bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2250: Combinational markers of neoantigen intratumor heterogeneity and neoantigen burden predict progression-free survival for lenvatinib plus PD-1 blockade in patients with intrahepatic cholangiocarcinoma
Authors: Lin Jianzhen , Liu Yiying , Yang Xu , Bai Yi , Long Junyu , Long Junyu , Li Yongchao , Wang Jiaqian , Wang Dongxu , Yang Xiaobo , Guan Mei , Huo Li , Pan Jie , Hu Ke , Gao Zhibo , Zhao Haitao 
Published: August 2019

Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant neoplasm derived from biliary epithelial cells. Although many targetable gene alterations have been identified, there has no molecular targeted drug available for these patients at present, which may be due to the high intratumor heterogeneity (ITH) of ICC. Previous studies have demonstrated that some ICC patients could be benefited from immune checkpoint inhibitors (ICIs), but the predictive biomarkers are still unknown. We used whole exome sequencing to evaluate the impact of neoantigen ITH and tumor neoantigen burden (TNB) in 45 ICC patients, in which 15 patients were treated by anti-PD1 inhibitor combined with lenvatinib. The median neoantigen and clonal neoantigen load of these patients were 0.65 and 0.29 per Mb, respectively. The median neoantigen ITH index was 0.45, with a range from 0.02 to 1. Survival analysis of those patients who received the combined treatment revealed significantly longer progression-free survival (PFS) in patients with higher TNB and low neoantigen ITH (9.5 vs 3.5 months, p=0.00583). Among the 30 patients without anti-PD1 combined therapy, there were 36.7% (11/30) ICC patients with high TNB and low neoantigen ITH, indicating these patients might be benefited from this combined therapy. One of these 45 patients had the highest TMB and TNB with high MSI and dMMR has the longest PFS (12 months) after the combined treatment. Besides, we found that the clonal KRAS mutation (G12D) occurred exclusively in patients with shorter PFS and OS and lower TMB and TNB, while the FLG mutation occurred only in patients with longer PFS and OS and higher TMB and TNB. These results indicated the potential relationship between mutations in KRAS and FLG and the levels of TMB and TNB, which needs to further investigation. Therefore, these data revealed that the high TNB and lower neoantigen ITH might be a promising marker for predicting the efficacy of the combination therapy of anti-PD1 inhibitor and lenvatinib in ICC patients.
Citation Format: Jianzhen Lin, Yiying Liu, Xu Yang, Yi Bai, Junyu Long, Junyu Long, Yongchao Li, Jiaqian Wang, Dongxu Wang, Xiaobo Yang, Mei Guan, Li Huo, Jie Pan, Ke Hu, Zhibo Gao, Haitao Zhao. Combinational markers of neoantigen intratumor heterogeneity and neoantigen burden predict progression-free survival for lenvatinib plus PD-1 blockade in patients with intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2250.
Abstract 2253: Rapid personalized selection of immune checkpoint blockage agent combinational treatment for an adenocarcinoma patient
Authors: Lee Kang-Yun , Chen Chien-Chung , Huang Won-Ting 
Published: August 2019

Abstract
The combination of immune checkpoint blockage (ICB) agent and chemotherapy for cancer treatment is gaining lots of attention lately. However, there is no clear biomarker or index for such treatment, particularly after tumor gaining resistance to ICI. In this study, an improved hollow fiber assay (HFA) was utilized based upon a novel substrate of microtube array membrane (MTAM) to test the possible patient response towards the combined treatment of immunotherapy and chemotherapy. In this case study, biopsy of a stage 4 adenocarcinoma (cT2N3M1b) patient, with the disease progression after a durable response to prior pemetrexed and Nivolumab, was retrieved and treated with enzyme for a homogenous cell suspension. Pieces of MTAM preloaded with 106 of cancer cell along with patient’s peripheral blood mononuclear cell (PBMC) were implanted subcutaneously in bulb C mice. These mice were grouped and subjected to two different ICB combinational treatments (1) Nivolumab with Paclitaxel and (2) Nivolumab with Pemetrexed. 10 days later MTAMs were explanted and cancer cells were subject to MTT assay for their viability. The results of two treatments clearly demonstrated the better efficacy of Nivolumab and Paclitaxel towards this patient cancer cells. Clinically, CT images taken before and after a two-month treatment show positive response towards the combinational treatment of Nivolumab and Paclitaxel. This case study suggests a rapid clinical regiment prediction/selection of ICB combinational treatment is possible in two weeks using MTAM/HFA and provides reasonable evident for the corresponding treatment.
Citation Format: Kang-Yun Lee, Chien-Chung Chen, Won-Ting Huang. Rapid personalized selection of immune checkpoint blockage agent combinational treatment for an adenocarcinoma patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2253.
Abstract 227: BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy
Authors: Hsu Chia-Yu , Chen Yun-Yu , Lo Chen-Fu , Chiu Tai-Yu , Chen Ching-Ping , Huang Chen-Lung , Huang Chung-Yu , Wang Min-Hsien , Chao Yu-Sheng , Shih Joe C. , Yeh Teng-Kuang , Tsou Lun K. , Chen Chiung-Tong 
Published: August 2019

