bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune subtype of mismatch repair deficient colorectal carcinoma.
Authors: He Ning , Jia Qingzhu , Jin Ge , Zhu Bo 
Published: May 2020

e15194 Background: Half of microsatellite instability-high (MSI-H) colorectal carcinoma (CRCs) patients do not response to checkpoint blockade (ICB) immunotherapy. We aimed to unleash the underlying mechanism of distinct efficacy to ICB by sophisticated depicting the immune microenvironment of MSI-H CRC. Methods: Public omics and clinical data of patients with MSI labels were collected from TCGA data portal (364 samples) and Gene Expression Omnibus (GSE39582, GSE13294, GSE13067, GSE35896, GSE24514, GSE25071, GSE79959, GSE103340, GSE29638, GSE33113 cohorts, 1119 samples). GEO datasets were used as discovering sets, and TCGA dataset was used as validating sets. The immune cell infiltrations and signaling pathways in the tumor microenvironment were quantified by single sample Gene Set Enrichment Analysis (ssGSEA), and the bio-similarities were estimated by t-Distributed Stochastic Neighbor Embedding (tSNE). Clustering was identified by k-mean unsupervised strategy with optimal k. Statistical analysis and data visualization were all carried out using the R. Results: Based on the whole transcriptome and immune cell infiltration profiling, both GEO and TCGA cohorts showed that MSI-H patients harbored unique pattern which significantly differed from the MSS counterpart. Unsupervised clustering further classified the MSI-H patients into “Hot” and “Cold” subgroups with remarkable different IFNG-related signatures, inflammatory response score, interferon-γ signaling score, and survival outcome. Screening assay identified 23 genes ( ADAMTSL3, DLGAP4, DNAH11, FFAR3, GABRA4, KCNA6, KCTD9, KIAA1033, KLHL6, LARGE, MORC1, NDST3, OR5H14, PAX5, PHF3, PIK3R5, RNF25, SPATA20, STAT4, TLR9, TMC3, TTC12, ZNF790) enriched and 5 genes ( CELSR3, DGKD, HECTD4, RECQL4, SLC9A4) spared in immune “hot” tumors. Moreover, “hot” tumor showed less WNT signaling pathway score, which was negatively correlated with the IFNG signaling and inflammatory response within the MSI-H CRC tumors. Conclusions: We firstly identified immune hot and cold groups from MSI-H CRCs, which may be related to different immunotherapy response. This result may help further understanding the anti-immunotherapy of MSI-H CRCs.
Pd-1 inhibitors plus nab-paclitaxel with S1 (AS) as first line in patients with advanced biliary tract cancer.
Authors: Gou Miaomiao , E Liu Tie , Yan Huan , Si Haiyan , Wang Zhikuan , Qian Niansong , Dai Guanghai 
Published: May 2020

e15195 Background: The way to treat advanced biliary tract cancers (BTCs) including Intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer, gallbladder cancer was disappointing. Hence, we explore the efficacy and safety of pd-1 inhibitors plus chemotherapy (nab-paclitaxel with S1, AS) as first line in patients with BTC. Methods: BTC patients from oncology department of Chinese PLA general hospital receiving PD-1 inhibitors with AS or AS alone were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). The second endpoint was objective response rate (ORR), disease control rate (DCR) and safety. Results: 32 patients given pd-1 inhibitors (Pembrolizumab, Nivolumab, Sintilimab, Toripalimab) plus AS and 26 patients used AS alone were included in the study. The median PFS was 5.43m in combined group, significantly longer than the 2.82m with monotherapy alone group (HR 0.46, 95% CI 0.25–0.84, P = 0.01). OS was not matured in the pd-1 inhibitors group. PFS of Intrahepatic cholangiocarcinoma subgroup seemed better than extrahepatic group in the AS group (5.54m VS 2.57m, P = 0.004).however, there was no evidence of difference in intrahepatic group compared the other group in the pd-1 inhibitor group (5.07m vs 5.43m, P = 0.453). liver metastatic was poor predictor of PFS in both Pd-1 combined or not group (2.43m vs 7.63m, P = 0.01; 2.14m vs 5.54m, P = 0.04 ).ORR was 25% and DCR were 84.3% in Pd-1 inhibitor group and ORR was 15.3% and DCR was 69.2% in chemotherapy alone group respectively. No significant difference was seen for ORR and DCR compared between two groups (P = 0.364, P = 0.169). Grade 3 or 4 treatment-related adverse events(AE) in pd-1 inhibitor group were hypothyroidism (n = 3), rash (n = 2), hepatitis (n = 1). No AE related death. Myelosuppression was similar between the anti-PD-1 combination group and the chemotherapy alone group (12.5% and15.3 %, respectively). Conclusions: Anti-PD-1 therapy plus nab-paclitaxel with S1 prolonged the PFS and improved the ORR, DCR compared the nab-paclitaxel with S1 alone in advanced BTC with controllable AE. Further clinical trials were needed and we conduct the phrase II clinic trail of Toripalimab with AS (TSA-01 study) is ongoing (clinical registration number: NCT04027764).
Novel synthetic immune modulators for the activation of tumor antigen-specific T cells.
Authors: Zhang Di , Shi Lihua , Tam Susan , Fung Man-Cheong 
Published: May 2020

