioassays that meet these criteria for a broad range of antibody modalities including Fc effector function, immune checkpoint modulation, bispecific antibody engagement, cytokine modulation, and others. Here we will present the latest technology advancements and bridging of the PBMC based ADCC cell killing assay with reporter based ADCC Bioassay.
Citation Format: Mei Cong, Pete Stecha, Aileen paguio, brock binkowski, Zhi-Jie Cheng, Frank Fan. Bridging MOA-based reporter bioassays with PBMC based ADCC for immunotherapy drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2393.