Abstract
Zinc(II)-dipicolylamine (Zn-DPA) have been described to specifically complex with phosphatidylserine (PS), which has a higher level at the external surface of cancer cells in tumorigenic condition. BPRDP056 is a Zn-DPA-SN38 conjugate designed to provide a PS-targeting drug delivery of cytotoxic payload SN-38 at the tumor microenvironment, thereby, decrease the dosage of SN38, while induce apoptosis in cancer cells. The in vivo therapeutic efficacy of BPRDP056 against the growths of human tumors has been shown significant in mice subcutaneously bearing a tumor type of pancreas, prostate, colon, liver, breast and glioblastoma, as well as in mice with an orthotopic pancreatic tumor. BPRDP056 shrunk tumors at a lower dosing intensity (~20%) of SN38 compared to CPT-11 in all models tested. Micro-Western assays showed that BPRDP056 exhibited apoptotic cell death signal levels similar to those of CPT-11 in the treated tumors in mice. Furthermore, pharmacokinetic and preliminary toxicology studies showed that BPRDP056 has a good stability in circulation with an acceptable therapeutic safety window in mice. BPRDP056 has been demonstrated with a tumor targeting ability and thus increases the cytotoxic payload SN38 concentration in situ for improved efficacy. Its therapeutic spectrum against malignant neoplasm will be expected to cover the PS-rich tumor microenvironment of all cancer types. BPRDP056 is a first-in-class Small Molecule Drug Conjugate for anti-cancer therapy.
Citation Format: Chia-Yu Hsu, Yun-Yu Chen, Chen-Fu Lo, Tai-Yu Chiu, Ching-Ping Chen, Chen-Lung Huang, Chung-Yu Huang, Min-Hsien Wang, Yu-Sheng Chao, Joe C. Shih, Teng-Kuang Yeh, Lun K. Tsou, Chiung-Tong Chen. BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 227.
Abstract 228: KSPi-ADCs: ADCs with novel kinesin spindle protein inhibitor payloads and a tailor-made linker chemistry
Authors: Lerchen Hans-Georg , Stelte-Ludwig Beatrix , Sommer Anette , Berndt Sandra , Rebstock Anne-Sophie , Johannes Sarah , Marx Leo , Mahlert Christoph , Greven Simone , Dietz Lisa , Joerissen Hannah , Weinmann Hilmar 
Published: August 2019

Abstract
Inhibitors of kinesin spindle protein (KSP/Eg5) have raised great interest because of their high antitumor potency which, however, could not be transferred into highly efficient clinical regimens due to dose limiting side effects such as neutropenia. We have developed a new, highly potent pyrrole subclass of KSPis as a novel payload class in ADCs. To increase the therapeutic window, a tailor-made effector chemistry has been designed. The tumor associated protease legumain (LGMN) is utilized for ADC cleavage to provide active metabolites with high and long-lasting exposure in tumors, thus matching the KSPi mode of action. LGMN is a lysosomal asparaginyl endopeptidase overexpressed in solid tumors which is associated with invasion, metastasis and poor survival. In our studies, we show an efficient LGMN mediated linker cleavage and payload release from different ADCs. In addition, the unique LGMN substrate sequence allows for high cleavage specificity and discrimination versus other proteases such as elastase, which has been associated with an undesired extracellular cleavage of e.g. vc-MMAE ADCs resulting in neutropenia. Variations of the linker chemistry were performed to retain high potency of the KSPi-ADCs against tumor cells while decreasing the activation of KSPi-ADCs in cells of healthy organs such as the liver. From this approach, highly potent KSPi-ADCs with improved tumor/organ ratios of active metabolites were obtained. In conclusion, ADC metabolism under legumain control is a versatile strategy to provide KSPi-ADCs with high potency and an improved safety profile.
Citation Format: Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Anette Sommer, Sandra Berndt, Anne-Sophie Rebstock, Sarah Johannes, Leo Marx, Christoph Mahlert, Simone Greven, Lisa Dietz, Hannah Joerissen, Hilmar Weinmann. KSPi-ADCs: ADCs with novel kinesin spindle protein inhibitor payloads and a tailor-made linker chemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 228.
Abstract 2283: Accurate and efficient Next-Generation Sequencing approach for liquid biopsy detection and monitoring
Authors: Chen Cai , Kasbek Christopher , Song Yang , Chen Si , Almalki Nouran , Li Jiangyu , Wan Yifei , Huang Jun , Ding Wei 
Published: August 2019