e15203 Background: Although checkpoint inhibitor immunotherapy and adoptive T-cell therapy revolutionized cancer treatments, such approaches suffer either from lack of target specificity for checkpoint inhibitors or inability to target intracellular tumor-related antigens from CAR-T therapy. Here, we report the development of novel Tavo Immune Modulator (TIM) biologics molecules which can specifically recognize tumor antigen-specific T cells through an engineered pMHC complex with peptides derived from intracellular tumor-related antigens. These molecules can selectively activate such T cells through engineered T cell co-stimulatory modulators for enhanced tumor cell killing. Methods: NY-ESO-1 and MAGE-A10 TIM molecules were constructed as fusions of HLA-A*02:01 MHC complexed with either NY-ESO-1 (157-165) or MAGE-A10 (254-262) epitope peptides at the N-termini and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with cancer specific T cells was evaluated by immunostaining. The activation and proliferation of tumor specific CD8+ T cells were confirmed in T cell activation and recall assays. Results: Both NY-ESO-1 and MAGE-A10 specific TIM molecules were generated which recognized corresponding tumor specific T cells. NY-ESO-1 TIM engineered with IL2 could activate NY-ESO-1 specific CD8+ T cell exclusively. Engineering additional T cell costimulatory factors along with IL2 on NY-ESO-1 TIM molecule could further boost T cell proliferation and activation in T cell recall assays. Besides NY-ESO-1, combinations of T cell costimulatory factors with MAGE-A10 TIM molecules enhanced specific T cell activation. Additional in vitro and in vivo studies are ongoing to demonstrate efficacy of such novel TIM molecules in eliminating different types of NY-ESO-1 and MAGE-A10 which are over-expressed on tumor cells. Conclusions: This study demonstrates the utility of NY-ESO-1 and MAGE-A10 TIM molecules in the selective recognition and activation of tumor antigen-specific T cells. Such novel biologics molecules may provide target specificity in tumor treatment, and potential targeting of intracellular tumor-related antigens presented as peptides in MHC complexes on cell surfaces. Selective activation of tumor-specific T cells may provide a unique method for the treatment of various solid tumors and warrants further investigation.
The potential biomarkers of checkpoint inhibitor immunotherapy in solid malignancies.
Authors: Hakim Nausheen , Chi Jeffrey , Patel Rajvi , Quinn Ryann , Zhu Xinhua 
Published: May 2020

e15226 Background: Tumor mutational burden (TMB), PDL1 status, microsatellite status (MS), tumor infiltrating lymphocyte, and the microbiome profile are commonly used biomarkers to predict which patients (pts) may benefit from immunotherapy (IO). However, they are imperfect and cannot be used to predict complete response (CR). Next Generation Sequencing (NGS) from Foundation Medicine has identified many gene mutations. We aim to identify potential biomarkers in pts who achieved CR with immunotherapies as opposed to in those who had upfront progression of disease (PD). Methods: We conducted a retrospective analysis of pts with metastatic solid tumors at our institution that received IO after NGS testing. Pts who achieved CR or PD per imaging studies and clinical settings were included. Gene alterations through NGS were identified in each group. Results: Eighty-one pts received IO who had NGS sent prior to treatment. Pembrolizumab, ipilimumab, nivolumab, durvalumab and atezolizumab were used as single agent or in combination with another IO or chemotherapy. 19 pts achieved CR, 18 pts had PD. In the CR group, melanoma and lung adenocarcinoma were most common tumor types (Table). 15 pts (78.9%) received IO as 1st line treatment. Most common gene mutations in CR group were ROS1 (52.6%), LRP1B (52.6%), GRIN2A (47.4%), and EPHA7 (42.1%) in 19 patients. 18 pts with various tumor types (Table) had PD. Most of IOs were given as 2nd or 3rd line setting in NR group. Most common gene alterations were MLL2 (33.3%), CDKN2A/B (27.8%), NTRK1 (27.8%), ARID1B (22.2%) in 18 patients. Conclusions: The cohort of patients who achieved CR with IO had the most common gene mutations of ROS1, LRP1B, GRIN2A, and EPHA7 which can potentially serve as a biomarker to predict response to IO. Increased frequencies of MLL2, CDKN2A/ B, NTRK1, ARID1B mutations were found in patients with PD. The gene mutations in CR and PD groups are mutually exclusive. Further explorations at tumor environment, RNA and proteins levels are needed to identify combined potential biomarkers to predict IO response, followed by validation in the prospective study. The limitation is that the study is retrospective. [Table: see text]
RAD51Bme as predictive biomarker for PD-1 blockade response in non-small cell lung cancer.
Authors: Guerreiro Inês Maria , Barros-Silva Daniela , Lopes Paula , Cunha Ana Luísa , Lobo João , Antunes Luís , Rodrigues Ana , Soares Marta Alexandra Silva , Henrique Rui , Jerónimo Carmen 
Published: May 2020

