bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5587: Novel monoclonal antibodies block N-glycosylation Sites of the MUC16 ectodomain in ovarian carcinoma
Authors: Thapi Dharmarao , Fernandez-Tejada Alberto , Axelrod Abraham J. , Rosales Nestor , Yan Xiujun , Stasenko Marina , Thapi Sahityasri , Wang Amy , Danishefsky Samuel J. , Spriggs David R. 
Published: July 2017

Abstract
The MUC16 gene encodes the CA125 antigen that imparts a negative survival impact on patients with high-grade serous ovarian cancer. Short elements from the C-terminal region of MUC16 transform 3T3 cells. Introduction of the 114 amino acid C-terminal portion of MUC16 promotes invasive growth in xenograft models. This effect is dependent on N-glycosylation sites of MUC16 and interactions present on the cell surface. Mechanisms by which the ectodomain promotes MUC16 oncogenic behaviors, the function of N-glycosylation and the implicated cell surface receptors are not fully delineated.
To unravel the complex MUC16 cancer biology, in this study we investigated the glycosylation-based mechanisms and potential partners involved in MUC16 oncogenic effects, and show that site-specific glycosylation of MUC16 plays a key role in mucin-related transformation by mediating complex cell surface interactions. These effects are mediated through MGAT5-dependent N-glycosylation of two proximal N- glycosylation sites within the 58 amino acid retained MUC16 ectodomain acting in combination with Galectin-3 and growth factor receptors. Neither N- nor O-glycosylation sites in the more distally located MUC16 regions can functionally substitute for those two sites. The tumor-enhancing properties of MUC16 depend on co-localization of MUC16, Galectin-3, and growth factors receptors on lipid rafts. Loss of either Galectin-3 expression or the glycosylation enzyme MGAT5 completely abrogates MUC16 tumor promotion. Using synthetic glycopeptides, we have developed novel monoclonal antibodies (mAbs) directed at the crucial ectodomain N-glycosylation sites to inhibit the glycosylation- dependent effects of MUC16 on metastasis and invasion. These novel antibodies were characterized in vitro and in vivo studies using various ovarian cancer cell lines. All of the antibodies against the N- glycosylation sites closest to the cell membrane of MUC16 block Galectin-3-mediated polymerization to cell surface signaling molecules and inhibit the tumor-promoting effects of MUC16. The implications are broad: both for the biological understanding of cancer mucin biology and for potential therapeutic strategies.
Citation Format: Dharmarao Thapi, Alberto Fernandez-Tejada, Abraham J. Axelrod, Nestor Rosales, Xiujun Yan, Marina Stasenko, Sahityasri Thapi, Amy Wang, Samuel J. Danishefsky, David R. Spriggs. Novel monoclonal antibodies block N-glycosylation Sites of the MUC16 ectodomain in ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5587. doi:10.1158/1538-7445.AM2017-5587
Abstract 5594: High throughput combinatorial profiling of checkpoint inhibitor antibodies on the iQue® Screener PLUS
Authors: Hasaka Tom 
Published: July 2017

Abstract
Checkpoint inhibitors have become valuable immuno-modulatory targets in the advancement of cancer treatment. Looking for the synergy between new checkpoint inhibitor antibodies and known inhibitors is an important aspect of this research. The iQue Screener PLUS platform is a powerful tool to simultaneously assess these interactions in a single well of a microtiter plate. ForeCyt® software provides plate-level analytics and high content visualization to generate deep insight rapidly. Using a mixed lymphocyte reaction (MLR) model, we profiled potential synergies of several known checkpoint inhibitors antibodies. Responses of PD-1, PD-L1, and CD73 inhibitors both individually, and in combination with CTLA-4 inhibitors, were assessed for proliferation, viability and cytokine secretion simultaneously in the same well. MultiCyt® cell-based and bead-based reagents were used for this analysis. Synergies ranging from 2-10 fold increase over CTLA-4 alone were observed in the secretion of TNFα and IL-1β. Results were obtained and analysis completed in a 384-well plate in 30 minutes. In conclusion, this study highlights the power of the iQue Screener PLUS platform to rapidly characterize multiple endpoints and the ForeCyt software to provide high content visualization that reveals actionable insights.
Citation Format: Tom Hasaka. High throughput combinatorial profiling of checkpoint inhibitor antibodies on the iQue® Screener PLUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5594. doi:10.1158/1538-7445.AM2017-5594
Abstract 5598: Adenosine signaling through A2AR limits the efficacy of anti-CTLA4 and chemotherapy in preclinical models
Authors: Ho Po , Hsieh Meng-Yin , Hotson Andrew , Miller Richard , McCaffery Ian , Willingham Stephen 
Published: July 2017