Abstract
Liquid biopsy detection using ctDNA has great potential in cancer diagnosis, monitoring, and predicting survival. However, detection sensitivity and specificity remain major challenge at the current stage. Here we utilized a targeted next-generation sequencing (NGS) approach to develop a noninvasive test to identify single nucleotide variations (SNVs), indels, fusions, copy number variations (CNVs) and microsatellite instability (MSI) present at low frequencies in different solid cancer patients. Target regions of interest were sequenced using tagging of individual molecules, followed by amplicon library generation and massive parallel sequencing using an Illumina platform. The variants were called and annotated using our in-house Actionable Genomic Interpretation System (AGIS) bioinformatics pipeline. This CLIA-approved NGS panel (LiquidGx™) detects more than 170 variants in 17 genes which were chosen mostly based on NCCN clinical actionable guidelines (AKT1, ALK, BRAF, EGFR, ERBB2, HRAS, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, RET, ROS1 and TP53) with detection limit of 0.1%. Mutations are detected with 94% sensitivity and 99.8% specificity in a short turnaround time of 3-5 business days. To assess the performance in a clinical setting, accurate sequencing was performed on 210 lung cancer patients; the frequency of mutations identified of each gene closely mirrored the published lung cancer tissue biopsy data. Fusions are detected from exosomal RNA, which could increase the sensitivity and/or concordance to tumor. For spike-in data validation, the limit of detection (LOD) of CNV can reach 2.2 -2.5 total gene copies. In addition to actionable mutations for targeted therapy, LiquidGx™ provides MSI status, which can predict a predisposition to mutations as a result from impaired DNA mismatch repair (MMR) and help predict if a tumor will respond to anti-PD-1 therapy. The LOD of our MSI detection is 2-4%. In summary, we have developed a potent liquid biopsy platform for highly sensitive genomic biomarker test. Our technology is also available as an assay development service and can be easily adaptable to the diagnosis and monitoring of different cancer types.
Note: This abstract was not presented at the meeting.
Citation Format: Cai Chen, Christopher Kasbek, Yang Song, Si Chen, Nouran Almalki, Jiangyu Li, Yifei Wan, Jun Huang, Wei Ding. Accurate and efficient Next-Generation Sequencing approach for liquid biopsy detection and monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2283.
Abstract 2289: Prognostic impact of progastrin levels in blood compared to MSKCC based clinical prognosis in metastatic renal cell cancer patients
Authors: Kohli Manish , Tan Winston , Payen Lea , Langlois-Jacques Carole , Liaud Pierre , Maucort-Boulch Delphine , Joubert Dominique , Prieur Alexandre 
Published: August 2019