e15235 Background: Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with likelihood of response to specific checkpoint inhibitors, prediction of response is rather imperfect and, thus, more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B, a DNA-repair gene, as candidate predictive biomarker for efficacy of anti-PD-1 therapy in patients with non-small cell lung cancer (NSCLC), correlating with patients’ outcome. Methods: PD-L1 immunoexpression and RAD51Bme levels were analysed in samples of NSCLC obtained from patients not treated with anti-PD-1 blockade (testing cohort) and patients treated with anti-PD-1 (validation cohort). Results: Of a total of 127 patients assessed, 58.3% depicted positivity for PD-L1 (PD-L1+). RAD51Bme levels significantly associated with PD-L1 immunoexpression. Patients with clinical benefit from immunotherapy disclosed higher RAD51Bme levels (p = 0.04) and significantly higher median progression free survival (PFS) (p = 0.02). PD-L1+ was also associated with longer overall survival (p = 0.03). Conclusions: We demonstrated that RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.
CIMAC-CIDC CyTOF harmonization.
Authors: Rahman Adeeb , Sahaf Bita , Davila Melanie , Fernandez Nicholas , McWilliams Emily , Millerchip Karen , Bentebibel Salah E , Haymaker Cara L. , Sigal Natalia , Duault Caroline , Thrash Emily , Del Valle Diane , Espiridion Beatriz Sanchez , Pichavant Mina , Bernatchez Chantale , Wistuba Ignacio Ivan , Gnjatic Sacha , Bendall Sean , Maecker Holden ,   CIMAC-CIDC Network
Published: May 2020

e15242 Background: The Cancer Immune Monitoring and Analysis Centers – Cancer Immunology Data Commons (CIMAC-CIDC) network is a National Cancer Institute-funded initiative to identify biomarkers of mechanisms and response to cancer immunotherapy clinical trials, using state-of-the-art assay technologies. A primary platform for CIMAC-CIDC biomarker studies is CyTOF mass cytometry, which is performed at all four CIMAC laboratories. Methods: To test the ability to generate comparable data across labs, a cross-site harmonization effort was undertaken. We first harmonized SOPs between centers. Because of a new acquisition protocol introduced by the vendor (Fluidigm), we also tested this protocol across sites before finalizing the harmonized SOP. We then performed a cross-site assay harmonization experiment, using 5 shared cryopreserved PBMC samples and one lyophilized control cell preparation, along with a shared lyophilized antibody cocktail consisting of 14 markers, as validated in the HIPC consortium, plus CD45. These reagents and samples were distributed to the four sites, and FCS files were centrally analyzed by both manual gating and automated methods (Astrolabe). Results: Average CVs across sites for each cell population were reported and compared to a previous multisite CyTOF study. Once a cell recovery issue at two sites was resolved, this experiment resulted in inter-site reproducibility of under 20% CV for most cell subsets, very similar to the previous study. Conclusions: These results emphasize the ability to reproduce CyTOF across sites, and also highlights procedures, such as use of spike-in control samples, useful for tracking variability in this assay.
Comprehensive next-generation sequencing to portray distinctive molecular characteristics of hypermutant lung cancer.
Authors: Zhang Hongbin , Wang Yuan , Ji Qiaoxia , Cai Hongmei , Liang Xiangcun , Xie Jiong , Li Hua , Wang Jun , Zhu Guiyun , Tian Erpeng , Zhu Lingling , Cui Lingzhi , Su Wenzhong , Yuan Mingming , Chen Rongrong , Zhao Min 
Published: May 2020

