bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 319: Impact of chemotherapy on lung cancer cells and their microenvironment, evaluated in tridimensional multicellular tumor spheroids
Authors: Hulo Pauline , Deshayes Sophie , Dehame Virginie , Grégoire Marc , Bennouna Jaafar , Blanquart Christophe 
Published: September 2020

Abstract
Introduction: Pembrolizumab, an anti-PD1 antibody, is approved in non pretreated advanced Non Small Cell Lung Cancer (NSCLC) with high expression of PD-L1, more than 50 %, on tumor cells. Conversely, the combination of platinum-based chemotherapy + pembrolizumab in this indication is not restricted to the level of PD-L1 expression. This suggests that chemotherapy could sensitize tumor tissue to Immune Checkpoint Inhibitors (ICIs). Based on those clinical datas, we propose to evaluate the impact of chemotherapy on tumor cells and on their microenvironment by using tridimensional multicellular tumor spheroids (MCTS).
Material and methods: MCTS integrated lung adenocarcinoma cells expressing GFP, fibroblasts with ruby fluorescent protein and monocytes/macrophages from healthy donors. MCTS were treated with repeated and combined chemotherapy drugs (carboplatin and gemcitabine, or carboplatin and paclitaxel), reproducing therapeutic schedules. Different biological factors were analysed : impact of chemotherapy on MCTS morphology, cell viability, invasion abilities, modifications in genes and protein expression profiles using differential gene expression sequencing (DGE-Seq) and flow cytometry, respectively.
Results: Chemotherapy decreased MCTS size and cell viability. Whereas carboplatin/gemcitabine mainly affected lung cancer cells inside MCTS, carboplatin/paclitaxel seemed to be cytotoxic mainly on peripheral malignant cells. Fibroblasts were resistant to chemotherapy, unlike macrophages which were strongly affected. A large RNA analysis was performed using DGE-Seq and showed that expression of several genes, and notably of CD274 (PD-L1) and CD273 (PD-L2), were induced after treatment. We confirmed PD-L1 up-regulation byflow cytometry.
Conclusion: Platinium-based chemotherapy up-regulate immune checkpoints expression in lung cancer cells. Our results are in line with the latest studies performed in mice. They underline that our MCTS model is closed to in vivo conditions. It could be developedas a drug screening tool.
Citation Format: Pauline Hulo, Sophie Deshayes, Virginie Dehame, Marc Grégoire, Jaafar Bennouna, Christophe Blanquart. Impact of chemotherapy on lung cancer cells and their microenvironment, evaluated in tridimensional multicellular tumor spheroids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 319.
Abstract 3193: FGFR4 mutationas a novel biomarker for immunotherapy in patients with non-small cell lung cancer
Authors: Jin Xiangfeng , Fan Xinglong , Tian Kaihua , Xu Hanlin , Ge Nan , Wang Yafei , Zhang Shiyue , Chen Hui , Yuan Shaohua , Wang Kai 
Published: September 2020

Abstract
Background: Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided a remarkable antitumor effect in non-small cell lung cancer (NSCLC), but only a limited number of patients can derive durable benefit. Therefore, more accurate biomarkers are highly needed. The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases is comprised of 4 members (FGFR1-4) that mediate the function of the FGFR ligand family. Although the genomic alterations (GAs) of FGFRs were frequently detected by targeted next-generation sequencing (NGS) and considered as potent oncogenes, their correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC remains unclear.
Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples of 3433 NSCLC patients from OrigiMed were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. Genomic data and ICIs treatment outcome of 2 cohorts of NSCLC patients were derived from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) databases.