Abstract
Background and Aims: Progastrin is a tumor promoting peptide which is detectable in the blood of patients with different cancers (Prieur et al. AACR 2017, Prieur et al. ASCO 2017). Progastrin gene is a direct target of the WNT/ß-catenin oncogenic pathway involved in tumorigenesis of many organs, but it is unknown if it has any prognostic significance in metastatic renal cell cancer (mRCC) patients. We evaluated progastrin as a prognosis marker along with known markers of prognosis in mRCCC.
Methods: 145 patients with mRCCC were enrolled in this study and blood samples were drawn after consent. Progastrin was measured using the ELISA cancerREAD®. Progastrin concentrations in the 145 mRCCC patients (test set) was assessed against 213 samples from asymptomatic volunteers from the French blood establishment (control set). The prognostic impact of progastrin levels was determined with overall survival (OS) using Cox proportional hazards and also compared to MSKCC based clinical prognosis (good;intermediate; poor). Statistical significance was considered at P≤0.05.
Results: The median follow-up of the cohort was 5.45 years (IQR: 1.87-9.95) and at the time of analysis 98/145 patients had died from disease progression. Plasma progastrin was detected in 95% of the patients (cut-off value 1 pM, range 0 to 272 pM, median value of 7.2 pM; IQR 3.20-19.71) compared to the control set (median value=0.61 pM; IQR 0.00-1.58). The Receiver Operating Characteristic analysis indicated an area under the curve of 0.92 (p&lt;0.0001; 95% CI 0.89 to 0.94). At the univariate level, MSKCC scores (good; intermediate; poor categories) in this cohort was associated with OS and was prognostic (p&lt;0.0001). We detected progastrin levels were higher with MSKCC score poor prognostic (p&lt;0.0002) (median 30.39 pM; IQR 9.31-57.20). Elevated progastrin was also independently associated with poor survival (p&lt;0.0001) and a multivariate model of MSKCC taken with progastrin levels remained significantly associated with poor survival (p&lt;0.0001).
Conclusion: Elevated progastrin levels in mRCCC is correlated with poor survival and further refines clinically used MSKCC prognostic scores. Progastrin assay is a simple and inexpensive blood test that might define subsets of mRCCC patients with poor survival who need to be identified for aggressive treatments.
Citation Format: Manish Kohli, Winston Tan, Lea Payen, Carole Langlois-Jacques, Pierre Liaud, Delphine Maucort-Boulch, Dominique Joubert, Alexandre Prieur. Prognostic impact of progastrin levels in blood compared to MSKCC based clinical prognosis in metastatic renal cell cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2289.
Abstract 2301: Antiglycan antibodies as predictors of therapeutic outcome in cervical cancer patients
Authors: PUROHIT SHARAD , Tran Paul M. , Tran Lynn K. , Song Xuezheng , Ferris Ferris G. , Wallbillich John J. , Dun Boying , She Jin-Xiong 
Published: August 2019

Abstract
Cervical cancer is a significant cause of cancer related death among women, with the highest mortality rates in developing countries. We aim to identify serum biomarkers for predicting outcome of radio therapy alone or combination of radiotherapy and brachytherapy. We measured natural anti-glycan IgG antibodies in the serum of stage II (n=276) and III (n=292) cervical cancer patients treated with radiation alone or in combination with brachytherapy on a suspension glycan array containing 184 glycans. Overall and progression free survival was used to determine the treatment outcome by Kaplan-Meier and Cox proportional hazards ratio. Significant protective effects were observed for Blood Group H antigens (HR=0.642, p=0.0013), Lewis Antigens (0.72, 0.015; 0.654, 0.003), Galili antigens (0.671, p=0.004), and other glycans belonging to Isoglobo (0.671,0.004) and 3fucosyllactose series (0.687,0.004). The protective effects remained significant after adjusting for stage and treatment. Our data suggest that measurement of natural anti-glycan IgG antibodies in serum can predict outcome of therapy in cervical cancer patients.
Citation Format: SHARAD PUROHIT, Paul M. Tran, Lynn K. Tran, Xuezheng Song, Ferris G. Ferris, John J. Wallbillich, Boying Dun, Jin-Xiong She. Antiglycan antibodies as predictors of therapeutic outcome in cervical cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2301.
Abstract 2341: Indoleamine 2,3 dioxegenase 1 (IDO1) and T-cell infiltration in esophageal cancer
Authors: Rosenberg Ari J. , Wainwright Derek A. , Fought Angela J. , Zhai Lijie , Lauing Kristen , Villaflor Victoria M. 
Published: August 2019