Abstract
Elevated levels of extracellular adenosine within the tumor microenvironment create an immunosuppressive niche that promotes tumor growth and metastasis. Adenosine signaling via the A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and has been shown to limit the efficacy of immunotherapies such as anti-PD-L1 or anti-PD-1 monoclonal antibodies (mAbs).
CPI-444 is a potent and selective oral A2AR antagonist that is currently being investigated in Phase 1/1b clinical trials alone and in combination with an anti-PD-L1 antibody (Atezolizumab) in selected solid tumors. New preclinical data suggests that combining CPI-444 with anti-CTLA-4 mAbs as well as chemotherapy treatment are also promising therapeutic strategies in solid tumors, suggesting a broad role for adenosine as an immune suppressive mechanism.
The efficacy of CPI-444 + anti-CTLA-4 mAb treatment was evaluated in MC38 and CT26 syngeneic mouse tumor models. In CT26, combination treatment eliminated established tumors in up to 90% of mice approximately 2 weeks after treatment was initiated. In MC38, combination CPI-444 and anti-CTLA-4 mAb treatment prolonged survival of 80% of mice compared to only 40% of mice that received CPI-444 or anti-CTLA-4 mAbs alone. The effect of CPI-444 + anti-CTLA-4 treatment on T-cell proliferation, T cell activation, and TREG function will be discussed.
Chemotherapy releases adenosine and ATP into the tumor microenvironment (TME). Multiple chemotherapies have also been shown to up-regulate the ecto-enzymes CD39 and CD73 that produce adenosine and further suppress immune function. In the MC38 model, CPI-444 treatment synergized with doxorubicin and eliminated established tumors 80% of treated mice. CPI-444 treatment was also synergistic with cyclophosphamide, inhibiting the growth of RENCA tumors, a model that is considered resistant to chemotherapy. Ongoing studies are evaluating the effect of CPI-444 + chemotherapy on tumor infiltrating lymphocyte localization, activation, and expression of CD73 and CD39.
These results suggest that blockade of the adenosine signaling pathway may be vital for enhancing anti-tumor responses in solid tumors that show an incomplete response to anti-CTLA4 therapy or chemotherapy.
Citation Format: Po Ho, Meng-Yin Hsieh, Andrew Hotson, Richard Miller, Ian McCaffery, Stephen Willingham. Adenosine signaling through A2AR limits the efficacy of anti-CTLA4 and chemotherapy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5598. doi:10.1158/1538-7445.AM2017-5598
Abstract 5611: Use of ecto-domain vimentin to target brain cancers
Authors: Babic Ivan , Mukthavaram Rajesh , Jiang Pengfei , Glassy Eric , Nomura Natsuko , Pingle Sandeep , Glassy Mark C. , Kesari Santosh 
Published: July 2017