e15255 Background: Tumor mutation burden (TMB) has been confirmed to predict the sensitivity to immunotherapy across multiple tumor types. Multiple genetic factors have been confirmed to increase the level of TMB, such as mutations in DNA damage repair (DDR) genes, POLE/POLD1, and high microsatellite instability (MSI). However, the extent that these factors contribute to hypermutation in lung cancer has not been fully investigated. Methods: We retrospectively reviewed the genetic profiles of 1000 lung cancer patients (pts) who underwent 1021-panel matched tumor-normal next-generation sequencing using tumor tissue samples and peripheral blood. Their TMB status were analyzed to determine the threshold of hypermutation. The clinicopathological characteristics, genetic profiles and genetic factors related to hypermutation were investigated for the pts in hypermutant cohort. Results: The threshold of hypermutation was determined as 19 muts/MB (top 5% in 1000 pts). As a result, 53 pts were included in the hypermutant cohort. A total of 1725 nonsynonymous somatic variants in 506 genes were identified. The most frequently mutated genes included TP53 (88.7%), LRP1B (71.7%), MLL2 (35.8%), EPHA5 (34.0%), and FAT1 (34.0%). KRAS was mutated in 17% pts, whereas mutations in EGFR, BRAF, ERBB2, MET were identified less commonly. MSI-high was observed in 5 cases. A germline mutation in BRCA1 gene was identified in an adenocarcinoma patient. Compared to genetic profiles of non-small cell lung cancer from TCGA database, mutations in multiple DDR genes were enriched in the hypermutant cohort (Table). No known driver mutation in POLE/POLD1 was identified. Conclusions: MSI-high and mutations in DDR genes may be associated with high level of TMB, whereas POLE/POLD1 driver mutations may not be related to hypermutant lung cancer. Hypermutant lung cancer displays distinctive molecular features that may be used as complementary indicators to screening pts sensitive to immunotherapy. [Table: see text]
Clinical value of piR-36026 and piR-651 in esophageal squamous cell carcinoma.
Authors: Peng Wei , Zhu Jun , Liu Delin , Qian Pudong , Zhang Qin , Li Houhuai , Cao Guochun 
Published: May 2020

e15265 Background: Piwi-interacting RNAs (piRNAs) are a novel type of small noncoding RNAs which have important biological functions in malignant diseases. However, little is known about the clinical value of piRNAs in esophageal squamous cell carcinoma (ESCC). Hence, we demonstrated that two representative piRNAs, piR-36026 and piR-651, to dig out their clinical value in ESCC. Methods: Quantitative real-time PCR was employed to detect the levels of piR-36026 and piR-651 expression in ESCC tissues. Furthermore, the correlation between them and ESCC patients' clinicopathological characteristics were explored. Receiver operating characteristic (ROC) curves were constructed for measuring significances of piR-36026 and piR-651 for ESCC diagnosis. Results: Both of piR-36026 and piR-651 were prominently increased in ESCC tissues compared with normal. Additionally, piR-36026 was related with ESCC patients' diameter (P = 0.013), TNM stage (P = 0.027), tumor differentiation (P = 0.008) and CEA (P = 0.013); and piR-651 was associated with diameter (P = 0.005), lymph node metastasis (P = 0.002), tumor differentiation (P = 0.008) and SCC (P = 0.002). The area under the ROC curve (AUC) of piR-36026 was up to 0.8634 (95% confidence interval: 0.8171-0.9089, P < 0.05). Similarly, the AUC of piR-651 was 0.8525 (95% confidence interval: 0.7804-0.9247, P < 0.05). Conclusions: These results demonstrated that both piR-36026 and piR-651 may play a crucial role in ESCC oncogenesis; and they may be diagnostic biomarker for ESCC.
Multipeptide vaccine to prevent epithelial ovarian cancer relapse by microenvironment immunomodulation.
Authors: Marquez-Manriquez Juan Pablo , Camacho-Hernandez Alejandro , Lucero-Diaz Pedro Alejandro , Gallardo-Rincon Dolores , Rosas-Delgado Martin Orlando , Barron Karla Ramirez , Durazo Alberto , Ruiz Jorge Alberto Cisneros , Meneses-Velazquez Diana Karen , Durazo-Acuna Alberto 
Published: May 2020