Abstract
Background: Immune checkpoint blockade is emerging as an important immunotherapeutic strategy in esophageal cancer, yet response rates remain low. IDO1 is a rate-limiting immunosuppressive enzyme that may contribute to resistance to immune checkpoint blockade in human cancer, and may be an important immunotherapeutic target. The expression pattern of IDO1 across esophageal cancer histologies remains poorly understood. Here, we utilize immunohistochemistry to characterize the expression pattern and relevance of IDO1 in esophageal cancer.
Methods: Tumor microarray containing samples of surgically resected esophageal carcinoma and normal esophageal tissue were stained for IDO1 and CD3ϵ (marker of T-cell infiltration). Demographic and staging data were collected. Light microscopic immunoscoring analysis was performed. Correlations were analyzed using Fisher’s exact test.
Results: 192 samples were assessed (180 esophageal carcinoma, 12 normal esophageal tissue.) Median age was 60 years (range 34-78). 69.3% of patients were male. Of the 180 esophageal carcinoma samples, 150 (83.3%) squamous cell carcinoma, 16 (8.9%) adenocarcinoma, 13 (7.2%) small cell carcinoma, 7 (3.9%) undifferentiated carcinoma, 2 (1.1%) carcinoid, 2 (1.1%) adenosquamous carcinoma, and 2 (1.1%) adenoid cystic carcinoma. IDO1 was positive in 81 samples (45.0%) overall with 52.0% in squamous cell carcinoma and 46.7% in adenocarcinoma. Positive IDO1 was associated with higher stage and nodal positivity (P=0.04). T-cell infiltration in esophageal carcinoma specimens was present in 133 samples (73.9%). IDO1 positivity correlated with increased T-cell infiltration (P&lt;0.01).
Conclusions: Here our study suggests that expression of IDO1 is positive in almost half of esophageal tumors, and is associated with T-cell infiltration. Additionally, positive IDO1 was associated with higher likelihood of nodal involvement and more advanced stage. These data suggest that IDO1 may play a role in adaptive immune resistance in T-cell inflamed tumors, and that incorporating IDO1 inhibition into an immunotherapeutic strategy in esophageal cancer may enhance T-cell mediated anti-tumor effect.
Citation Format: Ari J. Rosenberg, Derek A. Wainwright, Angela J. Fought, Lijie Zhai, Kristen Lauing, Victoria M. Villaflor. Indoleamine 2,3 dioxegenase 1 (IDO1) and T-cell infiltration in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2341.
Abstract 238: Therapeutic activity of the non-internalizing antibody drug conjugate 1959-sss/DM3 targeting galectin3-binding protein in human neuroblastoma
Authors: Capone Emily , Ponziani Sara , Giansanti Francesco , Gentile Roberta , Vittorio Giulia Di , Laurenzi Vincenzo De , Sallese Michele , Bibbò Sandra , Sala Arturo , Ippoliti Rodolfo , Sauniere Jean Frederic , Iacobelli Stefano , Sala Gianluca 
Published: August 2019

Abstract
Neuroblastoma is a solid tumour affecting the peripheral nervous system accounting for ∼13% of all pediatric cancer mortality. Despite immunotherapy with the GD2 antibody has improved the clinical outcome of a fraction of patients with metastatic neuroblastoma, the majority of patients with relapsing, high risk disease cannot be successfully treated. Recently, it has been shown that non-internalizing, linker-less antibody drug conjugates (ADCs) targeting the tumor extracellular environment can exert a potent therapeutic activity against different tumors.
We identified LGALS3BP (aka Mac-2 BP or 90K) as an important target for non-internalizing ADC development, as the protein is largely secreted by the majority of human tumors, while being virtually undetectable in normal adult tissues.
In this study, we show that a variant of the humanized 1959 antibody, targeting human LGALS3BP, coupled to the maytansinoid drugs DM3 by means of disulfide linker, bound human neuroblastoma cell lines harboring or not N-myc amplification, although with different affinity. Importantly, normal human fibroblasts were not decorated by the antibody. The ADC potently inhibited metastatic lesions in the liver and lungs of NSG mice injected intravenously with the neuroblastoma cell line SKNAS. Our findings offer a preclinical proof-of-concept for the development of a non-internalizing ADC endowed with potent therapeutic activity for neuroblastoma treatment through an innovative mechanism of action.
Citation Format: Emily Capone, Sara Ponziani, Francesco Giansanti, Roberta Gentile, Giulia Di Vittorio, Vincenzo De Laurenzi, Michele Sallese, Sandra Bibbò, Arturo Sala, Rodolfo Ippoliti, Jean Frederic Sauniere, Stefano Iacobelli, Gianluca Sala. Therapeutic activity of the non-internalizing antibody drug conjugate 1959-sss/DM3 targeting galectin3-binding protein in human neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 238.