bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-294: Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2
Authors: Traore Tary , Khattar Mithun 
Published: August 2018

Abstract
Antibody-drug conjugates (ADCs) are a highly potent class of drugs that specifically target cancer cells expressing a tumor associated antigen (TAA). The ADC TAK-522 (XMT-1522) consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxypropylamide, AF-HPA). An average DAR (drug-to-antibody ratio) of twelve AF-HPA molecules is achieved via a biodegradable polymer conjugation platform. We have characterized the ability of both the free payload AF-HPA and the ADC TAK-522 to induce immunogenic cell death (ICD) in vitro in multiple cell lines (NCI-N87, HT-29, SKBR3), as measured by cell surface expression of the ICD marker calreticulin (CRT) using microscopy and flow cytometry. CRT, usually contained in the lumen of the endoplasmic reticulum, translocated to the cell surface within a few hours after treatment with AF-HPA or TAK-522. Furthermore, we developed a novel syngeneic breast cancer (4T1) model expressing human HER2 at a relatively low antigen density. Treatment in this poorly immunogenic tumor model with TAK-522 but not Kadcyla showed significant inhibition of tumor growth in vivo. Importantly, a combination of anti-PD1 mAb and TAK-522 therapy substantially and synergistically enhanced the anti-tumor efficacy, resulting in complete responses in some mice. The frequency of complete responders was further increased when the two drugs were sequentially, rather than concurrently, administered such that TAK-522 administration was followed by anti-PD1 mAb therapy. These results suggest an immunological mechanism involving induction of immunogenic cell death by TAK-522, which in turn may activate the adaptive immune system by releasing tumor specific antigens. TAK-522 is currently being tested in a phase-1b clinical trial in patients with advanced breast, lung and gastric cancer expressing HER2. Based on our data, TAK-522 represents a potential candidate for combination therapies with immune checkpoint modulators in patients with poorly immunogenic HER2 expressing tumors.
Citation Format: Tary Traore, Mithun Khattar. Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-294.
Abstract LB-303: Novel peptide is synergistic with checkpoint inhibitor antiCTLA4
Authors: Leuschner Carola , Kern Clifford H. 
Published: August 2018

Abstract
Specific peptides are known to modulate cellular immune responses. Isolates of leukocytes containing tyrosine and glycine peptide sequences have been previously tested in HIV-positive, colon cancer, and other patients, where they were found to be safe and to demonstrate pleiotropic effects on CD4+ T cells, CD8+ T cells, and natural killer cells, as well as increased production of interferon gamma and other cytokines. We hypothesized, therefore, that Tyr-Gly peptides may enhance anti-tumor responses in combination with checkpoint inhibitors through stimulation of the immune system. INT-151 (synthetic Tyr-Gly), originally identified as the active component of a leukocyte isolate, was tested alone and in combination with the checkpoint inhibitor anti-CTLA4 in a murine syngeneic lymphoma model (E.G7-OVA) for anti-tumor effect and survival. Immune profiles in control and treatment groups were assessed for tumors and blood using FACs analysis to detect CD8+ T cells, CD4+ T cells, regulatory T cells (Treg), macrophages, and myeloid derived suppressor cells (MDSC). E.G7-OVA tumor bearing mice with an average tumor volume of 43 mm3, were treated 3x weekly for 17 days with INT-151 or anti-CTLA4 alone or in combination. The treatment group receiving INT-151 plus anti-CTLA4 had the lowest tumor volume (351 ± 38.9 mm3, N=6) compared with those treated with vehicle (876.7 ± 142.9 mm3, p &lt; 0.04, N=6), INT-151 alone (821 ± 52.2 mm3, p = 0.8, N=6), and anti-CTLA4 alone (616 ± 117.4 mm3, p = 0.1, N=6). Tumor growth inhibition was highest in the combination group (60 %) compared to single agents anti-CTLA4 (30 %) and INT-151 (7 %). Immune cell populations increased in tumors were CD8+ T cells, CD4+ T cells and M1 macrophages in the combination group. Regulatory T cells, mMDSC or gMDSC remained unchanged in any of the treatment groups compared to controls. The highest ratio of CD8+T/Treg cells of 8.5±2.1 was found in the combination group (INT-151+anti-CTLA4, p&lt;0.001) compared to 4.4±0.9 for anti-CTLA4 and 2.5±0.5 for vehicle and INT-151 (3.2±1.05). The E.G7-OVA mouse model also demonstrated increased survival on day 40 in groups treated with INT-151 plus anti-CTLA4 (55%, N=9) compared to single agent INT-151 (30 %, N=10), anti-CTLA4 (0%, N=8) and vehicle (0 %, N=10). These data demonstrate synergistic activity of INT-151 in a syngeneic murine lymphoma model. Combining a checkpoint inhibitor with INT-151 could be a safe and promising therapeutic strategy for lymphoma and other malignancies.
Citation Format: Carola Leuschner, Clifford H. Kern. Novel peptide is synergistic with checkpoint inhibitor antiCTLA4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-303.
Abstract LB-304: Customizable, in vitro protein glycosylation for antibacterial and anti-cancer vaccines
Authors: Stark Jessica C. , Jaroentomeechai Thapakorn , Dubner Rachel S. , Hsu Karen J. , Glasscock Cameron , DeLisa Matthew P. , Jewett Michael C. 
Published: August 2018

Abstract
Changes in protein glycosylation are important hallmarks of cancer biology, serving as biomarkers for cancer progression and predictors of cancer prognosis. Moreover, tumor-associated carbohydrate antigens (TACAs) provide potential targets for therapeutic and prophylactic interventions. However, development of anti-cancer immunotherapies and vaccines directed against TACAs has been limited due to the significant challenges associated with synthesizing proteins bearing defined glycan structures in vivo. These challenges arise due to the complex, non-templated nature of the glycosylation process and the inability to control glycosylation components at precise ratios in living cells. To address these challenges, we describe a novel cell-free glycoprotein synthesis (CFGpS) technology that seamlessly integrates protein biosynthesis with asparagine-linked (N-linked) protein glycosylation. The platform is flexible and modular, allowing the decoration of proteins with structurally diverse, yet homogeneous glycans, including the eukaryotic trimannosyl N-glycan (mannose3-N-acetylglucosamine2, Man3GlcNAc2), which forms the core of all tumor-associated N-glycans. We demonstrate the utility of this platform through the production of antibacterial glycoconjugate vaccines directed against the highly infectious pathogenic bacterium Franciscella tularensis. Importantly, we are able to synthesize and glycosylate a variant of E. coli maltose binding protein (MBP) that has been shown to elicit humoral and cell-based immunity to polysaccharide antigens in mice. Our work demonstrates a novel approach for the customizable glycosylation of immunogenic proteins with TACAs in a cell-free system. The ability of the CFGpS platform to synthesize defined glycan structures uniquely enables the production of novel antibacterial and anti-cancer vaccines.
Citation Format: Jessica C. Stark, Thapakorn Jaroentomeechai, Rachel S. Dubner, Karen J. Hsu, Cameron Glasscock, Matthew P. DeLisa, Michael C. Jewett. Customizable, in vitro protein glycosylation for antibacterial and anti-cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-304.
Abstract LB-328: Influence of radiation on the evolution of orthotopic xenografts initiated from glioblastoma stem-like cells
Authors: McAbee Joseph H. , Rath Barbara H. , Camphausen Kevin A. , Tofilon Philip J. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common and malignant primary adult brain cancer with a median survival of 15 months despite treatment with surgical resection followed by chemo-radiotherapy. By examining changes that occur following irradiation of brain tumor xenografts initiated from glioma stem-like cells (GSCs), this study seeks to better understand the impact of radiotherapy on GBM evolution. Therefore, we intracranially implanted CD133+ NSC11 cells, a well-documented GSC line, into nude mice. After 21 days, bioluminescence imaging was performed to confirm the presence of tumor prior to randomization into control and radiation therapy groups (3x5Gy). Following treatment, brain samples were collected at various time points out to morbidity to investigate changes in tumor morphology and histology. Further, tumors from morbid mice (control and 3x5Gy) were collected for viral integration site analysis (VISA). Initial survival analysis demonstrated a significant survival advantage for mice undergoing radiation therapy (+34.2 days) compared to controls. On gross examination of morphology at morbidity, brains bearing irradiated tumors contained tumor tissue that was softer, more adherent to the skull, and more likely to efface olfactory bulb(s) than control tumor brains. H&E staining demonstrated that irradiated tumors were more dense/compact and did not grow as infiltrative as tumors from control mice. These histological changes were followed up with VISA to determine whether certain clones were responsible for this difference. VISA revealed that irradiated tumors were heterogeneously enriched for clones with different integration sites when compared to control tumors and in vitro tumor lines. Heat map analysis of the number of clones present in each sample demonstrated that control tumors harbor fewer clones than in vitro lines and that radiated tumors harbor the fewest clones of all. Initial data also revealed that various doses of radiation (3x5Gy or 10x5Gy) can provide very similar selection pressures to limit the number of clones. Our results demonstrate that radiation, a treatment component for almost all glioblastoma patients, can have wide-ranging effects on the evolution of this dynamic tumor. In particular, the pressures imposed by radiation treatment seem to lead to the selection of a reduced number of clones. This selection may have future implications for tumor evolution and the treatment of recurrent GBM.
Citation Format: Joseph H. McAbee, Barbara H. Rath, Kevin A. Camphausen, Philip J. Tofilon. Influence of radiation on the evolution of orthotopic xenografts initiated from glioblastoma stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-328.
Abstract LB-348: Negative roles of C/EBPα in MDSC-mediated tumor angiogenesis and immune suppression
Authors: Qu Peng , Min Yongfen , Yang Li , Lin Charles 
Published: August 2018

Abstract
Myeloid-derived suppressor cells (MDSCs) are highly increased in peripheral blood of cancer patients, as well as tumor bearing animal models. These cells have long been known to suppress the host immune response to cancer. In the present study, we found that CCAAT/enhancer binding protein alpha (C/EBPα) expression was significantly reduced in MDSCs from tumor-bearing mice compared to non-tumor-bearing hosts. Tumor-conditioned medium down-regulated C/EBPα expression, suggesting tumor secreted factors inhibiting the gene expression. Consistent with the function of C/EBPα in regulating the balance between proliferation and growth arrest in hematopoietic progenitors, the specific deletion of C/EBPα on myeloid lineage resulted in distinctly enhanced the proliferation and expansion of MDSCs, as well as an increase of myeloid progenitors and a decrease of other mature cells. In addition, the deletion of C/EBPα in MDSCs enhanced the pro-angiogenic, immune suppressive and pro-tumorigenic behavior of these cells by upregulating the production of iNOS and arginase, as well as MMP-9 and VEGF. Accordingly, tumors growing in C/EBPα conditional null mice displayed greater MDSC infiltration, increased vascularization and accelerated tumor growth. Taken together, this study reveals dual negative roles of C/EBPα in the expansion as well as pro-angiogenic and immune suppressive functions in MDSCs.
Citation Format: Peng Qu, Yongfen Min, Li Yang, Charles Lin. Negative roles of C/EBPα in MDSC-mediated tumor angiogenesis and immune suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-348.
Abstract LB-363: Characterization of in vitro and in vivo models generated from disseminated tumor cells of patients without manifest metastasis
Authors: Werno Christian , Weidele Kathrin , Treitschke Steffi , Botteron Catherine , Scheitler Sebastian , Polzer Bernhard , Werner-Klein Melanie , Klein Christoph Andreas 
Published: August 2018

Abstract
We recently showed that dissemination of few melanoma cells to the lymph nodes is a quantitative risk factor for death from melanoma. However, the analysis of disseminated tumor cells (DTC) is limited by their extremely low frequency, resulting in a lack of in vitro/in vivo models for mechanistic studies of early systemic disease. Therefore, the objective of this study was to develop protocols to expand single DTC from lymph nodes of melanoma patients to establish better preclinical models for adjuvant cancer therapies. Sentinel lymph nodes from melanoma patients were cut in halves, disaggregated and analyzed for the presence of gp100-positive DTC. The other half was used for diagnostic assessment by histopathology. Single DTC within the lymph node-derived single cell suspension were then propagated under specific sphere forming conditions and expanded by transplantation in immunodeficient mice. DTC based pre-clinical in vitro/in vivo models were then characterized on molecular level and were used for functional analyses. To test drugs on DTC in presence of a human immune system we additionally generated humanized xenograft models. We successfully established cell lines and xenografts from DTCs of 17 melanoma patients. We confirmed the origin of the cells by genomic fingerprint and analyzed the genomic profile of the expanded cells over various culture and animal passages. DTC cell lines were used for functional analysis and for testing the efficacy of targeted therapies. In addition, we set up a novel preclinical mouse model based on expanded melanoma DTC. For this, we established a human immune system in immunodeficient mice, which were then transplanted with melanoma DTC-derived cells. Interestingly, the presence of a human immune system significantly induced tumor formation, as well as dissemination of melanoma cells and improved the response to a targeted therapy compared to mice without a humanized immune system. The development of DTC based pre-clinical in vitro/in vivo models enables mechanistic studies on DTCs and drug tests against the target cells of adjuvant therapies in the presence of human immune cells. These models may help to identify candidate adjuvant therapies targeting DTCs and to understand mechanisms of drug resistance of currently applied targeted therapies.
Citation Format: Christian Werno, Kathrin Weidele, Steffi Treitschke, Catherine Botteron, Sebastian Scheitler, Bernhard Polzer, Melanie Werner-Klein, Christoph Andreas Klein. Characterization of in vitro and in vivo models generated from disseminated tumor cells of patients without manifest metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-363.
Abstract LB-377: Validation and application of a comprehensive next generation sequencing system for molecular characterization of solid tumor tissues
Authors: Dehghani Mehdi , Li Lei , Brobey Reynolds , Wang Yue , Rosenblatt Kevin P. , Amato Robert J. 
Published: August 2018

