bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control of cancer progression by extracorporeal removal of soluble TNF-alpha receptors.
Authors: Josephs Steven , Segal Robert , Panahi Marilyn , Ong Matthew , Kunkel Mark , Jafri Amir , Foster Jonathan D. , Ogilvie Gregory K. 
Published: February 2020

20 Background: Tumor necrosis factor (TNF)-alpha is a potent antineoplastic cytokine which exerts tumor destruction in part through vascular disruption. Local administration of TNF-alpha exerts profound anti-cancer effects as observed in studies using isolated limb perfusion. However, systemic administration of this cytokine is associated with vascular leakage and limits clinical use. Methods: One method of stimulating localized effects of TNF-alpha is through removal of its soluble receptors, sTNF-R1 and sTNF-R2 using extracorporeal apheresis; ie, Immunopheresis. In this comparative oncology study, we utilized the proprietary LW-02 device to remove sTNF-Rs in pet dogs with varying types of solid malignancies (Part A; n = 12) or with oral malignant melanoma (Part B; n = 8). Canine patients received between 12-24 apheresis treatments over the course of 4 to 8 weeks. Results: In the over 300 immunopheresis treatments, no device associated adverse effects were reported. Consistent reduction of sTNF-Rs was observed, as measured by decreased plasma levels during treatment as well as elution of sTNF-Rs from the cartridge. Of 17 evaluable dogs who completed treatment, 7 had disease stabilization or regression as confirmed by cRECIST criteria. Conclusions: These data strongly support the clinical translation of the LW-02 device as a potential therapeutic approach for treating solid malignancies/melanoma, either as mono- or as adjuvant therapy.
Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.
Authors: Shen Yuanyuan , Hummel Justin , Trindade Isabel Cristina , Papageorgiou Christos , Shyu Chi-Ren , Mitchem Jonathan B. 
Published: February 2020

25 Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p < 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r > |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.
The immunogenomic difference between Asian and non-Asian esophageal squamous cell carcinoma (ESCC) patients: An analysis of the Cancer Genome Atlas (TCGA) cohort.
Authors: Kuo Hung-Yang , Guo Jhe-Cyuan , Hsu Chia-Lang , Huang Ta-Chen , Hsu Chih-Hung 
Published: February 2020

27 Background: Recently reported global phase 3 trials of immune checkpoint inhibitor (ICI) versus second-line chemotherapy for esophageal cancer revealed that Asian population appear to obtain more benefit from ICI than non-Asian patients even in ESCC subgroups. Whether this observation could be explained by the immunogenomic difference between Asian and non-Asian ESCC remains uncertain. Methods: We retrieved the data of genetic alterations and gene expression profiling from ESCC patients of TCGA dataset, and compared the mutational profiles, immune subtypes, composition of immune cell infiltrates, and T cell-related signatures between Asian and Non-Asian patients with ESCC. Abundance of immune cell infiltrates were estimated by averaging expression values of the corresponding immune cells’ transcriptomic markers defined by Danaher et al. (J Immunother Cancer. 2017; 5:18.). The 6 immune subtypes were adopted from Thorsson et al (Immunity. 2018;48(4):812-830). The T-cell related signatures were determined by averaging the corresponding genes' expression values following previous reports. Results: We retrieved 93 patients with ESCC (Asian: non-Asian= 45: 48) from TCGA database. There is no statistical difference in overall survival between Asian and non-Asian ESCC patients. Higher mutation frequencies of TP53, NFE2L2, ZNF750, and lower mutation frequency of SMARCA4 were seen in Asian patients than in non-Asian patients. As for the immune contexture, we found that the composition of immune cell infiltrate, the distribution of immune subtypes, and a variety of T cell-related gene signatures including the 6-gene interferon-gamma signature, the 10-gene interferon-gamma signature defined by Merck or by Ribas et al, and the 13-gene inflammatory signature defined by Gajewski et al, were not significantly different between Asian and non-Asian groups. Conclusions: Our analysis failed to identify statistically significant difference in the immunogenomics of ESCC tumors between Asian and non-Asian patients in the TCGA cohort. Further immunogenomic studies focusing on patients from Asian countries with high ESCC prevalence are warranted.
Deleterious alterations of DNA damage response and repair (DDR) genes in association with clinical benefit to programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1)-based therapy in esophageal squamous cell carcinoma (ESCC).
Authors: Guo Jhe-Cyuan , Lin Chia-Chi , Huang Ta-Chen , Chang Chun-Jung , Kuo Hung-Yang , Hsu Chih-Hung 
Published: February 2020