e15268 Background: Typically cancer vaccines for relapse prevention in epithelial ovarian cancer (EOC) are administrated in distant anatomical sites away from the primary tumor location. Ideally for EOC relapse prevention vaccines we should explore different anatomical sites related with the original tumor location and nearby lymph nodes, in order to observe if the administration would have better clinical impact due to a potential access to the tumor microenvironment. Moreover most trials for EOC relapse prevention use one or few targets and is mainly unknown if they are relevant to promote EOC relapse. We treated EOC patients with a multi-peptide vaccine administered in lymph nodes (LN) and in the peritoneum area and were able to suppress cancer relapse with not significant adverse effects after eight years. Methods: We enrolled n = 25 EOC patients in our study and identified by systematic review and validated by siRNA six proteins involved in EOC relapse and fourteen peptides were predicted. Twelve peptides were immunogenic by Granzyme B ELISPOT, DTH and ELISA. Patients were immunized with the vaccine in axillary and inguinal LN subcutaneously every week for four weeks, every two-weeks four times and finally every month for a total of thirty-six months. Clinical and laboratory evaluations were performed every 2-months and at the end of the study. Results: 100% of the patients developed both antibodies against all the peptides by ELISA and CD8 specific cells. The peptides of the six proteins were able to induce T cell expansion in both peptides and purified protein (p = 0.0001) and (p = 0.05), respectively for Ape-1. The selected targets were all able to induce DTH and ELISA responses with statistical significance. Peptides predicted from Bcl-2, survivin, Ape-1, Sox2, EGFR and RCAS1/EBAG9 were able to increase and sustain the levels of Granzyme B ELISPOT. Bcl-2 A peptide (p = 0.001), Bcl-2 B (p = 0.005), Bcl-2 C (p.0002), survivin A (p = 0.001), Survivin C (0.05), Ape-1 A (0.0001), Ape-1 D (p = 0.001), Sox2 A (p = 0.003), Sox2 B (p = 0.0001), EGFR B (p = 0.0001) and EGFR D (p = 0.001). Conclusions: Treating EOC patients in remission in zones hardly explored previously in order to potentially improve the activation of antigen-specific Th1 and CD8 cells with specific peptides seems promising as a feasible and safe approach to prevent EOC relapse.
Enhancement of the therapeutic effects of oncolytic vaccinia virus by using autologous and allogeneic cell-based delivery platforms.
Authors: Minev Boris , Santidrian Antonio F. , Minev Ivelina , Nguyen Duong , Zamarin Dmitriy , Marincola Francesco , Draganov Dobrin Draganov 
Published: May 2020

e15271 Background: Clinical trials with oncolytic viruses for cancer treatment have shown limited efficacy due to viruses’ rapid clearance by patients’ innate and adaptive immune systems. In a recent first-in-human clinical trial, we confirmed the safety and feasibility of our approach to enhance oncolytic vaccinia virus (OVV) delivery and improve tumor targeting by utilizing an autologous cell-based cell delivery system (auto-OVV). We also developed an allogeneic cell-based platform (SuperNova1c - SNV1c) aiming to protect and potentiate OVV’s antitumor effects in large patient populations. Methods: We evaluated the immunomodulatory potential of auto-OVV by an extensive time-course analysis of cytokines in patients’ plasma (Luminex profiling) and peripheral blood immune cells (flow cytometry). We also analyzed the ability of SNV1c to protect the OVV from antibody/complement inactivation in vitro and in vivo following intratumoral injection in various mouse tumors. The immune cell infiltrations of the injected tumors were also analyzed. Results: Therapy with auto-OVV induced a coordinated activation of cytokine, T cell and NK responses in patients as early as 1 day, peaking around 1-week and lasting for up to 1-month post treatment. Effective OVV amplification in cancer patients correlated with significant changes of multiple innate and adaptive immune parameters. Patient stratification into groups with transient versus persistent viral DNA was linked to opposing and mutually exclusive patterns of robust activation of NK versus T cell responses, respectively. SNV1c showed significantly enhanced protection of OVV in vitro and led to statistically significant tumor growth inhibition as compared to control non-treated tumors or to naked OVV-treated tumors. Importantly, local administration of SNV1c induced systemic therapeutic effects. Five days after SNV1c administration, tumor infiltrating lymphocytes from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations, decreased Tregs, and improved effector to Treg ratios, associated with tumor growth inhibition at both treated and untreated tumor sites. Conclusions: This study establishes the timeline of treatment-related immunological changes and identifies potential immunological correlates associated with the OVV persistence in vivo. We also demonstrate the ability of our cell-based platforms to protect and potentiate OVV by circumventing innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy.