bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5641: CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager
Authors: El-Murr Nizar , Henry Christophe , Francesconi Elisa , Attenot Florence , Virone-Oddos Angela , Vidard Laurent , Wu Lan , Yang Zhi-Yong , Chiron Marielle 
Published: September 2020

Abstract
SAR442257 (CD38/CD28xCD3) is a trispecific T cell engager designed for the treatment of multiple myeloma (MM). Its cytotoxic activity and anti-tumor efficacy is dependent on the expression of CD38 by malignant plasma cells and the recruitment and activation of T cells via CD3 and CD28. Here we show that MM cells also express CD28 on their membrane and investigate how this expression impacts the cytotoxic activity of the trispecific antibody. Using CRISPR, CD28 knock-out (KO) models were generated from two MM cell lines that have different receptor densities of CD38 and CD28: KMS-11 (CD38 ~3 000/cell; CD28 ~35 000/cell) and RPMI8226 (CD38 ~129 000/cell; CD28 ~84 000/cell). T-cell-mediated cytotoxicity was evaluated in vitro using either effector CD8+ T cells or total PBMC isolated from healthy donors. Binding of SAR442257 to tumor cells in the presence of saturating concentrations of anti-CD38 antibodies was evaluated by flow cytometry using APC-labeled SAR442257 and FITC-labeled anti-CD38 antibodies. In vitro killing assays showed that SAR442257 is active on both CD38 high and CD38 low MM cell lines (EC50 in the pM range for WT cell lines; Table 1). Following CD28 KO, SAR442257 remained active but displayed reduced cytotoxic activity as compared to WT CD38+ CD28+ cells. The reduced cytotoxic activity was noticeable in both CD38 low and CD38 high MM models suggesting that the expression of CD28 by MM cells contributes to the cytotoxic activity of the trispecific antibody. We further show that when other anti-CD38 antibodies are bound to CD38, binding of SAR442257 to tumor cells and T-cell mediated cytotoxicity are rescued by CD28 as evidenced by loss of binding and cytotoxic activity in CD28KO cells. Overall, these data show that SAR442257 is active on both CD38 high and low MM models and that CD28 expressed on MM tumor cells can be directly targeted by SAR442257, enhancing its cytotoxicity and allowing it to bind MM cells when CD38 is occupied by other anti-CD38 antibodies
Table 1.T cell mediated killing assays. EC50rel, Relative EC50; CI, Confidence interval.EC50rel (pM) [±CI95%]KMS-11RPMI8226WTCD28KOWTCD28KOEffector CD8+ T cells4.1 [2.9 ; 5.9]30.2 [16.9 ; 54.0]0.2 [0.1 ; 0.3]0.5 [0.3 ; 0.8]Total PBMC26.0 [7.8 ; 87]&gt;250032.0 [14.8 ; 69.2]304.0 [118.0 ; 787.0]
Citation Format: Nizar El-Murr, Christophe Henry, Elisa Francesconi, Florence Attenot, Angela Virone-Oddos, Laurent Vidard, Lan Wu, Zhi-Yong Yang, Marielle Chiron. CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager [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 5641.
Abstract 5970: Function and regulatory mechanism of GPM6A in hepatocellular carcinoma development and progression
Authors: Li Rui Zong , Xu Gang , Zhu Min Ji , Wu Jian , Wu Jian 
Published: September 2020

Abstract
BACKGROUND: GPM6A is a glycoprotein found in endothelial cells and is considered to be a malignant lymphoma oncogene. However, the role of GPM6A in the development of hepatocellular carcinoma (HCC) is unknown. Through Affymetrix gene expression microarray and bioinformatics analysis, very low GPM6A expression was found in HCC tissue. The present study aims to explore the function and regulatory mechanism of GPM6A in HCC development and progression.
METHODS: Levels of GPM6A expression was determined in various hepatoma cell lines and HCC specimens from different base disorders, and its role on cell proliferation was investigated in GPM6A stably over-expressing cell lines. Modulating effects of a specific miRNA were evaluated with miRNA mimetic transfection.
RESULTS: Much lower GPM6A levels were found in HCC occuring in HBV-infection or nonalcoholic steatohepatitis. TCGA data confirmed that low GPM6A expression in HCC correlates with a poor overall survival and progression-free survival rate (p=0.018 and 0.004). Over-expression of GPM6A inhibited proliferation in SMMC-7721 and MHCC-97H cells by 31% and 30%, respectively (p&lt;0.01), and led to decreased colony formation by 40%. Overexpression of GPM6A was found to significantly reduce wound healing and migration rates in these two cell types. miR-96-5p was expressed at 6 to 61-fold higher in HCC tissues than adjacent tissues (p&lt;0.01); whereas GPM6A gene expression was at 3 to 55-fold lower (p&lt;0.01) in a negative correlation between miR-96-5p levels and GPM6A levels in HCC specimens (r=-0.64, p&lt;0.05). Further experiments demonstrated that miR-96-5p acted directly on the 3'UTR of the GPM6A gene, and transfection of miR-96-5p significantly decreased GPM6A mRNA expression by 50% in two hepatoma cell lines. Moreover, MiR-96-5p transfection promoted proliferation (66%, 59%, p&lt;0.01), migration (10%, 9%, p&lt;0.05) and invasion (557±66 vs. 226±19; 235±36 vs. 153±17, p&lt;0.05-0.01) of SMMC-7721 and MHCC-97H hepatoma cells; whereas the function of oncogenic microRNA-96 was significantly inhibited in GPM6A-overexpressed hepatoma cells.
CONCLUSIONS: GPM6A expression in HCC is commonly suppressed, and correlated to a poor prognosis. Its low expression in HCC tissues is most likely attributed to upregulated miR-96-5p, which may function as an oncolytic regulator through suppressed GMP6A that may block proliferation, cloning formation, migration and invasion of hepatoma cells.
Citation Format: Rui Zong Li, Gang Xu, Min Ji Zhu, Jian Wu, Jian Wu. Function and regulatory mechanism of GPM6A in hepatocellular carcinoma development and progression [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 5970.
Abstract 6011: Mesenchymal stem cells promote PD-L1 expression in lung cancer cells
Authors: Zhao Hui , Yang Hui , Sun Jinqiu , Liang Guoqiang , Zhao Qianqian , Zhang Xiufang , Liang Shengxian , Guo Rui , Zhong Li 
Published: September 2020

Abstract
Background
Effects of mesenchymal stem cells (MSCs) on tumors have been extensively studied in recent years, but results still remain controversial. In this study we investigated the roles of MSCs on the expression of programmed death-ligand 1 (PD-L1) in lung cancer cells. Since overexpression of PD-L1 has been found to attenuate body's immune system against tumor cells, PD-1/PD-L1 blockages have become the most effective immunotherapy to the late stage non-small cell lung cancer (NSCLC). Therefore, understanding the effects of MSCs on PD-L1 expression is critical in managing immunotherapy for NSCLC patients.
Method
PD-L1 expressions were tested in two NSCLC cell lines, A549 and H1299 using qRT-PCR and Western Blot to qualitatively measure mRNA and protein levels, respectively. MSCs were isolated from umbilical cord blood and co-cultured with A549 and H1299 cells in complete medium using Transwell filters for 24-h, 48-h and 72-h. Then both A549 and H1299 cells were collected and PD-L1 expressions were tested. MSC-Conditioned Medium (MSC-CM) was generated by culturing 80% confluence of MSCs with serum-free medium. After 48 h, the medium was collected as MSC-CM. Both A549 and H1299 were then cultured in MSC-CM for 24-h, 48-h and 72-h, and PD-L1 expressions were measured from these two cell lines separately.
Result
Both MSCs and MSC-CM significantly increased the PD-L1 mRNA levels in the two NSCLC cells, while the MSC-CM had stronger stimulation to PD-L1 expressions (P &lt; 0.0001) comparing to MSCs treatment (P&lt;0.01). A549 cells reached the most significant effect at 48-h, while H1299 cells attended the same effect at 24-h treatment. The similar results were observed with PD-L1 protein levels. Both cell lines showed increased PD-L1 protein expressions after treating with MSCs and MSC-CM, but the augmented scales were smaller than the mRNA levels. The PD-L1 protein expressions in A549 cells increased significantly (p &lt; 0.05) at 48-h when treating with MSCs, while increased much higher when treating with MSC-CM (P &lt; 0.01). H1299 cells also showed the similar increase in PD-L1 protein expressions after 24-h treatment.
Conclusion
Both MSCs and MSC-CM significantly increase PD-L1 expressions in lung cancer cells, which ultimately attenuate the immune system against tumor cells.
Citation Format: Hui Zhao, Hui Yang, Jinqiu Sun, Guoqiang Liang, Qianqian Zhao, Xiufang Zhang, Shengxian Liang, Rui Guo, Li Zhong. Mesenchymal stem cells promote PD-L1 expression in lung cancer cells [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 6011.
Abstract 6056: A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach
Authors: Gan Xin , Shi Lei , Shan Qianqian , Chen Fei , He Yun , Rong Yiping , Du Qiumei 
Published: September 2020

Abstract
CD73, an ecto-5'-nucleotidase, plays a major role in de-phosphorylation of the extracellular adenosine monophosphate (AMP) to adenosine, which in turn is a potent immunosuppressive metabolite that modulates the immune reaction within the tumor microenvironment (TME). High concentration of adenosine, predominantly signaling through the A2A receptor, suppress innate and adaptive immune cell responses, leading to tumor escape of immune surveillance. Recent studies have shown a significant overexpression of CD73 in solid tumors alongside it's functional upregulation by inflammatory mediators and hypoxia. Thus, inhibition of CD73 enzymatic activity and its surface expression in the TME may improve anti-tumor immune activity.
To test this hypothesis, we designed and developed a fully human antibody with unique structure to recognize CD73. This antibody can block the enzymatic activity of CD73 in addition to reducing the surface expression of CD73. Both enzymatic and non-enzymatic dependent functions of CD73 were significantly dampened. The antibody demonstrates a superior anti-tumor activity over reference antibodies in in-vitro and in-vivo models.
Our findings indicate that the antibody has promising potential as an effective therapy for PD-1/PD-L1 nonresponsive or refractory patients, as well as a broader patient population that may benefit from a unique mechanism of action of CD73-targeting antibody.
Citation Format: Xin Gan, Lei Shi, Qianqian Shan, Fei Chen, Yun He, Yiping Rong, Qiumei Du. A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing 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 6056.
Abstract 6535: A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties
Authors: Harper James , Leinster Andrew , Rath Nicola , Burke Shannon , Mulgrew Kathy , Jin Hong , Wilkinson Robert W. 
Published: September 2020

Abstract
Oncolytic viruses offer the potential to be transformative in the treatment of cancers through their ability to selectively infect, replicate in and kill tumors whilst able to potently activate the immune system. Their activity can be further augmented through the addition of transgenes leading to tumor selective gene expression. Our proprietary Newcastle Disease virus (NDV) backbone has previously been demonstrated to have broad oncolytic activity whilst inducing potent anti tumor immune effects in preclinical models. We set out to test whether the incorporation of an IL-12 transgene into the NDV backbone could result in transgene dependent enhancement in anti tumor efficacy. In vitro, the addition of IL-12 into the NDV genome did not alter NDV infectivity in tumor or non-cancer cells compared to the backbone virus and infection of cancer cells resulted in the production of bioactive IL-12. In an immune-deficient xenograft model, a single systemic administration of NDVhuIL-12 resulted in tumor selective replication and local IL-12 production within the tumor microenvironment (TME). In syngeneic tumor models, local tumoral administration of NDVmuIL-12 resulted in the generation of an elevated and more durable type II interferon response compared to NDV-GMCSF; though similar pharmacokinetic profiles were observed. This difference in cytokine response correlated with superior single agent efficacy of NDVmuIL-12 compared to NDV alone in the B16F10 model. Furthermore, NDVmuIL-12 demonstrated anti tumor efficacy in several NDV refractory models, suggesting tumor expression of IL-12 was necessary to drive anti tumor activity in some circumstances. Across all models tested significant changes in the tumor immune microenvironment, previously associated with enhanced anti tumor immunity were observed in NDVmuIL-12 tumours compared to backbone virus alone. There is an abundance of pre-clinical data demonstrating that IL-12 can exert potent anti tumor activity, but its clinical application has been hindered through its toxicity when administered systemically. These data provide evidence that recombinant NDV could be utilised to deliver IL-12 to the TME when administered systemically and that the addition of IL-12 potentiates the anti tumor activity of NDV.
Citation Format: James Harper, Andrew Leinster, Nicola Rath, Shannon Burke, Kathy Mulgrew, Hong Jin, Robert W. Wilkinson. A recombinant Newcastle disease virus expressing IL-12 has potent pre-clinical immunomodulatory and anti tumor properties [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 6535.
Abstract 6662: Effects of tumor treating fields (TTFields) on dendritic cells functionality
Authors: Voloshin Tali , Davidi Shiri , Kaynan Noa , Schneiderman Rosa , Volodin Alexandra , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: September 2020

Abstract
Introduction Tumor Treating Fields (TTFields) are a clinically applied anti-neoplastic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. In this study we evaluated the effects of in vitro TTFields application on dendritic cell (DC) properties that include maturation, phagocytosis, and migration.
Methods Bone marrow cells were flushed from the femurs and tibias of 5-7 week old C57BL/6 mice to generate bone marrow-derived DCs. For the DC maturation assay, TTFields treated cancer cells were added at a ratio of 1:1 for 24 h. DC maturation was analyzed using flow cytometry to assess surface expression of major histocompatibility complex class II (MHC II), CD40, and CD80 activation markers. For the phagocytosis assay, CellTrackerTM Deep Red Dye, pre-stained TTFields treated cancer cells were added at a ratio of 1:1 for 2h and phagocytosis by DCs was evaluated using flow cytometry. DC migration assays were performed using a modified Matrigel coated Boyden chamber either with or without C-C Motif Chemokine Ligand 19 (CCL19), utilized as a chemoattractant.
Results TTFields treated cancer cells were effectively phagocytosed by DCs, while untreated control cells did not show similar outcomes. In addition, activation markers were found to be upregulated in DCs that were co-cultured with TTFields treated cells. This up-regulation was observed for all the costimulatory molecules analyzed. DC migration assays, showed no significant difference in migration rates between untreated and TTFields treated DCs, with or without the chemoattractant CCL19.
Conclusions These in vitro results indicate that TTFields treated cancer cells promote DC elicited phagocytosis and DC maturation. Moreover, in contrast to previous studies reporting that TTFields show an inhibitory effect on cancer cell migration, we demonstrate that TTFields do not impair the migratory properties of DCs.
Citation Format: Tali Voloshin, Shiri Davidi, Noa Kaynan, Rosa Schneiderman, Alexandra Volodin, Moshe Giladi, Uri Weinberg, Yoram Palti. Effects of tumor treating fields (TTFields) on dendritic cells functionality [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 6662.
Abstract 744: Volatile organic compounds (VOCs) from exhaled Breath for lung cancer Staging using TD-GC-MS
Authors: Muhammad Kanhar Ghulam , Madeeha Channa , Wei Fu , Xin Xu Lin , Hu Yanjie , Ying Kejing , Liu Jun , Chen Xing 
Published: September 2020

Abstract
Background: Breath analysis is a promising noninvasive screening technique that offers a wide range of probable possibilities to facilitate early diagnosis of lung cancer (LC).
Method: Exhaled breath samples of 352 subjects were analyzed to detect C6∼C30 VOCs through thermal desorption coupled with gas chromatography-mass spectrometry (TD-GC-MS). Data were divided into three categories Lung Cancer (LC), Benign Pulmonary Disease (BPD) and Healthy control (HC). Statistical classification models were used to analyze VOCs to distinguish between HC, BPD and LC patient's early and advanced stages. Receiver operator characteristics (ROC) curves were used to select different VOCs to evaluate the accuracy, specificity, and sensitivity of the diagnostic model.
Results: The analysis resulted that 10,9,11 and 10 VOCs have a significant correlation to discriminate Histology, stage, BPD from LC and HC from LC. The diagnostic model predicted accuracy, sensitivity, and specificity of NSCLC vs. SCLC is 92%, 96% and 90% with area under curve AUC&gt;0.913. As of ROC curve with AUC&gt;0.819 has distinguished Stage I-II vs. stage III-IV with accuracy, sensitivity, and specificity 72%, 84%, and 80%. Whereas the ROC curve with AUC&gt;0.795 has distinguished BPD from LC with accuracy, sensitivity, and specificity 83%, 89%, and 84%. While ROC curve with AUC&gt;0.945, accuracy, sensitivity and specificity 92%, 96%, and 90% have distinguished HC from LC.
Conclusion: This study confirms that TD GC-MS is a sensitive and dependable method to distinguish the VOCs in exhaled breath. We have witnessed significant differences in breath of BPD, HC and LC subjects. Where 10,8,11 and 10 VOCs have distinguished between early from the advance stage, NSCLC from SCLC, BPD from LC and HC from LC. These VOCs has the potential to help improve LC diagnosis and prognosis. However, with the expansion of multi centers to other regions could result in more vital findings and will help improve breath analysis and the diagnosis standard.
Keywords: Breath Analysis, VOC markers, lung cancer, TD-GC-MS.
Citation Format: Kanhar Ghulam Muhammad, Channa Madeeha, Fu Wei, Xu Lin Xin, Yanjie Hu, Kejing Ying, Jun Liu, Xing Chen. Volatile organic compounds (VOCs) from exhaled Breath for lung cancer Staging using TD-GC-MS [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 744.
Abstract CT081: Poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients - a Phase 2 study
Authors: Le Xiuning , Goldman Jonathan , Clarke Jeffrey , Techekmedyian Nishan , Piotrowska Zofia , Chu David , Bhat Gajanan , Lebel Francois , Socinski Mark 
Published: September 2020

Abstract
Introduction and Purpose of Study: Effective and approved therapy for treating non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations is an unmet medical need. Poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants. We evaluated the efficacy and safety of poziotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations (ZENITH20-1) in an independent cohort of a multi-cohort, multi-center Phase 2 study. Methods: Poziotinib (16 mg) was administered orally QD, allowing dose reductions for AEs, with follow up for 24 months. The primary endpoint was objective response rate (ORR), evaluated by central radiographic review using RECIST v1.1. The ORR endpoint was to be met if the lower bound of 95% CI&gt;17% in the As-Treated Population. The secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Safety monitoring was conducted throughout the study. Results: A total of 115 patients with a median age of 61 years (33-83) were enrolled. Patients had received and failed prior therapy (median of 2 [1-9]) with majority receiving both chemo and immunotherapy. The median relative dose intensity was 72% (7-100%) with 65% having dose reductions. 10% of patients discontinued due to related AEs. The ORR was 14.8% (95% CI 8.9%-22.6%), and the DCR was 68.7% (95% CI 59.4%-77.0%). Seventeen patients had a confirmed partial response (PR), 5 patients had unconfirmed PR and 62 (53.9%) patients had stable disease (SD). Overall, 75 (65%) patients had tumor size reductions. The median DoR was 7.4 months (95% CI 3.7-9.7) and the median PFS was 4.2 months (95% CI 3.7-6.6). Safety profile was mechanism related and similar to other 2nd generation tyrosine kinase inhibitors with the most common treatment-related Grade ≥3 AEs (preferred term) being rash (28%), diarrhea (26%), stomatitis (9%) and paronychia (6%). The incidence of treatment-related pneumonitis, an important AE associated with TKIs, was 4%. Conclusion: Although the ORR primary endpoint was not met, poziotinib induced tumor size reduction in the majority (65%) of patients. The tumor size reduction combined with long duration of response demonstrated the clinical activity of poziotinib in treating this patient population. We are further optimizing dosing and AE management.
Citation Format: Xiuning Le, Jonathan Goldman, Jeffrey Clarke, Nishan Techekmedyian, Zofia Piotrowska, David Chu, Gajanan Bhat, Francois Lebel, Mark Socinski. Poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients - a Phase 2 study [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 CT081.