Abstract
Identification of somatic molecular alterations in solid tumors and metastases can provide critical information regarding tumor biology and tumor heterogeneity. These alterations can also reveal activated pathways in a patient's disease, enabling personalized treatment assignment. However, the optimal methods and panels remain unknown. The present study was conducted to assess the use of the Oncomine Comprehensive Cancer Panel in identifying molecular alterations in fresh and preserved cancer tissues from a solid tumor registry at The University of Texas Health Science Center at Houston. Results were compared with pathologic findings. The assay was found to be highly specific (&gt;99%) and sensitive (&gt;99%), with low false-positive and false-negative rates for single-nucleotide variants, indels, copy number alterations, and gene fusions. This tumor-agnostic molecular assessment assay holds potential as a straightforward and reliable method to determine molecular alterations in solid tumor samples. Overall, 23 (88%) of these 26 patients had at least one loss-of-function or gain-of-function molecular alteration (80/180 total high-priority alterations), of which 68% (66/80) led to selection of targeted therapy. This next-generation sequencing assay not only detected at least one clinically actionable alteration, but also it can be a great translational research tool. For instance, using this panel we detected EGFRvIII in a significant number of renal cell cancer core biopsies (43%). The biological importance of this alteration in renal cancer growth and progression and its clinical importance as a therapeutic or prognostic marker needs to be investigated further.
Citation Format: Mehdi Dehghani, Lei Li, Reynolds Brobey, Yue Wang, Kevin P. Rosenblatt, Robert J. Amato. Validation and application of a comprehensive next generation sequencing system for molecular characterization of solid tumor tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-377.
Abstract LB-378: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
Authors: Cortés-Ciriano Isidro , Lee June-Koo , Xi Ruibin , Jain Dhawal , Jung Youngsook L. , Yang Lixing , Gordenin Dmitry , Klimczak Leszek J. , Zhang Cheng-Zhong , Pellman David S. , Park Peter J. 
Published: August 2018

Abstract
Chromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of &gt;50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.
Citation Format: Isidro Cortés-Ciriano, June-Koo Lee, Ruibin Xi, Dhawal Jain, Youngsook L. Jung, Lixing Yang, Dmitry Gordenin, Leszek J. Klimczak, Cheng-Zhong Zhang, David S. Pellman, Peter J. Park. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-378.
Abstract LB-381: Effects of sequencing parameters and panel size on mutational burden calculations
Authors: Yourstone Scott , Mola Natalie , Weigman Victor J. 
Published: August 2018

Abstract
Immunotherapies are an emerging approach for cancer treatment that leverage the power of the immune system to attack cancer cells. By targeting immune check-point pathways such as PD-1, these treatments have been highly effective for some patients diagnosed with skin, bladder, lung, or kidney cancer. However, response rates for these treatments vary, making it beneficial to identify patients who are likely to respond to the treatment. Qualitative methods for predicting immunotherapy response are available but are technically challenging and subjective. An emerging quantitative predictor of immunotherapy response, tumor mutational burden (TMB), measures the number of somatic mutations per Mb of the genome. TMB calculations using whole exome data have been shown to correlate with patient response to immunotherapies. However, derivation of this score is not well characterized, nor is the score universally performed across laboratories. Here we describe the results from calculating TMB scores varying cancer panel size and amount of sequencing generated. First, variants are called in matched tumor and normal samples within Exomes. Then low coverage variants are removed along with variants outside the targeted, high-confidence regions in each panel. The remaining variants in the normal samples constitute the germline variants and are subtracted from the number of variants identified in tumor samples to yield the TMB score. We then repeated this across multiple indications across TCGA to review robustness of score in indications across the spectra of burden. TMB scores from the our comprehensive cancer closely resembles scores calculated using whole exome data across indications. We propose rules for gene content and sequencing depth for providing a range of burden scores that could be used for determining thresholds needed for determining therapeutic implications. We suggest that only a small subset of genes are required for accurate TMB estimation, thus reducing costs associated with predicting patient response to immunotherapy.
Citation Format: Scott Yourstone, Natalie Mola, Victor J. Weigman. Effects of sequencing parameters and panel size on mutational burden calculations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-381.