Abstract
Pritumumab is a natural human IgG1 kappa antibody derived from a regional draining lymph node of a patient with cervical carcinoma. The recognized antigen is an altered form of vimentin, called ecto-domain vimentin (EDV), that is expressed on the cell surface of epithelial tumor cells. For brain cancers, immunohistological analysis showed the binding of pritumumab to EDV to be restricted to tumor cells and not normal cells and tissues suggesting EDV may be a useful biomarker. A recombinant version of the mAb was made using the GPEx® system in CHO cells that showed comparable binding activity by flow cytometry, immunohistochemical analysis, Western blot analysis, and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC; EC50 of 39.6ng/ml) activity. Further studies include establishing xenograft models with both SCID and athymic nude mice in which pritumumab was effective in preventing tumor growth of both brain cancer stem cells as well as pancreatic cancer in nude mice but not in SCID mice suggesting an active immune response is necessary for optimal treatment. Analysis of a blood brain barrier model suggests pritumumab shows minimal distribution in normal brain tissues and significant binding in tumor areas of brain tissues indicating the mAb crosses the tumor brain barrier. Overall, these data together suggest that EDV is a suitable target and biomarker for brain cancers.
Citation Format: Ivan Babic, Rajesh Mukthavaram, Pengfei Jiang, Eric Glassy, Natsuko Nomura, Sandeep Pingle, Mark C. Glassy, Santosh Kesari. Use of ecto-domain vimentin to target brain cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5611. doi:10.1158/1538-7445.AM2017-5611
Abstract 5627: Uncovering novel signaling pathways that mediate tumor cell killing by T effector cells
Authors: Kuilman Thomas , Vredevoogd David , Peeper Daniel S. 
Published: July 2017

Abstract
Recent advances in the understanding of tumor immunology have led to the development of various immunotherapeutic strategies, some of which show unprecedented clinical efficacies. Two of the most effective treatments, ipilimumab and pembrolizumab / nivolumab target the immune checkpoints factors CTLA-4 and PD-1, respectively. While not all patients respond to immunotherapy, those that do frequently show long-lasting clinical responses. These accomplishments have led to a surge in research focusing on the question how the immune system can be stimulated for more common durable therapy responses.
A current focus of tumor immunological research is the identification of mechanisms allowing cancer cells to evade recognition and/or killing by the immune system while facing immunotherapy. For example, abrogation of interferon-γ signaling pathway has been shown to result in escape of immune surveillance after pembrolizumab treatment. However, it is likely that other tumor cell-intrinsic mechanisms play a role, too.
To uncover novel pathways that are involved in resistance to immune checkpoint inhibitors, we aim to identify transcriptional changes in tumor cells that result from effector T-cell exposure. To this end, we established a co-culture platform of a panel of Mart1-expressing melanoma cell lines with primary CD8+ T cells expressing a matching TCR. The cell lines display varying degrees of sensitivity to T cells, allowing us to bioinformatically uncover differential expression depending on this range of sensitivities. Rather than concentrating on single genes, we have focused on pathways, gene sets and ontologies. These analyses have been integrated with various publically available transcriptomic data sets to identify a set of mechanisms that may contribute to T-cell mediated killing. We will systematically abrogate key factors using CRISPR technology in our co-culture platform and assess whether this affects T-cell mediated killing. Our ultimate goal is to test whether these factors, or their signaling pathways, are involved in resistance to immunotherapy in patients, and to develop new strategies to prevent immunotherapy resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Thomas Kuilman, David Vredevoogd, Daniel S. Peeper. Uncovering novel signaling pathways that mediate tumor cell killing by T effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5627. doi:10.1158/1538-7445.AM2017-5627
Abstract 5629: Modeling cyclophosphamide induced ovarian toxicity in a novel translational canine model
Authors: Basu Puja , Egbert Rebecca , Pasternak Evan , Petroff Brian , Songsasen Nucharin 
Published: July 2017

Abstract
Reproductive failure following chemotherapy and/or ionizing radiation is a major adverse event, for which there are no established preventive measures. In previous studies, our laboratory has documented that the selective estrogen receptor modulator, tamoxifen (TAM) is effective in both prevention and reversal of ovarian toxicity from cyclophosphamide (CTX) in rodent models. To validate the effectiveness of this approach in a more relevant model system, we have developed a canine ovarian explant tissue model system. Dogs present with many cancers spontaneously and their pathology and treatment approaches mirror those of the human cancers. Thus, canine cancers and their treatments are excellent translational models for human diseases. Furthermore, dogs share the same environment as humans and have longer life spans than rodents. Our laboratory has recently established a dog ovarian explant tissue model system using fresh ovaries collected at the time of ovariohysterectomy. In the current study, we hypothesized that ovarian toxicity induced by CTX will be reduced by co-administration of TAM. Using this system, freshly prepared ovarian cortical tissue sections are cultured in the presence of TAM and CTX. Ovarian tissue viability is assessed by primordial and primary follicle morphometry, where the number of primordial, primary and apoptotic follicles were counted in 9 sections of 1 mm3 of ovarian cortical tissue from each dog, using CTX (at 0, 1 and 10µM) concentrations combined with TAM (0 and10µM). The number and percentage of each follicle was assessed. In addition, granulosa cells proliferation is assessed using bromodeoxyuridine (BrdU) incorporation. Further, we show that, as in women, anti-mullerian hormone (AMH) can be used as an indicator of follicle reserves in the dog, thereby establishing their use as an in-vivo monitoring system to test ovarian viability in future clinical studies. This study is intended to underpin a subsequent canine clinical trial testing TAM as a countermeasure against infertility from cancer treatment in dogs.
Note: This abstract was not presented at the meeting.
Citation Format: Puja Basu, Rebecca Egbert, Evan Pasternak, Brian Petroff, Nucharin Songsasen. Modeling cyclophosphamide induced ovarian toxicity in a novel translational canine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5629. doi:10.1158/1538-7445.AM2017-5629
Abstract 5664: PLAG prevents the loss of circulating neutrophils in the chemotherapy induced neutropenia model
Authors: Kim Yong-Jae , Jung Jinseon , Lee Ha-Reum , Sohn Ki-Young , Kim Heung-Jae , Yoon Sun Young , Kim Jae Wha 
Published: July 2017

Abstract
Chemotherapy-induced neutropenia (CIN) is a common dose-limiting toxicity in cancer patients undergoing cytotoxic chemotherapy. It is generally understood that myelosuppression is the major mechanism resulting in CIN. However, an excessive extravasation (diapedesis) of neutrophils in response to tissue damage-caused by anti-cancer agents is also a possible mechanism. In this study, we have investigated the effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) for the maintenance of circulating neutrophil in the gemcitabine induced neutropenia. In CIN mouse model using anticancer drugs, PLAG effectively protected the loss of circulating neutrophils as similar to CXCR2 antagonist, reparixin. And succeeded in vitro neutrophil migration assay also revealed that chemo-attractive activity of neutrophil induced by treatment of anticancer drugs was completely interrupted by PLAG addition. Chemokine (C-X-C motif) ligand 2 (CXCL2) and CXCL8 were effectively induced by treatment of gemcitabine with dose dependent manner in monocyte cell lines and mainly mediated via the signal transducer and activator of transcription 3 (STAT3) signaling pathway. PLAG effectively attenuated gemcitabine induced CXCL2 and CXCL8 expression via interrupting STAT3 activity and also regulated gemcitabine induced macrophage 1 antigen (MAC-1) and L-selectin expression, which means that PLAG interrupted the acceleration of neutrophil extravasation under CIN. Also we have verified that PLAG analogues and metabolites were not affected on neutrophil migration unlike PLAG, suggesting that acetylated diacylglycerol has a key role to regulate on neutrophil migration. Collectively, modulating effect of PLAG on excessive neutrophil extravasation by chemotherapy via attenuating STAT3/CXCL2(8) pathway could be used as very powerful regimen for preventing of neutropenia during diverse chemotherapy.
Citation Format: Yong-Jae Kim, Jinseon Jung, Ha-Reum Lee, Ki-Young Sohn, Heung-Jae Kim, Sun Young Yoon, Jae Wha Kim. PLAG prevents the loss of circulating neutrophils in the chemotherapy induced neutropenia model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5664. doi:10.1158/1538-7445.AM2017-5664
Abstract 5672: Quantitative cell-based assays for characterization of antibodies targeting co-stimulatory immune checkpoint receptors
Authors: Gilden Julia K. , Wang Jun , Beck Michael , Grailer Jamison , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhe-jie Jey 
Published: July 2017

Abstract
The human immune system is regulated by a broad network of co-inhibitory and co-stimulatory receptors that control the type, scale, and duration of immune responses. These receptors are now recognized as promising immunotherapy targets for the treatment of many cancers and autoimmune diseases. Immunotherapies that block co-inhibitory receptors such as PD-1 and CTLA-4 are showing unprecedented efficacy in the treatment of some tumors, and have generated interest in the characterization of additional immunotherapy targets that may broaden the number of patients who can be helped by these drugs. Immunotherapy research programs are now exploring a wide range of both co-inhibitory (e.g. LAG-3, TIGIT, Tim-3) and co-stimulatory (e.g. GITR, 4-1BB, OX40) receptors, individually and in combination. Quantitative and reproducible functional bioassays are essential tools in the development of biologics for cancer immunotherapy. Most existing assays rely on primary cells and suffer from lengthy protocols and high day-to-day and donor-to-donor variability. These approaches are cumbersome, error-prone, and do not produce data of the quality required for drug development in a quality control environment. To address this, we have developed a suite of cell line-based reporter bioassays for co-stimulatory immune checkpoint targets including GITR, 4-1BB, OX40, and CD40. In these assays, stable cell lines express luciferase reporters driven by response elements under the precise control of intracellular signals mediated by each co-stimulatory receptor. These bioassays reflect mechanisms of action for drug candidates designed for each co-stimulatory receptor and demonstrate high specificity, sensitivity and reproducibility. Reporter-based bioassays can serve as powerful tools in immunotherapy drug development for antibody screening, potency testing and stability studies.
Citation Format: Julia K. Gilden, Jun Wang, Michael Beck, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhe-jie Jey Cheng. Quantitative cell-based assays for characterization of antibodies targeting co-stimulatory immune checkpoint receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5672. doi:10.1158/1538-7445.AM2017-5672
Abstract 5674: Cancer immunogenomics for the development of personalized ovarian cancer vaccine
Authors: Want Muzamil Y. , Tsuji Takemasa , Koya Richard , Battaglia Sebastiano 
Published: July 2017

Abstract
Ovarian cancer (OC) is the fifth leading cause of cancer death in the United States with approximately 20,000 women being diagnosed every year. Since OC development is mainly asymptomatic, patients are often diagnosed at late stage and present local and distal metastases. This offers a clinical challenge, as roughly 70% of the patients develop chemoresistant disease. With the advent of cancer immunogenomics it is now possible to identify tumor specific mutations, or neoantigens/neoepitopes, that can be exploited for the development of personalized T cell therapies via DC vaccines or adoptive cell therapy (ACT). We therefore hypothesize that tumor cells isolated from malignant ascites reflect the genomic landscape of the primary tumor, offering a unique opportunity to identify clinically actionable tumor neoantigens. We utilized primary tumor, tumor cells isolated from malignant ascites and metastatic samples to create patient-derived xenografts (PDX) mice and to interrogate the tumor mutational landscape. Somatic mutations were identified by whole exome sequencing (WES) and RNASeq analysis in tumor samples, using PBMCs as germline control. In parallel 20 PDX of ovarian cancer were established in NSG mice by injecting 2×106 cells/mouse subcutaneously (SQ, n=10) and intraperitoneally (IP, n=10). Tumor growth was monitored weekly via caliper measurement for mice injected SQ and via abdominal circumference for mice injected IP. Mutational analysis and prediction of high affinity peptides was done using bioinformatics approach. We have utilized different algorithms that are based on Artificial Neural Networks or published motifs for predicting binding of 8-11 mer peptides to number of Human MHC alleles (HLA) and out of 168 mutated peptides identified, 30 were found to have high affinity for different HLAs compared to wild type peptide. Mutated and wild type peptides were pulsed into dendritic cells and co-cultured with CD8+ T cells for 20 days. Validation of stimulated CD8+ T cells by these mutated peptides using ELISPOT is underway. TCR specific for neoantigen from CD8+T cells will be identified and cloned using retroviral vectors. Transfected CD8+ T cells with neoantigen specific TCR will be confirmed by co-culturing them with dendritic cells pulsed with wild type and mutated peptides. Further engineered CD8+ T cells specific for neoantigens will be tested for adoptive cell therapy in the established PDX models of ovarian cancer.
Citation Format: Muzamil Y. Want, Takemasa Tsuji, Richard Koya, Sebastiano Battaglia. Cancer immunogenomics for the development of personalized ovarian cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5674. doi:10.1158/1538-7445.AM2017-5674