bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4866: Development and characterization of novel CD40 antibody agonists for cancer immunotherapy
Authors: Vitale Laura A. , O’Neill Thomas , Widger Jenifer , Crocker Andrea , He Li-Zhen , Weidlick Jeffrey , Sundarapandiyan Karuna , Storey James , Thomas Lawrence , Goldstein Joel , Marsh Henry C. , Keler Tibor 
Published: July 2016

Abstract
CD40 is a key molecule in the regulation of immune responses and its activity can be modulated using antibodies. In particular, agonist CD40 antibodies are highly effective in preclinical tumor models either through direct interaction with CD40-expressing lymphomas, or indirectly through the activation of an adaptive anti-tumor immune response. To date, limited clinical data have been reported with strong CD40 agonist antibodies; nonetheless it seems likely that targeting this pathway will require a balance between the benefits of immune stimulation to drive anti-tumor responses, and the damage that can result from non-specific immune cell activation. We set out to develop novel human anti-CD40 antibodies with different levels of agonist activity to identify a lead candidate for systemic application.
Anti-CD40 monoclonal antibodies (mAbs) were generated by immunization of human Ig transgenic mice with recombinant and cell surface expressed human CD40. Hybridomas developed from these mice were screened using CD40 binding assays and activity on a reporter cell line engineered to express CD40 and NFêB-responsive luciferase. The variable regions of lead antibodies that displayed differential activity were cloned into vectors containing human IgG1 or IgG2 constant domains and expressed in CHO cells.
These human CD40 mAbs were further characterized by analysis of binding affinity, CD40L blocking activity, B cell and dendritic cell activation, and anti-tumor activity in xenograft tumor models. We found a wide range of activities among the CD40 mAbs that is linked to epitope specificity as well as the isotype. In general, the IgG2 isotype mAbs had greater signaling activity than their IgG1 counterparts. The lead candidate mAbs are undergoing additional testing related to functional and toxicity parameters before a final candidate is nominated for clinical development.
Citation Format: Laura A. Vitale, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, James Storey, Lawrence Thomas, Joel Goldstein, Henry C. Marsh, Tibor Keler. Development and characterization of novel CD40 antibody agonists 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 4866.
Abstract 4874: Interleukin-12/FasTI: A novel bi-functional fusion protein for cancer immunotherapy
Authors: Yang Xi , Tietje Ashlee , Yu Xianzhong , Wei Yanzhang 
Published: July 2016

Abstract
Whereas cancer immunotherapy with cytokines demonstrates effective in activating immune response against tumor cells, one major obstacle with the use of these cytokines is their severe side effects when delivered systemically at high doses. Another challenge is that advanced tumor cells often evade immunosurveillance of the immune system and block the Fas-mediated apoptosis by down-regulating its expression. In the present study, we report the design and preliminary evaluation of the antitumor activity of a novel fusion protein:mIL-12/FasTI, consisting of mIL-12 and the transmembrane and intracellular domains of Fas. The fusion construct (pmIL-12/FasTI) was transfected into mouse lung carcinoma cell line TC-1. Stable cell clones expressing the fusion protein were established as assayed by RT-PCR and immunohistochemistry. ELISA and cell proliferation analyses demonstrated that NK cells were effectively activated by the fusion protein with increased IFN-ã production and cytotoxicity. Enhanced caspase 3 activity of the clones when co-cultured with NK cells demonstrated that apoptosis was induced through Fas/FasL signaling pathway. The bifunctional protein is clearly more effective than IL-12 alone. It, therefore, represents a promising new therapeutic agent for cancer treatment when combined with tumor cell-specific gene delivery.
Citation Format: Xi Yang, Ashlee Tietje, Xianzhong Yu, Yanzhang Wei. Interleukin-12/FasTI: A novel bi-functional fusion protein 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 4874.
Abstract 4878: Quantitative cell-based bioassays for therapeutic development targeting immune checkpoint and co-stimulatory receptors
Authors: Grailer Jamison , Stecha Pete , Wang Jun , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: July 2016

Abstract
Immunotherapy harnesses the immune system to fight cancer and has proven to be a very promising therapeutic strategy. Drug targets in cancer immunotherapy include both inhibitory and co-stimulatory immune receptors on T cells or NK cells, in particular. Current approaches to assay immunotherapy biologics rely on primary cells, are highly variable, and are not suitable for a quality control environment during drug development. We have developed a panel of cell-based assays using a bioluminescent reporter platform that can quantitatively determine the potencies of antibodies and ligand proteins targeting immune checkpoint receptors and co-stimulatory receptors including PD-1, CTLA-4, LAG-3, GITR, 4-1BB, OX40 and CD40. For each target, a stable cell line was generated in an immune cell background to stably express an immune checkpoint or co-stimulatory receptor and a luciferase reporter driven by a response element specifically responding to signaling induced by TCR or directly from the immune receptor. These bioassays reflect biological mode-of-action for each class of drug candidate and are able to determine the potencies for on-market biologic drugs including PD-1 antibodies pembrolizumab and nivolumab, and CTLA-4 antibody ipilimumab. The assay signals are robust, specific, and have good repeatability and linearity. Therefore they can serve as valuable tools for drug screening, QC lot release and stability studies in immunotherapy drug development.
Citation Format: Jamison Grailer, Pete Stecha, Jun Wang, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays for therapeutic development targeting immune checkpoint and co-stimulatory receptors. [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 4878.
Abstract 4894: Relationship of characterization of the immunological microenvironment and pathological response in advanced rectal cancer after oxaliplatin-based neoadjuvant chemotherapy
Authors: Sekizawa Kentaro , Ichikawa Yasushi , Ishibe Atsushi , Suwa Hirokazu , Momiyama Masashi , Kato Ikuma , Ota Mitsuyoshi , Endo Itaru 
Published: July 2016

Abstract
Background:
Characterization of the immunological microenvironment has been demonstrated to be associated with prognosis and the effect of chemotherapy of various cancers. Then it has been shown by their role several studies in 5-FU-based neoadjuvant chemoradiotherapy for rectal cancer. However, their role in neoadjuvant chemotherapy (NAC) for rectal cancer remains unknown. The objective of this study was to examine the relationship between immune reactions and the pathological response to induction oxaliplatin-based NAC in patients with advanced rectal cancer.
Methods:
A total of 65 patients with advanced rectal cancer who underwent induction oxaliplatin-based NAC followed by surgical resection were enrolled. The resected tumor specimens were counted positive cell of tumor infiltrating lymphocytes (TILs) and macrophages by using immunohistochemical staining for CD3, CD8, Foxp3, CD86, CD206. We analyzed for the relationship between the numbers of TILs or macrophages at the stroma in resected specimens and the pathological response to induction oxaliplatin-based NAC.
Results:
The numbers of Foxp3+ TILs in resected specimens were strongly correlated with pathological response. Patients with higher number of Foxp3+ TILs showed poor pathological response (p&lt;0.001). There were no statistically significant differences between the number of CD3+, CD8+ TILs and pathological response, but patients with higher ratio of CD8+/FOXP3+ TILs was associated with good pathological response (p = 0.023). No associations were observed between the numbers of CD86+, CD206+ macrophages and pathological response.
Conclusions:
In rectal cancer patients, T lymphocyte-mediated immune reactions significantly correlated with pathological response of oxaliplatin-based NAC for advanced rectal cancer. These were similar to the T lymphocyte-mediated immune responses in the neoadjuvant radiation therapy for rectal cancer.
Citation Format: Kentaro Sekizawa, Yasushi Ichikawa, Atsushi Ishibe, Hirokazu Suwa, Masashi Momiyama, Ikuma Kato, Mitsuyoshi Ota, Itaru Endo. Relationship of characterization of the immunological microenvironment and pathological response in advanced rectal cancer after oxaliplatin-based neoadjuvant chemotherapy. [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 4894.
Abstract 4898: Effects of chemotherapeutic agents on the tumor immune microenvironment
Authors: Belvin Marcia P. , Luoh Shiuh-Ming , Cheung Jeanne , McNamara Erin , Cubas Rafael , Kim Jeong 
Published: July 2016

Abstract
Immunotherapeutic agents have shown dramatic success in oncology in recent years and several have been approved in melanoma and lung cancer. One strategy for extending the benefit of immunotherapy is to evaluate these agents in combination with standard of care chemotherapy, with the goal of bringing the benefit of immunotherapy into earlier lines of treatment.
We have carried out a systematic evaluation of the effects of different classes of chemotherapeutic agents (including alkylating agents, platinum based agents, and taxanes) on the tumor immune microenvironment of syngeneic murine tumor models (CT26 and MC38) in two different strains of mice (BALB/c and C57BL/6). We found that different chemotherapeutic agents caused markedly different changes in the composition and cell phenotype of the tumor immune environment. The majority of chemotherapeutic agents resulted in a mild to moderate increase in CD8+ T cells in the tumor. Some agents also altered the activation state of these CD8+ cells as measured by the level of PD-1 and IFN-gamma. A subset of the chemotherapeutic agents resulted in profound changes in the number of CD4+ cells, including regulatory T cells, as well as changes in myeloid subpopulations including monocytes, neutrophils, and macrophages. In addition to single agents studies, we carried out combination studies of selected chemo agents with simultaneous addition of anti-PD-L1. Several of these combinations caused pronounced increases in efficacy above single agent treatment. We will present the combination pharmacodynamic marker changes and efficacy of these treatments.
Our findings demonstrate that chemotherapeutic agents can stimulate the tumor immune environment, at least transiently, through multiple mechanisms. Different subsets of chemotherapeutic agents display unique changes in the tumor immune infiltrate, and may require different immunotherapeutic approaches. These findings provide a rationale for testing immunotherapy-chemotherapy combinations in the clinic.
Citation Format: Marcia P. Belvin, Shiuh-Ming Luoh, Jeanne Cheung, Erin McNamara, Rafael Cubas, Jeong Kim. Effects of chemotherapeutic agents on the tumor immune microenvironment. [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 4898.
Abstract 4902: A mouse GITRL fusion protein drives T-cell activation and antitumor activity in preclinical mouse models of cancer
Authors: Leyland Rebecca , Watkins Amanda , Mulgrew Kathy A. , Bamber Lisa , Tigue Natalie J. , Dick Emily , Holoweckyj Nick , Young Lesley , Morrow Michelle , Hammond Scott A. , Leow Ching Ching , Wilkinson Robert W. , Stewart Ross 
Published: July 2016

Abstract
GITR is a member of the TNFR superfamily of proteins and is expressed on resting regulatory T-cells and on other T-cells following activation. Signals through GITR have been shown to drive increased T-cell activity and reduced regulatory T-cell function. In order to explore the potential of therapeutically targeting GITR in a cancer setting, we generated a mouse GITRL fusion protein (mGITRL FP) consisting of the extracellular domain of mGITRL linked to a structural domain and an IgG Fc domain. The antitumor activity and pharmacodynamic effects of this molecule were then explored in the colorectal syngeneic model of cancer (CT26). Treatment of mice with mGITRL FP mediated anti-tumor activity that was dependent on isotype and exposure. The anti-tumor activity could be attributed at least in part to the increased activation and proliferation status of CD8+ and CD4+ T-cells, as evidenced by increases in Ki67 expression and ICOS upregulation. Intratumourally we observed a significant decrease in the frequency of CD4+ T-cells (including T regs), but a corresponding increase in cytotoxic CD8+ T-cells. OX40 is another member of the TNFR superfamily, that has similar expression and functions to GITR. In order to better understand the potential differences between targeting of these two pathways, the activity and pharmacodynamic effects of the mGITRL FP were additionally compared and contrasted to those of a mOX40L FP and the observed differences will be discussed.
