bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A12: PDL-1 blockade and Sunitinib enhance the efficiency of oncolytic viral therapy
Authors: Mostafa Ahmed , Gratton Kathy , Lawson Keith A. , Shi Zhong-Qiao , Thirukkumaran Chandini , Morris Don G. 
Published: October 2015

Abstract
Purpose: Oncolytic viruses (OV) are attractive for use against multiple tumours given their ability to prime therapeutic immune responses in addition to their direct cytotoxic effects. We investigated the utility of reovirus, an OV currently in phase III clinical trials, as a novel immunotherapeutic against renal cell (RCC), non small cell lung (NSCLC) and breast carcinomas (BrCa) as both a monotherapy and in combination with sunitinib, a first line metastatic RCC agent. In addition the utility of adding an immune checkpoint inhibitor was investigated.
Experimental Design: In-vitro, cytotoxicity, viral replication and chemokine production were assessed in a panel of human and murine cancer cell lines following exposure to reovirus, sunitinib or their combination. In-vivo, RENCA (murine renal cell carcinoma) cells were implanted subcutaneously into female balb/c mice to establish a syngeneic immunocompetent model of RCC. Tumor growth and overall survival were assessed following treatment with reovirus, sunitinib or their combination. IFN-γ, myeloid-derived suppressor cells (MDSC), and protective immunity were assessed by ELISA, flow cytometry (Gr1+/CD11b+) and adoptive transfer experiments, respectively. PDL-1 and PD-1 expression on both tumour and immune cells were assayed.
Results: In vitro, exposure of RCC cell lines to reovirus resulted in an inflammatory cytotoxic response that was augmented through combination with sunitinib. In vivo, reovirus significantly reduced RENCA tumor burden and generated an anti-tumor immune response that was augmented by sunitinib. Combinations with sunitinib also lead to a decrease in myeloid-derived suppressor cells (MDSC) and resulted in improved overall survival and enhanced protective immunity. Preliminary results in NSCLC and BrCa are suggestive that this strategy maybe applicable to many cancer histologies. Both PDL-1 and PD-1 expression were up regulated by RV (similar to IFN gamma) in the majority of cell lines tested suggesting a potential role for checkpoint blockade (CB).
Conclusions: Reovirus has both direct oncolytic and immunotherapeutic activity against RCC, which is augmented through combination with sunitinib. The role of immune CB is ongoing. These proof-of-principle investigations provide clear rationale to investigate RV/sunitinib/immune CB as a promising approach for early phase clinical trials as a novel treatment strategy for cancer.
Citation Format: Ahmed Mostafa, Kathy Gratton, Keith A. Lawson, Zhong-Qiao Shi, Chandini Thirukkumaran, Don G. Morris. PDL-1 blockade and Sunitinib enhance the efficiency of oncolytic viral therapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A12.
Abstract A18: A systems biology approach to predict immunotherapy augmented abscopal effects
Authors: Poleszczuk Jan , Prokopiou Sotiris , Robertson-Tessi Mark , Luddy Kimberly , Moros Eduardo , Fishman Mayer , Djeu Julie , Enderling Heiko 
Published: October 2015

Abstract
Introduction and Objectives: Radiation-induced abscopal effects are characterized by regression of tumor nodules outside the local radiation treatment field. Abscopal effects have been reported in metastatic lymphoma, melanoma, lung and breast cancer as well as renal cell carcinoma amongst others. Radiotherapy causes a perturbation to the local immune profile that is propagated throughout the lymphatic system, shifting systemic immune surveillance towards tumor eradication in distant, non-irradiated sites as well as circulating micrometastases. We hypothesize that abscopal effects could be triggered by targeting combined radiation and immunotherapy to immunogenic hubs in the patient-specific interconnected metastatic-lymphatic network.
Materials and Methods: We develop a mathematical model of the systemic response to local radio-immunotherapy. Patient-specific positron emission tomography (PET) scans provide the size and location of each tumor nodule. Metastatic geography is mapped onto the lymphatic network and connections between metastatic sites and lymphatic nodes are calculated. We quantify immune signal flow through the lymphatic network and amplifications through metastatic sites. A local model describes the temporal coevolution of tumor size with effector and regulatory T cells. The local and global models are coupled to quantify systemic responses to local treatment of each tumor site.
Results: The ‘virtual patient’ framework successfully simulates the abscopal effect reported for 2 patients with widely metastatic melanoma and non-small cell lung cancer. Model simulations suggest that only one or two tumor nodules in each patient serve as immunogenic hubs that could trigger an abscopal response. Radio-immunotherapy of any other lesion would result in local tumor control but systemic disease progression.
Conclusions: Careful selection of immunogenic ‘hub’ nodules holds the key to successful abscopal disease control. The presented mathematical framework may help to identify the immunogenicity of each tumor nodule. Before serving as a novel decision support tool, rigorous calibration and validation remains to be pursued as more clinical abscopal data becomes available.
Citation Format: Jan Poleszczuk, Sotiris Prokopiou, Mark Robertson-Tessi, Kimberly Luddy, Eduardo Moros, Mayer Fishman, Julie Djeu, Heiko Enderling. A systems biology approach to predict immunotherapy augmented abscopal effects. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A18.
Abstract A59: Novel inhibitors of human IDO1 and TDO
Authors: Banerjee Monali , Middya Sandip , Shrivastava Ritesh , Raina Sushil , Yadav Dharmendra , Singh Satveer , Manna Anindita , Chakraborty Debjani , Surya Arjun 
Published: October 2015

Abstract
In several human cancers, increased production of the tryptophan metabolite kynurenine by the enzymes indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) creates a tolerogenic environment that promotes tumor driven immune suppression. One or both of these enzymes is up-regulated in a number of immune cells and in approximately 50% of human tumors (Pilotte et al., 2012). We have designed and synthesized novel inhibitors of IDO1 and dual inhibitors of IDO1 and TDO (PCT/US14/24920) that inhibit IDO1 in vitro and drop kynurenine production in established human cellular models of IDO1 (IFNγ treated HeLa cells) and/or TDO (A172 glioblastoma cells) and enhance T cell proliferation in a mixed culture assay. Further, these molecules cause a steep and durable reduction in plasma kynurenine in LPS treated c57/Bl6 mice, demonstrating inverse correlation between drug and kynurenine levels. In order to evaluate their therapeutic potential we monitored tumor penetration by the compounds and concomitant tumor kynurenine reduction in Balb/c mice implanted with the murine colon carcinoma CT-26 cell line. Several compounds drastically reduced tumor kynurenine levels compared to vehicle treated animals. One such compound, Compound 1, was further evaluated for its ability to reduce tumor burden both as monotherapy and in combination with doxorubicin. Currently we have nominated candidate compounds which are either IDO1 specific or IDO1/TDO dual inhibitors for regulatory toxicology.
Citation Format: Monali Banerjee, Sandip Middya, Ritesh Shrivastava, Sushil Raina, Dharmendra Yadav, Satveer Singh, Anindita Manna, Debjani Chakraborty, Arjun Surya. Novel inhibitors of human IDO1 and TDO. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A59.
Abstract A80: Validation and clinical correlation of triplex CD3, CD8 and FOXP3 IHC of tumor-infiltrating lymphocytes in follicular lymphoma
Authors: Mansfield James R. , Slater Christian , Byers Richard 
Published: October 2015

Abstract
It is clear that immune cells play many sometimes conflicting roles in the tumor microenvironment and it would be extremely useful to be able to visualize the distributions of multiple phenotyped immune cells in-situ in solid tumors. However, obtaining phenotypic information about the various cells that play these roles in and around the tumor has been a challenge. Existing methods can either deliver phenotypic information on homogenous samples (e.g., flow cytometry) or morphologic information on single immunomarkers (standard IHC). These limitations can be largely overcome through a multiplexed staining, imaging and analysis methodology using standard clinical FFPE tissue sections. Although multiplex methods have been shown to be particularly useful not much has been presented on the validation of such methods. We present here a validation of the method for CD3, CD8 and FOXP3 in tissue microarray containing triplex follicular lymphoma cores from 40 subjects [24 male, 16 female, age 35 to 75 years at diagnosis, median 55 years , 2- 171 months follow-up]. This involves a sequential multi-marker labeling for 3 antigens and a counterstain; automated multispectral imaging to separate chromogens; and an automated analysis that can quantitate the per-cell marker expression, determine the cellular phenotype, count these cells separately in the tumor compartment and in the stroma and provide high-resolution images of their distributions. The IHC for each marker was optimized in as single-stain IHC and then those specifications used as a part of the triplex stain. The samples were scored using an automated scoring methodology and the results from the triplexed method are compared to analyses done on singly stained sections with excellent correlation (R greater than 0.9 in all cases), showing that multiplexed staining methods can replicate standard IHC methods while maintaining the inter-distribution and visualization of the markers in a single section.
Citation Format: James R. Mansfield, Christian Slater, Richard Byers. Validation and clinical correlation of triplex CD3, CD8 and FOXP3 IHC of tumor-infiltrating lymphocytes in follicular lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A80.
Abstract A82: The cholesterol metabolite, 27-hydroxycholesterol, promotes breast cancer metastasis
Authors: Nelson Erik Russell , Wardell Suzanne E. , McDonnell Donald P. 
Published: October 2015

Abstract
Breast cancer remains the most common cancer in women and is the second leading cause of cancer death in women. It is important to note that the majority of patients eventually succumb to the metastatic spread of their disease, not to the primary tumor itself. The magnitude of this problem provides strong rationale for studies that may lead to the development of new chemopreventative strategies and/or lifestyle changes that reduce breast cancer metastasis. It is of significance, therefore, that patients taking inhibitors of 2-hydroxy-3-methylglutaryl coenzyme A (statins) experience a significantly increased relapse free survival time. Therefore, our recent finding that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, exerts partial agonist activity on both the estrogen receptors (ERs) and liver X receptors (LXRs), suggests a potential mechanistic link between hypercholesterolemia and breast cancer pathology. We demonstrate that 27HC (1) increases in vivo tumor growth and lung metastases, (2) promotes an epithelial to mesenchymal like transition, and (3) in a myeloid cell dependent manner, alters the metastatic microenvironment to promote cancer cell colonization. Our ongoing work is aimed at identifying the specific mechanisms by which 27HC induces these changes and thereby increases metastasis. In summary, our data thus far strongly indicate a role for 27HC in breast cancer pathophysiology and metastasis. These results provide additional support for the exploration of potential chemopreventative benefits of lower cholesterol diets, pharmacological inhibitors of HMG-CoA reductase or the enzyme responsible for the synthesis of 27HC (CYP27A1), and macrophage ablative strategies.
This work was supported by an NIH-NCI grant to ERN (4R00CA172357-03).
Citation Format: Erik Russell Nelson, Suzanne E. Wardell, Donald P. McDonnell. The cholesterol metabolite, 27-hydroxycholesterol, promotes breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A82.
Abstract A83: The role of Ikaros in effector and regulatory T cell homeostasis in a murine pancreatic cancer model
Authors: Nelson Nadine , Xiang Shengyan , Zhang Xiaohong , Szekeres Karoly , Tomar Ghansah 
Published: October 2015

Abstract
The alternatively spliced transcription factor Ikaros is crucial for normal lymphocyte development. Ikaros plays a role as a tumor suppressor in murine T cells. In pancreatic cancer hosts, the balance between effector and regulatory T cells is lost, leading to immunosuppression and reduced anti-tumor immunity. In this study, we aim to identify the role of Ikaros in regulating effector CD4+ and CD8+ and regulatory T cell homeostasis in a pancreatic tumor microenvironment. Using our murine heterotopic model of pancreatic cancer, we isolated splenocytes from tumor-bearing (TB) and control mice and performed western blot and qRT-PCR analyses to evaluate Ikaros mRNA and protein expression, respectively. Flow cytometry analyses were also used to immunophenotype T cell populations in splenocytes from control and TB mice. Next, magnetic activated cell sorting (MACS) was used to sort CD3+ T cells from TB and control splenocytes for western blot analyses of Ikaros expression. We also carried out in vitro and in vivo experiments using apigenin, a plant flavonoid and protein kinase inhibitor with anti-inflammatory, anti-tumor and anti-proliferative properties, to shed insight into how Ikaros may be regulated and its involvement in T cell development. Our results showed no difference in Ikaros mRNA expression but reduced expression of all Ikaros isoforms in splenocytes from TB mice compared with controls. Ikaros protein expression was also downregulated in sorted TB T cells, compared with control. Analyses of T cells by flow cytometry revealed a significant decrease in effector CD4+ and CD8+ T cell percentages but an increase in CD4+CD25+ regulatory T cells (Treg) in TB splenocytes compared with controls. In vitro, treatment of splenocytes with apigenin stabilized Ikaros' protein expression. In the presence of Panc02 cells, Ikaros protein expression was downregulated. However, the addition of apigenin to the co-culture blocked this downregulation. These correlated with in vivo findings that showed partial reversal of some Ikaros isoforms in TB mice treated with apigenin. Apigenin treatment also significantly increased CD4+ and CD8+ T cell percentages but decreased Treg percentages. We are currently performing experiments to determine how Ikaros may be regulated in T cells and its effect on their functions. Thus far, our findings suggest that PC progression is associated with reduced Ikaros expression, which may lead to loss of T cell homeostasis and thus, dampened anti-tumor immune responses.
Citation Format: Nadine Nelson, Shengyan Xiang, Xiaohong Zhang, Karoly Szekeres, Ghansah Tomar. The role of Ikaros in effector and regulatory T cell homeostasis in a murine pancreatic cancer model. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A83.
Abstract A84: IRF8 regulates GM-CSF expression in T cells and tumor cells to mediate myeloid-derived suppressor cell differentiation
Authors: Paschall Amy , Zhang Ruihua , Bardhan Kankana , Qi Chen-Feng , Peng Liang , Lu Geming , Yang Jianjun , Merad Miriam , Zimmerman Mary , McGaha Tracy , Zhou Gang , Mellor Andrew , Abrams Scott I. , Morse Herbert , Ozato Keiko , Xiong Huabao , Liu Kebin 
Published: October 2015

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR05) of the Conference Proceedings.
Citation Format: Amy Paschall, Ruihua Zhang, Kankana Bardhan, Chen-Feng Qi, Liang Peng, Geming Lu, Jianjun Yang, Miriam Merad, Mary Zimmerman, Tracy McGaha, Gang Zhou, Andrew Mellor, Scott I. Abrams, Herbert Morse, Keiko Ozato, Huabao Xiong, Kebin Liu. IRF8 regulates GM-CSF expression in T cells and tumor cells to mediate myeloid-derived suppressor cell differentiation. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A84.
Abstract B19: Targeting histone deacetylase 6 in T-cells to improve melanoma immunotherapy
Authors: Laino Andressa Sodre , Woods David M. , Celis Esteban , Weber Jeffrey , Sotomayor Eduardo 
Published: October 2015

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR09) of the Conference Proceedings.
Citation Format: Andressa Sodre Laino, David M. Woods, Esteban Celis, Jeffrey Weber, Eduardo Sotomayor. Targeting histone deacetylase 6 in T-cells to improve melanoma immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B19.
Abstract B51: Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans
Authors: Bramante Simona , Kaufmann Johanna K. , Veckman Ville , Nettelbeck Dirk M. , Hemminki Otto , Liikanen Ilkka , Vassilev Lotta , Cerullo Vincenzo , Oksanen Minna , Heiskanen Raita , Joensuu Timo , Kanerva Anna , Pesonen Sari , Vähä-Koskela Markus , Koski Anniina , Hemminki Akseli 
Published: October 2015

Abstract
Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as ipilimumab or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno-virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial.
We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a panel of melanoma cell lines and animal models in combination with low-dose cyclophosphamide, and summarized the melanoma-specific human data from the Advanced Therapy Access Program (ATAP).
The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK-MEL-28 melanoma xenografts in nude mice when combined with low-dose cyclophosphamide. Furthermore, virally-expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. Four out of nine melanoma patients treated in ATAP were evaluable for possible therapy benefit with modified Response Evaluation Criteria In Solid Tumors (RECIST): one patient had minor response, two had stable disease, and one had progressive disease. Treatments appeared safe and well-tolerated. Two patients were alive at 559 and 1501 days after treatment.
Ad5/3-D24-GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma.
Citation Format: Simona Bramante, Johanna K. Kaufmann, Ville Veckman, Dirk M. Nettelbeck, Otto Hemminki, Ilkka Liikanen, Lotta Vassilev, Vincenzo Cerullo, Minna Oksanen, Raita Heiskanen, Timo Joensuu, Anna Kanerva, Sari Pesonen, Markus Vähä-Koskela, Anniina Koski, Akseli Hemminki. Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B51.