Results: GAs of FGFR gene family were detected in 5% (172/3433) of patients with NSCLC in the OrigiMed database, including 84 FGFR1 GAs, 34 FGFR4 GAs, 28 FGFR2 GAs, and 26 FGFR3 GAs. No significant difference was observed in the frequency of FGFR4 GAs within the histologic subtypes. Compared with wild-type (WT), FGFR4 GAs were associated with a significantly higher tumor mutational burden (TMB) (6.55 vs. 4.6 muts/Mb, respectively, p&lt;0.001). Survival analysis from 2 independent cohorts confirmed that patients with FGFR4 GAs had remarkable clinical benefit to ICIs compared with WT patients in both progression free survival (PFS) (13.17 months vs 3.17 months, respectively, p=0.025) and durable clinical benefit (DCB) (80% vs 29.3%, respectively, p=0.03). Furthermore, FGFR4 GAs were an independent risk factor of PFS (HR: 0.22, 95%CI: 0.055-0.92, p=0.037) and overall survival (OS) (HR: 0.23, 95%CI: 0.057-0.92, p=0.038).
Conclusion: Our results supported that the FGFR4-mutated NSCLC patients were associated with an increased TMB and favorable response to ICIs. This suggests that GAs of FGFR4 may have implications as a biomarker for guiding ICI treatment.
Citation Format: Xiangfeng Jin, Xinglong Fan, Kaihua Tian, Hanlin Xu, Nan Ge, Yafei Wang, Shiyue Zhang, Hui Chen, Shaohua Yuan, Kai Wang. FGFR4 mutationas a novel biomarker for immunotherapy in patients with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3193.
Abstract 3223: The Cancer Genomics Cloud enables complex and multi-omic data science in the cloud
Authors: Ray Manisha , DiGiovanna Jack , Radenkovic Jelena , Tosic Marko , Mirkovic Nikola , Majic Boris , Andjus Vladan , Davis-Dusenbery Brandi 
Published: September 2020

Abstract
The Cancer Genomics Cloud (CGC), powered by Seven Bridges, is an NCI-funded platform to make the analysis of cancer data faster, easier, and more accessible. As datasets grow larger, more diverse, and more complex, they have become increasingly challenging for many cancer researchers. The CGC provides a centralized resource for analysis by co-localizing three components within the same cloud platform: 1) large cancer datasets like The Cancer Genome Atlas (TCGA); 2) tools and workflows for analyzing public and private data; and 3) the computational capabilities to do large-scale analyses. In addition to the simplicity of data access; the CGC also contains &gt;400 of best-practice workflows, the flexibility to bring private tools and notebooks, and the ability to complete interactive analyses, all with the speed of cloud computing. The number of available datasets and tools are rapidly increasing, connecting researchers to datasets from a wide range of sources and data types, such as proteomics and imaging.
The platform has been continuously expanded to include new applications and features since its launch in 2016. Here we describe how new features have been implemented to broaden the data and workflows accessible to cancer researchers. First, we have integrated with several new nodes within the Cancer Research Data Commons to enable access and analysis on proteomics, canine, and other cancer datasets, which alongside with the genomics data on the CGC, enables true multi-omic analysis. Second, we have expanded our infrastructure to enable computation on both Google and Amazon cloud environments, allowing for analysis of data held in either environment. We have also added support for RStudio within the CGC, along with Python and Julia notebooks. Researchers can complete their entire workflow on the platform, from data discovery through visualizations, while streamlining collaboration and speeding the time from hypothesis to conclusion. Altogether, these added features enable a network of Findable, Accessible, Interoperable, and Reusable (FAIR) datasets towards making cancer data analysis faster, easier, and more accessible for all.
Citation Format: Manisha Ray, Jack DiGiovanna, Jelena Radenkovic, Marko Tosic, Nikola Mirkovic, Boris Majic, Vladan Andjus, Brandi Davis-Dusenbery. The Cancer Genomics Cloud enables complex and multi-omic data science in the cloud [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3223.
Abstract 3228: An online tool to balance baseline covariates for mouse clinical trials
Authors: Mao Binchen , Ouyang Davy , Li Henry , Guo Sheng 
Published: September 2020

Abstract
INTRODUCTION: Randomization is a cornerstone of controlled studies such as mouse clinical trials (MCT). However, simple randomization schemes often lead to unbalanced group allocations, therefore reducing the statistical power of experimental studies. This issue becomes more relevant and critical in MCTs where it is usually necessary to allocate a large number of mice into multiple groups/arms, so that all groups have close tumor volumes (measured by average and variance) as well as other covariates such as body weight, while at the same time also using as few mice as possible. Possible allocations grow exponentially by mouse and group number, and it is computationally intractable to identify optimal allocation schemes; instead, heuristic methods are used to search for near-optimal solutions. Studylog® systems can balance tumor volume with at most one baseline covariate. Randmice, a newly developed tool by Stimunity, shows good performance in balancing bilateral tumors, but it cannot balance more than two baseline covariates. We have developed a fast, in-house, online tool to balance any number of baseline covariates and, in addition, users can assign different weights to each baseline covariate based on levels of importance.
METHODS: We used a two-step method to balance designated baseline covariates for MCTs. First, we used a matched algorithm to find sub-matches from a population of mice, by grouping together mice with similar values of baseline covariates. Based on these sub-matches, we then used an optimization method to minimize the imbalance of baseline covariates guided by a weighted score function. Once the optimization was complete, a summary statistic table and a diagnostic plot for the top 10 group allocation solutions were displayed for picking the most suitable solution.
RESULTS: We used our baseline covariate balancing tool for a benchmark set of mouse clinical trials with more than one baseline covariate to be balanced out, with the difference of key baseline covariates among groups well under control with close means. The tool completed the allocations in a few minutes by running on a single-CPU computer.
CONCLUSIONS: We have developed a fast and powerful online tool to help preclinical researchers balance key baseline covariates in their studies, particularly in mouse clinical trials.
Citation Format: Binchen Mao, Davy Ouyang, Henry Li, Sheng Guo. An online tool to balance baseline covariates for mouse clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3228.
Abstract 3232: In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies
Authors: Holt Sanne , Vermond Sophie , Hazenoot Monique Hazenoot , Overman Jeroen , Aarbiou Jamil Aarbiou , DeGroot Jeroen DeGroot 
Published: September 2020

Abstract
Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells are part of a big wave of immunotherapies showing great promise in cancer clinical trials. With the first T cell based therapies targeting hematological malignances now approved, their next challenge is solid tumors. Solid tumors create an additional challenge due to the lack of tumor specific target antigens, posing significant safety risks, i.e. on-target on-tumor, on-target off-tumor and off-target toxicities. Toxic effects previously reported vary from mild-severe cytokine release syndrome (CRS) to neurotoxicity and death.
We have developed in vitro assays utilizing primary human cells from healthy tissue and/or differentiated iPCS-derived cells to assess on-target off-tumor and/or off-target cytotoxicity for engineered T cell therapies. The presence of CAR-T cell mediated cytotoxicity was measured through co-culture with healthy human primary cells to assess unwanted CAR-T reactivity as well as a high target antigen expressing control cancer cell line to confirm CAR-T functionality. The human primary cell type was selected based on its potential safety risk by establishing low level protein expression of the target antigen. Readouts included IFNγ production determined by MesoScale Discovery platform as a measure of T cell activation and Hoechst/PI staining of target cells by flow cytometry.
Our study generated high quality data of the CAR-T cell, confirming functionality by showing consistent T cell activation and killing against a positive control cell line. Moreover, we were able establish a clear absence of activity against the primary human cells thus providing insight into the safety of the CAR-T therapy.
The developed safety assays provide a robust and rapid platform to assess on-target off-tumor and off-target effects within immuno-oncology therapies, either TCR or CAR-T cells, in both early stage development or late stage testing of the therapeutic product. Through inclusion of a wide range of human primary cells, both high risk tissues and major organs at risk of off-target toxicity, a clear safety profile can be generate in vitro for these novel T cell therapies. Safety risks associated with cell based IO-therapies is the biggest challenge for the success of these therapies, performing a thorough safety screen on healthy primary human tissues is therefore crucial.
Citation Format: Sanne Holt, Sophie Vermond, Monique Hazenoot Hazenoot, Jeroen Overman, Jamil Aarbiou Aarbiou, Jeroen DeGroot DeGroot. In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3232.
Abstract 3247: Development of CAR-T cell therapy for B-ALL using a point-of-care approach
Authors: Abdo Luiza , Barros Luciana Rodrigues , Viegas Mariana Saldanha , Marques Luisa Vieira , de Sousa Ferreira Priscila , Chicaybam Leonardo , Bonamino Martín Hernán 
Published: September 2020

Abstract
Introduction: CD19-targeted CAR-T cell immunotherapy is now an approved treatment for B cell leukemias and lymphomas. Current protocols for producing CAR-T cells use viral vectors for genetic modification and take 12-15 days to expand sufficient numbers of T cells, constituting an important bottleneck for the widespread use of this therapy. The development of non-viral, plasmid-based systems like Sleeping Beauty (SB) transposons, coupled with the emergence of large scale, closed electroporation devices, present the opportunity of generating high numbers of CAR-T cells in a short period of time and transforming this in a point-of-care (POC) therapy.
Methods and Results: In this work, mononuclear cells were isolated using Ficoll and electroporated using Nucleofector IIb electroporator combined with plasmids encoding 19BBz CAR (in the pT3 SB transposon backbone) and SB100x transposase. Cells were rested for 24h and used for in vitro and in vivo experiments. The phenotype was assessed by flow cytometry. The in vitro cytotoxicity assay was performed using Calcein-AM dye on target cells incubated with different ratios of effector cells. 8-12-week-old-female-NSG were injected iv. 5 × 106 RS4;11 GFP or 105 Nalm-6 GFP and after 3 days were treated with different doses of recently electroporated CAR-T cells. CAR expression on day 1 following electroporation ranged between 5-15% and in vitro cytotoxic activity against RS4;11 or Nalm-6 CD19+ B cell precursor leukemia lines was low or absent. NSG mice engrafted with RS4;11 and treated with 1 × 105 19BBz+ cells showed improved survival when compared to mice treated with mock electroporated cells. POC approach was also efficient against Nalm-6, where 19BBz+CAR-T cells (7 × 105 per mice) improved the survival of mice. In both models, decreased tumor burden in blood and spleen was observed in mice treated with 19BBz. Head to head comparison of 19BBz cells used in POC approach or expanded for 8-12 days in vitro showed similar antitumor activity in vivo against RS4;11 cells, leading to equivalent improvements in mice survival.
Conclusion: In summary, we show that the POC strategy is a viable approach for the use of CAR-T cells, obviating the need for T cell expansion while having the potential to greatly decrease the total cost and time of CAR-T cell therapy manufacturing.
Citation Format: Luiza Abdo, Luciana Rodrigues Barros, Mariana Saldanha Viegas, Luisa Vieira Marques, Priscila de Sousa Ferreira, Leonardo Chicaybam, Martín Hernán Bonamino. Development of CAR-T cell therapy for B-ALL using a point-of-care approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3247.
Abstract 326: Differences of drug sensitivities between 2-dimensional and 3-dimensional culture systems in triple negative breast cancer cell lines
Authors: Muguruma Masako , Teraoka Saeko , Miyahara Kana , Ueda Ai , Kawate Takahiko , Ishikawa Takashi 
Published: September 2020

Abstract
[BACKGROUND] In vitro chemosensitivity tests are not always consistent to clinical results (Hutchinston L et al., Nat Rev Clin Oncol. 2011), partly because of lacking extracellular matrix-cell interactions in 2-dimensional (2D) cell culture system (Antoni D et al., Int J Mol Sci. 2015). Three-dimensional cell culture (3D) system maintains cells with a higher degree of structural complexity and homeostasis, analogous to tissues and organs compared with 2D cell culture system. Thus, 3D cell culture system will be expected for alteration of the animal experiment in chemosensitivity test (Bokhari M et al., J Anat. 2007). Cytotoxic agents are crucial for treating triple negative breast cancer (TNBC).[AIM] To clarify differences of drug sensitivities between 2D and 3D culture in TNBC cell lines, we compared IC50s for Cisplatin (CDDP), Docetaxel (DTX), Epirubicin (EPI) and Bromodomain inhibitor (JQ1).
[METHODS] Thirteen TNBC cell lines were examined; HCC1599, HCC1937, HCC38, MDA-MB-468, HCC1806, HCC70, MDA-MB-436, MDA-MB-231, Hs578T, BT549, MDA-MB-453, BT20, and HCC1395. For 2D culture, cells were plated on general 96 well cell culture plate for 24 hours. For 3D culture, cells were plated on the PrimeSurface® 96 well plate (SUMITOMO BAKELITE) for 72 hours. Then, those were incubated in media including CDDP, DTX, EPI or JQ1 for 72 hours. The cell viability was quantified using CellTiter-Glo 2.0 and CellTiter-Glo 3D cell viability Assay (Promega), respectively.
[RESULTS] For CDDP, IC50s were highly correlated between 2D and 3D culture (r=0.928) . The mean of IC50 value showed higher in 3D culture (27.67±8.40μM) than 2D culture (12.86 ± 17.23μM). For EPI, the correlation was r=0.593. The mean value showed higher in 3D culture (1.41±1.30μM) than 2D culture (0.62±0.72μM). For DTX and JQ1, the mean values were 1.78 ± 2.05nM and 4.31 ±4.72μM in 2D culture, respectively. However, IC50 failed to be obtained in several TNBC cell lines (HCC1937, HCC38, HCC1806, Hs578T and HCC1395 for JQ1 and MDA-MB-436, MDA-MB-453 and BT20 for DTX) in 3D culture.
[CONCLUSION] IC50 value was higher in 3D culture than in 2D culture for CDDP and EPI. The correlation of IC50s between 2D and 3D depended on drugs with the highest in CDDP. We are under investigation on reasons why sensitivity tests for DTX and JQ1 failed in 3D culture system.
Citation Format: Masako Muguruma, Saeko Teraoka, Kana Miyahara, Ai Ueda, Takahiko Kawate, Takashi Ishikawa. Differences of drug sensitivities between 2-dimensional and 3-dimensional culture systems in triple negative breast cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 326.
Abstract 3265: Anti-GITR agonist antibody for cancer immunotherapy
Authors: Yang Teddy , Dai Ken , Wang Dongxu , Qi Qianqian , Liu Hu 
Published: September 2020

Abstract
Glucocorticoid-induced TNFR-related (GITR) is a gene coding for a member of the TNF receptor superfamily. GITR is expressed at low levels on resting responder T lymphocytes and is up-regulated in T regulatory cells (Treg cells) and in activated T cells. GITR agonist which upregulated co-stimulatory signal to T cells or inhibition of Treg induced suppression which reverts Treg proliferation, is likely to enhance immunity in response to infection and tumor immunity. Therefore, GITR is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule. In this study, various types of GITR immunogens, including gene, protein and cell line, are used for H2L2 mice immunization. Then we generate and characterize panels of anti-GITR monoclonal antibodies which not only could specifically bind to human GITR, but also show cross-reactivity to cyno GITR. Such anti-GITR antibody can increase the expression of NF-κB gene by cross-linking by anti-Fab, and induce the release of INF-γ from T cell. In harsh pH or temperature condition, the anti-GITR antibody can keep the stability. And at high concentration, the viscosity of the anti-GITR antibody is good. Moreover, in vivo study showed that the anti-GITR antibody can effectively inhibit tumor growth. Above results demonstrated that the anti-GITR antibody is expected to develop further for clinical study single or combine with other immune checkpoint antibody.
Citation Format: Teddy Yang, Ken Dai, Dongxu Wang, Qianqian Qi, Hu Liu. Anti-GITR agonist antibody for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3265.