Citation Format: Rebecca Leyland, Amanda Watkins, Kathy A. Mulgrew, Lisa Bamber, Natalie J. Tigue, Emily Dick, Nick Holoweckyj, Lesley Young, Michelle Morrow, Scott A. Hammond, Ching Ching Leow, Robert W. Wilkinson, Ross Stewart. A mouse GITRL fusion protein drives T-cell activation and antitumor activity in preclinical mouse models of 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 4902.
Abstract 4928: MiR expression profiles can predict response to systemic treatment in patients with advanced colorectal cancer
Authors: Poel Dennis , Neerincx Maarten , Sie Daoud L.S. , van Grieken Nicole C.T. , Shankaraiah R , van der Wolf F. S.W. , van Waesberghe J. H.T.M , Burggraaf J. D. , Eijk Paul P. , Ylstra Bauke , Verhoef Cees , van de Wiel Mark A. , Verheul Henk M.W. , Buffart Tineke E. 
Published: July 2016

Abstract
Background and aim: Patients with advanced colorectal cancer (mCRC) are commonly treated with systemic treatment consisting of fluoropyrimidine-based regimens being ineffective in 20-25% of the patients. Currently, selection criteria for patients to predict who will respond to this treatment is lacking. The aim of this study is to identify which patients will respond to first line fluoropyrimidine-based treatment based using microRNA (miR) expression profiles in order to avoid ineffective treatment.
Material and methods: Total RNA was isolated from 88 fresh frozen colorectal cancer tissue samples consisting of ≥ 70% tumor cells, collected from patients with mCRC. MiR expression profiles were generated by next generation sequencing using the Illumina High Seq 2000 platform. Of all patients clinical and pathological data, including treatment response based on RECIST criteria, were collected. Class prediction and miR selection were performed using the GRidge package in R. Penalized selection and internal cross validation were used to select miRs predictive for treatment response.
RESULTS: Next generation sequencing resulted in a mean of 10.087.107 (range 6.114.932 to 74.313.067) reads per sample corresponding to 2567 unique mature miR sequences, including 457 novel candidate and 2110 known miRs sequences (miRbase version 19). Penalized regression analysis on tumor specific miRs identified an expression profile which was predictive for clinical benefit (defined as response and stable disease) from first line treatment.
Conclusion: With miR profiling of CRC tissue samples response prediction to first line fluoropyrimidine-based treatment in patients with mCRC is possible. We foresee that selection of treatment using miR expression profiling will avoid unnecessary treatment related toxicity and improve outcome for patients with mCRC
Citation Format: Dennis Poel, Maarten Neerincx, Daoud L.S. Sie, Nicole C.T. van Grieken, R Shankaraiah, F. S.W. van der Wolf, J. H.T.M van Waesberghe, J. D. Burggraaf, Paul P. Eijk, Bauke Ylstra, Cees Verhoef, Mark A. van de Wiel, Henk M.W. Verheul, Tineke E. Buffart. MiR expression profiles can predict response to systemic treatment in patients with advanced colorectal 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 4928.