28 Background: Previous studies have indicated genetic alterations (GA) of DDR genes and tumor mutational burden (TMB) as potential markers for anti-PD-1/PD-L1 therapy in several cancer types. The study explored whether GA of DDR genes and TMB are associated with clinical benefit (CB) for ESCC patients receiving anti-PD-1/PD-L1 therapy. Methods: Thirty-five ESCC patients treated with PD-1/PD-L1 blockade antibody, alone or in combination, were enrolled. Tumor response was evaluated per RECIST 1.1, and CB was defined as complete response, partial response or stable disease at least 6 months. Formalin-fixed paraffin-embedded ESCC tissues were analyzed by FoundationOne CDx. All loss-of-function alterations were considered as deleterious according to previous reports (Teo MY, et al: Clin Cancer Res 2017; 23:3610-8 and J Clin Oncol 2018; 36:1685-94). Results: All of 35 enrolled patients was male: 16 and 19 received PD-1/PD-L1 blockade alone and PD-1/PD-L1-based combination therapy, respectively. The response rate was 14%, and the CB rate was 29%. All patients had GA of TP53 (100%), followed by CDKN2A/B (71%), and FGF3, FGF4 plus FGF19 (40%). The median TMB was 4 muts/Mb (range 1-16) and all evaluable ESCC tissues (N=31) were microsatellite stable. Twenty-one (60%) patients had GA of DDR genes, but only 4 (11%) patients had deleterious GA of DDR genes. The clinicopathological characteristics were not significantly different between patients with or without GA of DDR genes or those with or without deleterious GA of DDR genes. Patients harboring deleterious GA of DDR genes trended to have improved response rate (25% vs. 12.9%, P = 0.063), CB rate (50% vs. 22.6%, P = 0.268), and median PFS (4.1 vs. 1.8 mon, P = 0.074). Neither TMB nor all GA of DDR genes was associated with response or CB. Conclusions: Deleterious GA of DDR genes may be associated with therapeutic efficacies of anti-PD-1/PD-L1 therapy in patients with ESCC. (Funded by NHRI-107A1-CACO-01181816, NHRI-108A1-CACO-01191916, MOST-106-2314-B-002-225-MY2, NTU-108L901403, and MOST 108-3017-F-002-004-).
Prognostication model based on genomic expression in the tumor microenvironment of ER-positive, HER2-negative stage III breast cancer via machine learning.
Authors: Abdou Yara , Jerez Jessica , Baird Andrew , Dolan Jillian , Lee Seongwon , Park Shinyoung , Lee Sunyoung S. 
Published: February 2020

3 Background: Stroma in the tumor microenvironment (TME) is known to impact prognosis and responses to therapy. Few mathematical models exist to prognosticate patients, based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 98 patients with stage III estrogen receptor (ER) positive (+) and HER2 negative (-) breast cancer were obtained from TCGA. Twenty six gene groups composed of 191 genes (refer to presentation) enriched in cellular and non-cellular elements of TME, mutational burden (MB), and clinical data were analyzed by Kaplan-Meier (KM) analysis and multivariate nonlinear regression assisted by machine learning to achieve confined optimization with model-data minimization among multiple distribution functions. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in stage 3 ER+HER2- breast cancer. Fifteen genes (CD8A, CD8B, FCRL3, GZMK, CD3E, CCL5, TP53, ICAM3, CD247, IFNG, IFNGR1, ICAM4, SHH, HLA-DOB, CXCR3) and five genes (LOXL2, PHEX, ACTA2, MEGF9, TNFSF4) out of 191 genes associated with good and poor prognosis were identified. Genomic expression of the fifteen and five gene groups were labeled as G and P, respectively. RS = 9.3185 – 0.3250 × (Age at diagnosis0.0001) – 8.2979 × (P/G−0.0051). Based on RS, patients were clustered into two groups; high and low RS groups, showing two KM curves with P = 0.05, HR = 2.878 (95% CI 1.903 – 3.471), confirming the validity of RS modeling. Analysis of immune profiles in high and low RS groups shows that expression of genes associated with desmoplastic reaction, neutrophils, and immunosuppressive cytokines are higher in high RS groups; and those related to immune system activation are higher in low RS groups (p < 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis identified TME-related genes and gene groups that are strongly associated with worse prognosis in stage 3 ER+HER2- breast cancer. RS could potentially prognosticate patients in the clinic with available genomic profiles.
Activation of memory/effector T cells and association between prognosis and OX40-positive T cells in advanced head and neck cancer patients treated with anti-programmed death-1 antibody.
Authors: Ohmura Hirofumi , Yamaguchi Kyoko , Hanamura Fumiyasu , Kenrou Tanoue , Kawagoe Shiho , Arimizu Kohei , Matsushita Yuzo , Kajitani Tatsuhiro , Tamura Shingo , Shimokawa Hozumi , Uchino Keita , Oda Hisanobu , Shinohara Yudai , Ito Mamoru , Tsuchihashi Kenji , Isobe Taichi , Ariyama Hiroshi , Kusaba Hitoshi , Akashi Koichi , Baba Eishi 
Published: February 2020

