bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B058: Development of AVID200, a novel and highly potent TGF-beta neutralizing immunotherapy
Authors: O'Connor-McCourt Maureen D. , Lenferink Anne E.G. , Zwaagstra John , Sulea Traian , Baardsnes Jason , Collins Catherine , Cantin Christiane , Couture Lucie , Tao Limei , Durocher Yves , Singh Renu , Koropatnick James 
Published: November 2016

Abstract
Introduction: Elevated TGF-beta ligand markedly augments cancer progression primarily by suppressing the immune system in the tumor microenvironment, in particular by suppressing T-cell recruitment and/or activation. We developed AVID200, a novel decoy receptor trap that potently blocks TGF-beta and induces T-cell infiltration into tumors. This promotes the “T-cell-inflamed” tumor state, which is expected to render tumors sensitive to immune checkpoint inhibitors and other immunotherapeutics.
Experimental Procedures: AVID200 is a computationally designed novel class of avidity-enhanced receptor-ectodomain-based trap that binds and neutralizes TGF-beta 1 and 3 with low pM potency. Several trap formats have been produced and tested, with each format exhibiting varying characteristics, including differing circulating half-lives and in vitro blocking potencies. AVID200 was evaluated for efficacy in in vivo studies using the syngeneic 4T1 triple negative breast cancer (TNBC) tumor model. Additionally, ex vivo studies were performed on CD4+ and CD8+ T-cells harvested from the draining lymph nodes of treated animals.
Results: In efficacy studies using the syngeneic 4T1 TNBC model, novel TGF-beta traps were shown to promote significant T-cell infiltration into tumors. This infiltration resulted in reduced primary tumor growth as well as significant reductions in metastatic lesions. Additionally, ex vivo studies revealed that trap treatment decreased T-cell apoptosis, promoted T-cell proliferation in response to tumor cell lysates in the presence of dendritic cells, as well as increased the capacity of T-cells to specifically lyse 4T1 tumor cells.
Conclusion: AVID200 is a novel computationally-designed TGF-beta trap that neutralizes TGF-beta 1 and 3 with pM potency and markedly promotes the “T-cell-inflamed” tumor state. Combination studies with immune checkpoint inhibitors are ongoing.
Citation Format: Maureen D. O'Connor-McCourt, Anne E.G. Lenferink, John Zwaagstra, Traian Sulea, Jason Baardsnes, Catherine Collins, Christiane Cantin, Lucie Couture, Limei Tao, Yves Durocher, Renu Singh, James Koropatnick. Development of AVID200, a novel and highly potent TGF-beta neutralizing immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B058.
Abstract B068: Hydrocortisone, prednisolone, methylprednisolone, and dexamethasone inhibit CetuGEX™-mediated ADCC in vitro
Authors: Goletz Christoph , Rühmann Johanna , Habel Beate , Danielczyk Antje , Goletz Steffen 
Published: November 2016

Abstract
Introduction: Antibody dependent cellular cytotoxicity is a key mode of action of therapeutic antibodies. ADCC enhancement as well as a broader coverage of F/V allotypes leads to maximal utilization of the anti-tumor effect. Glycooptimization provides the best available opportunity to maximize ADCC activity of monoclonal antibodies. Utilizing the GEX™ platform allows the combination of minimizing fucosylation, maximizing galactosylation and branching, which maximally increases the ADCC activity. The GEX™ platform comprises a comprehensive portfolio of proprietary glycoengineered human suspension cell lines, which allow for the high yield production of proteins with tailored glycosylation patterns. Productivities of 22g/L perfusion bioreactor volume have been achieved for ADCC optimized monoclonal antibodies. Cancer therapies with monoclonal antibodies including CetuGEX™ are often accompanied by treatment with glucocorticoids in order to prevent or counteract side effects like infusion reactions. However, the immunosuppressive character of glucocorticoids may also have the potential to inhibit the ADCC effect and immune cells mediating ADCC, respectively. In this study, we analyzed the influence of different glucocorticoids on ADCC mediated by CetuGEX™.
Methods: By using a europium release assay with an EGFR-expressing cancer cell line and PBMCs as effector cells we tested the ability of hydrocortisone, prednisolone, methylprednisolone and dexamethasone to inhibit ADCC mediated by CetuGEX™. In addition, we analyzed the direct effect of glucocorticoids on effector and target cells using flow cytometry.
Results: All tested glucocorticoids inhibited the CetuGEX™-mediated ADCC. This effect was not caused by a decreased expression of EGFR on the target cells. NK cells which are key effector cells mediating ADCC were found to be less activated in presence of glucocorticoids and CetuGEX™ compared to CetuGEX™ alone.
Conclusions: Glucocorticoids have a negative influence on ADCC mediated by NK cells which is one of the key modes of actions of CetuGEX™ and other ADCC enhanced antibodies. Therefore, the use of glucocorticoids during may impair clinical the efficacy ADCC-enhanced antibodies and should be avoided or at least minimized.
Citation Format: Christoph Goletz, Johanna Rühmann, Beate Habel, Antje Danielczyk, Steffen Goletz. Hydrocortisone, prednisolone, methylprednisolone, and dexamethasone inhibit CetuGEX™-mediated ADCC in vitro [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B068.
Abstract B084: Transparent tumor tomography (T3): Spatial analysis for PD-L1 checkpoint blockade immunotherapy
Authors: Lee Seung-Young 
Published: November 2016

Abstract
Untangling the complexity of programmed death-ligand 1 (PD-L1) expression within a heterogeneous tumor microenvironment is an urgent challenge in PD-1/PD-L1 immune checkpoint blockade therapy. Here, we address this challenge with a method, termed transparent tumor tomography (T3), facilitating three-dimensional (3D) visualization and spatial analysis of distributions of multiple biomarkers including Her2, CD45, Ki-67, CD31, and PD-L1 throughout transgenic mouse mammary tumors. Based on our T3 imaging, we reveal that PD-L1 expression within the tumor microenvironment is highly adaptable to tumor status for efficiently preventing immune cell infiltration into the tumor. We also determine spatial pharmacokinetics of anti-PD-L1 antibody in the whole mouse mammary tumor in the context of hypoxia, CD31+ blood vessels, and target PD-L1+ cells. Finally, we demonstrate broad distribution of tumor infiltrating CD3+CD8+ cytotoxic T cells following radiation and anti-PD-L1 antibody therapy. These results provide unique spatial insights into PD-L1 cloaking and PD-L1 blockade therapy.
Citation Format: Steve Seung-Young Lee. Transparent tumor tomography (T3): Spatial analysis for PD-L1 checkpoint blockade immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B084.
Abstract B098: A panel of well characterized syngeneic models for in vivo screening analysis: MuScreenTM
Authors: Jin Ying , Zhang Lan , Zhang Juan , Murphy Eric , Li Zhongliang , Qiao Meng , Shi Qian 
Published: November 2016

Abstract
Background: Syngeneic tumor models have proven to be one of the most robust model systems for cancer immunotherapy. However, in vitro screens that are frequently used in oncology to quickly identify cells, models, and PD effects for further study often fail in immuno-oncology, due to immunotherapeutics targeting the complex host immune system. Alternatively, an in vivo screen with a panel of models addresses many of these questions, e.g. PD and efficacy, but may be cost prohibitive. Material and methods: Leveraging in-house detailed profiling data on our syngeneic models, including efficacy benchmarking with aPD-1, aPD-L1 and aCTLA-4 antibodies, RNAseq data on tumor samples, and FACS analysis on both baseline and treatment response tumor samples, CrownBio recently launched a new service platform: MuScreen. MuScreen includes up to 20 well-characterized syngeneic models in a 3 month screening run. Both PD and efficacy may be determined in the run, allowing researchers to make decisions based on results observed from a large dataset. To address the cost issue, test agents from multiple clients are pooled together for each run (sharing vehicle and other common groups) providing a significant reduction in the number of animals used and the associated costs. Results: CrownBio has established the largest collection of syngeneic models with well-characterized immunotherapy data. In the first MuScreen run, we have generated new data on common IO agents, e.g. aPD-1 antibodies, with FACS analysis, IHC, and efficacy data. The first complete set of MuScreen data will be shown. Design parameters, such as starting tumor size, group size, of the MuScreen studies will be discussed. Conclusions: MuScreen is the first in vivo screening tool for cancer immunotherapeutics. It provides detailed response data on a panel of syngeneic models, therefore enabling decision making in a cost and time efficient manner.
Citation Format: Ying Jin, Lan Zhang, Juan Zhang, Eric Murphy, Zhongliang Li, Meng Qiao, Qian Shi. A panel of well characterized syngeneic models for in vivo screening analysis: MuScreenTM [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B098.
Abstract B104: Impact of PD-1 blockade on epigenetic and transcriptional reprogramming of exhausted T cells
Authors: Pauken Kristen E. , Sammons Morgan A. , Odorizzi Pamela M. , Manne Sasi K. , Godec Jernej , Khan Omar , Sen Debattama , Kurachi Makoto , Barnitz R. Anthony , Bengsch Bertram , Huang Alexander C. , Schenkel Jason M. , Vahedi Golnaz , Haining W. Nicholas , Berger Shelley L. , Wherry E. John 
Published: November 2016

Abstract
Blocking PD-1 can reinvigorate exhausted CD8 T cells and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram exhausted CD8 T cells into effector or durable memory CD8 T cells. Here, we found reinvigoration of exhausted T cells by PD-L1 blockade caused re-acquisition of some features of effector T cells, but minimal memory development. Indeed, after checkpoint blockade, reinvigorated T cells became re-exhausted if antigen remained high, and failed to become memory T cells upon antigen clearance. Exhausted T cells acquired an epigenetic profile distinct from effector and memory T cells that was minimally altered by blocking PD-L1. Nevertheless, modest enhancer changes resulted in transcriptional network rewiring that may provide opportunities to enhance checkpoint blockade. These data indicate that epigenetic fate inflexibility may limit current immunotherapies and suggest that improving (re)differentiation to memory following PD-1 pathway blockade could enhance clinical outcomes.
Citation Format: Kristen E. Pauken, Morgan A. Sammons, Pamela M. Odorizzi, Sasi K. Manne, Jernej Godec, Omar Khan, Debattama Sen, Makoto Kurachi, R. Anthony Barnitz, Bertram Bengsch, Alexander C. Huang, Jason M. Schenkel, Golnaz Vahedi, W. Nicholas Haining, Shelley L. Berger, E. John Wherry. Impact of PD-1 blockade on epigenetic and transcriptional reprogramming of exhausted T cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B104.
Abstract B115: Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease
Authors: Liu Jing , Blake Stephen , Yong Michelle , Harjunpaa Heidi , Ngiow Shin Foong , Takeda Kazuyoshi , Young Arabella , Allen Stacey , Smyth Mark J. , Teng Michele WL 
Published: November 2016

Abstract
Immunotherapy has recently entered a renaissance phase with the approval of multiple agents for the treatment of cancer. Immunotherapy stands ready to join traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as a pillar of cancer treatment. Although immunotherapy has begun to have success in advanced cancer treatment, its scheduling and efficacy with surgery to treat earlier stages of cancer and prevent distant metastases has not been systematically examined. Here, we have used two models of spontaneously metastatic breast cancers in mice, to illustrate the significantly greater therapeutic power of neoadjuvant, compared with adjuvant immunotherapies in the context of primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior and post surgery may provide a predictor of outcome. These data now provide strong rationale to extensively test and compare neoadjuvant immunotherapy in humans.
Citation Format: Jing Liu, Stephen Blake, Michelle Yong, Heidi Harjunpaa, Shin Foong Ngiow, Kazuyoshi Takeda, Arabella Young, Stacey Allen, Mark J. Smyth, Michele WL Teng. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B115.
Abstract B120: Synergistic potentiation of the anti-metastatic effect of anti EGFR mAbs by its combination with immunotherapies targeting the ganglioside NGcGM3
Authors: Gonzalez Addys , Blanco Rances , Carr Adriana , Leon Kalet 
Published: November 2016

Abstract
Epidermal growth factor receptor (EGFR) plays an important role in cancer progression. Several anti-EGFR mAbs has demonstrated significant clinical effect in the therapy of cancer. However, their impact on patients overall survival has been limited mainly by the emergence of different forms of tumor resistance. N-glycolyl variant of GM3 ganglioside (NGcGM3) has received some attention as a privileged target for cancer therapy. This ganglioside is specifically expressed in some tumors, and it has been associated with a poor prognostic in colon and lung cancer. Several reports in the literature have documented a functional relationship between GM3 and EGFR at tumor cell membrane. GM3 physically associates to EGFR inhibiting its ligand depend phosphorylation, but it also facilitates an alternative/compensatory signaling cascade mediated by Uroquinase Plasminogen Activator Receptor (uPAR) and integrin α5β1 interaction. However, no conclusive information exists on the difference between N-glycolyl and N-Acetyl variants of GM3 regarding their interaction with EGFR and uPAR. We hypothesized that the enrichment on NGcGM3 expression in some tumors relates to advantages of this ganglioside variant, perhaps by ensuring that both EGFR and uPAR pathways optimally signal to promote tumor growth and metastasis. Following this idea, we explored the impact of a combination of immunotherapies against this two “physically or functional related targets” in the tumor. We found a clear synergistic effect of this combination in two different transplantable tumor models of lung metastasis. We show that in treated metastasis, the combination turns off more the signaling through both EGFR and uPAR/α5β1 integrin pathway and both the antibody and cellular immune response induced was important. Overall, our results support the potential combination of therapies targeting NGcGM3 with anti EGFR antibodies to increase their efficacy in future clinical trials.
Citation Format: Addys Gonzalez, Rances Blanco, Adriana Carr, Kalet Leon. Synergistic potentiation of the anti-metastatic effect of anti EGFR mAbs by its combination with immunotherapies targeting the ganglioside NGcGM3 [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B120.
Abstract B124: Roles for Tnfsf11 expression by group 3 innate lymphoid cells
Authors: Bando Jennifer K. , Song Christina , Gilfillan Susan , Colonna Marco 
Published: November 2016

Abstract
Innate lymphoid cells (ILC) are important sources of effector cytokines during homeostasis and diverse inflammatory conditions. A specialized group of ILC, the Group 3 ILC (ILC3), produces IL-22 and IL-17A, and contributes to maintenance of the gut epithelial barrier and the host response to extracellular microbes. ILC3s express Tnfsf11, a type II receptor required for osteoclastogenesis. The functions of Tnfsf11 in ILC3s are not fully understood. Here we show that Tnfsf11-deficient ILC3s are hyperproliferative and express altered cell surface markers at steady state. Additionally, Tnfsf11-deficient ILC3s produce increased amounts of effector cytokines in response to the activating cytokine IL-23. Although mature osteoclast-, lymph node-, and M cell-development are dysfunctional in Tnfsf11−/− mice, Tnfsf11 expression is not required in ILC3s for these developmental pathways. Thus, Tnfsf11 regulates ILC3 homeostasis in the gut.
Citation Format: Jennifer K. Bando, Christina Song, Susan Gilfillan, Marco Colonna. Roles for Tnfsf11 expression by group 3 innate lymphoid cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B124.
Abstract B130: Dysregulated Toll-like receptor responses as an oncogenic driver
Authors: Majer Olivia , Liu Bo , Lee Angus Yiu-fai , Barton Greg 
Published: November 2016

Abstract
Inflammation mediated by the transcription factor NFkB is a hallmark of many cancers. Toll-like receptor (TLR) signaling activates NFkB and many tumors undergo an upregulation of TLR expression. However, it still remains unknown to what extent TLR signaling directly contributes to tumorigenesis. A mutagenesis screen of the Unc93b1 protein, a trafficking factor for endosomal TLRs, identified numerous gain-of-function mutations that lead to enhanced TLR signaling. This system allows me to selectively upregulate the activity of certain TLRs and test their contribution to the development of spontaneous inflammation and cancer. So far, my work has focused on a group of Unc93b1 mutations that confer hyper-responsiveness of TLR7 and TLR9, two endosomal nucleic-acid sensing receptors. Knock-in mice carrying this mutation show an early onset of autoinflammation and autoimmunity, demonstrating the critical role of Unc93b1 in maintaining immunological tolerance of these receptors. In ongoing work, I want to investigate the underlying molecular mechanisms that mediate this TLR hyperresponse and identify new regulators of Unc93b1 that might engage in this pathway. Furthermore, I want to apply this system in exploring the contribution of chronic TLR7 and TLR9 stimulation in the development of B-cell lymphoma, a cancer type whose pathogenesis relies on constitutively active NFkB downstream of TLR engagement. My study will reveal novel regulatory pathways that control TLR-mediated inflammation and their physiological relevance in tumorigenesis.
Citation Format: Olivia Majer, Bo Liu, Angus Yiu-fai Lee, Greg Barton. Dysregulated Toll-like receptor responses as an oncogenic driver [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B130.
Abstract B134: Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization
Authors: Zhang Liman , Chen Shuobing , Ruan Jianbin , David Liron , Mao Youdong , Wu Hao 
Published: November 2016

Abstract
The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a ∼90° hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 inflammasomes.
Citation Format: Liman Zhang, Shuobing Chen, Jianbin Ruan, Liron David, Youdong Mao, Hao Wu. Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B134.