Abstract 4940: Use of whole slide digital image analysis for determination of expression of Twist-1 in normal panceata and stage IV pancreatic ductal adenocarcinomas
Authors: Jacobsen Max , Sandusky George , Shah Kavita 
Published: July 2016

Abstract
Pancreatic cancer is the 4th most common cause of cancer deaths in this country. Close to 50,000 deaths occur every year. This is due to the fact that most patients are not diagnosed until presentation at a stage IV. In a recent study, it is estimated that more than 10 years go by between the first genetic mutation and the formation of invasive cancer. More mutations occur in metastatic lesions after an additional 6 years. Both SNAIL and TWIST have gained more attention as biomarkers because that contribute to E-cadherin dysregulation that allows the tumor cells to invade. In this study we evaluated 17 cases of pancreatic ductal adenocarcinoma using twist-1 antibody to evaluate tumor cell expression in these cases. All paraffin blocks were retrieved from the IU pathology department files via an IRB approved protocol. The unstained slides were stained with primary antibody Twist-1 using the DAKO Flex system. Control sections were treated with an isotype control using the same concentration as primary antibody to verify the staining specificity. The Aperio whole slide system was used to image the slides. Computer-assisted morphometric analysis of digital images was carried out using the Aperio Image scope software using the positive pixel algorithm. The algorithm was used to quantify the Twist-1 positivity of normal pancreas, and pancreatic ductal adenocarcinoma. This algorithm is the only FDA approved algorithm for human clinical trials. The immunostaining of Twist-1 was found only in the ductal epithelial carcinoma cells in the pancreas. There was no staining in the stroma in any of the normal pancreas and ductal pancreatic carcinoma cases. We analyzed 5 normal pancreata, and 12 pancreatic ductal adenocarcinomas. The data from the image analysis was 3.38% expression in normal pancreata and 11.44% expression in the pancreatic ductal adenocarcinoma. In summary, the image analysis data demonstrates the overexpression of Twist-1 in stage IV pancreatic adenocarcinomas compared to the normal pancreas. This suggests that this marker may be a predictor of tumor invasiveness and metastasis.
Citation Format: Max Jacobsen, George Sandusky, Kavita Shah. Use of whole slide digital image analysis for determination of expression of Twist-1 in normal panceata and stage IV pancreatic ductal adenocarcinomas. [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 4940.
Abstract 4941: Overexpression of Reg proteins in human pancreatic ductal adenocarcinoma and acinar-to-ductal metaplasia
Authors: Li Qing , Wang Hao , Zogopoulos George , Shao Qin , Liu Jun-Li , Gao Zu-Hua 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types, with a 5-year survival rate &lt;5%. Tumor specific biomarkers that can aid in early detection and treatment monitoring are urgently needed in order to improve the outcomes. Human Reg family proteins (Reg1A, Reg1B, Reg3A, Reg3G and Reg4) are a group of calcium-dependent (C-type) lectins that promote cell growth and respond to inflammatory stimulants. We examined their associations with pancreatic ductal adenocarcinoma (PDAC). In patients with PDAC, the serum levels of Reg1A and 1B were significantly elevated (p = 0.0003 and 0.0018), which correlated with TNM stages of the patients. By using immunohistochemistry (IHC), the expression of Reg1A, Reg1B and Reg4 was observed in the malignant glandular epithelium of pancreatic intraepithelial neoplasia (PanIN) and invasive PDAC. The intensity of Reg1A and Reg1B staining positively correlated with the histological grades of PanIN. The serum levels and tissue expression of Reg1A and Reg1B were negatively correlated with the differentiation grades of invasive PDAC. Additionally, patchy expression of Reg1A andReg3A/G was also observed in areas with acinar-to-ductal metaplasia (ADM) adjacent to cancer cells. Our data suggests that the changes in Reg proteins were closely associated with the carcinogenesis of PDAC. Reg1A and 1B proteins showed specificity for pancreatic ductal differentiation and could be used as clinical markers for early detection of PDAC, monitoring therapeutic response and predicting tumor recurrence after therapy and tumor metastasis. The expression of Reg family proteins in both ADM and PanIN cells supports the notion that ADM could be an alternative mechanism of PDAC carcinogenesis.
Citation Format: Qing Li, Hao Wang, George Zogopoulos, Qin Shao, Jun-Li Liu, Zu-Hua Gao. Overexpression of Reg proteins in human pancreatic ductal adenocarcinoma and acinar-to-ductal metaplasia. [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 4941.