35 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.
Preclinical evaluation of anti-ROR1 CAR T cells employing a ROR1 binding SCFV derived from the clinical stage mab cirmtuzumab.
Authors: Prussak Charles E. , Oh Christopher , Velez Lujan Juliana , Lam Sharon , Zhang Jieyu , Fernandez Jayde , Sinha Navyaa , Pham Jessica , Shi Haoming , Shin Caitlin , Kaufman Gunnar F. , Widhopf II George F. , Cohen Ezra E.W. , Kipps Thomas J. ,   University of California, San Diego Moores Cancer Center
Published: February 2020

41 Background: Chimeric antigen receptor (CAR)-modified T cells (CAR-T) were generated targeting cells expressing ROR1, which is present on many malignant cancers and has been associated with cancer stemness and chemo-resistance. The ROR1 CAR utilizes the humanized single-chain fragment variable (scFv) binding domain of UC-961 (cirmtuzumab), which exhibits high affinity and specificity for human ROR1 and has demonstrated an excellent safety profile in Phase 1 studies. Methods: CAR constructs with varying spacer regions and intracellular co-stimulatory domains, using the scFV of cirmtuzumab, were constructed and used to generate CAR-T cells from healthy donors. These ROR1 CAR-T cells were tested for cytotoxicity against lymphoid cancer cells in vitro and in vivo studies that employed immune-deficient mice engrafted with labeled human leukemia cells MEC1 or MEC1-ROR1, which had been transfected to stably express ROR1. Results: The 2nd generation and 3rd generation CAR-T-cells with analogous spacer regions were comparably potent and selectively cytotoxic for cells bearing the ROR1 target antigen. But the 2nd generation CARs demonstrated greater potency in vitro even at low effector to target ratios. For the in vivo studies, mice received a single injection of ROR1 CAR-T cells or activated T cells from the same donor as a control. The ROR1 CAR-T cells rapidly cleared the leukemic cells from the animals, whereas animals receiving control T cells or no therapy quickly succumbed to progressive disease within 3 weeks. The administered CAR-T products remained highly active following administration and could be detected for ≥ 3 months without evidence for T cell exhaustion. Conclusions: The generated CAR-T cells utilizing constructs with the Fv of cirmtuzumab, a humanized mAb highly specific for ROR1, onco-embryonic surface antigen, effectively and selectively killed neoplastic cells bearing ROR1 both in vitro and in vivo. As ROR1 expression and signaling has been associated with cancer stemness and chemo-resistance utilizing ROR1 CAR-T therapy to target cancer cells might mitigate tumor escape. These data strongly support the rationale for continued development of our ROR1 CAR-T.
Aspartyl (asparaginyl) β-hydroxylase (AABH), a serum biomarker for lung cancer.
Authors: Moshiri Kiarash 
Published: February 2020

45 Background: There are no serum biomarkers currently approved for the detection of lung cancer, a leading cause of cancer associated mortality world wide. More than 180,000 cases of lung cancer will be diagnosed in the United States in 2020 by other means such as by X-ray and CT scanning methods, which have inherently lower sensitivity and higher cost when compared generally to serological methods. While the five year survival for lung cancer is 15%, a survival rate of 50% can be achieved when detection is made early in individuals with localized cancer. Current detection methods, however, enable such detection in only about 18% of cases overall. Methods: A prospective serum biomarker Aspartyl (Asparaginyl) ß Hydroxylase (AABH), has been previously found to be elevated by immunohistochemical staining (IHC) in a broad range of cancers, including lung cancer. AABH was detected in > 99% of tumor specimens tested (n > 1000) but absent in adjacent tissue. The present study introduces a double monoclonal sandwich ELISA which provides detection and comparative quantification of AABH in serum of lung cancer patients vs. normal, and high-risk controls such as cigarette smokers without cancer. This is relevant since 87% of lung cancers are attributable to cigarette smoking, and associative parallels can be seen with recent reductions in rates of smoking. Results: Increased levels of serum AABH were found in 99% of patients with lung cancer (n = 192). Serum AABH was found to be undetectable in individuals not known to have cancer (n = 129, specificity = 93%). In patients with lung cancer, AABH was detectable at all stages. In a population of 50 smokers not known to have cancer, the mean serum AABH level was 0 ng/ml with 90% specificity. Conclusions: The AABH serum ELISA therefore has great promise as an additional diagnostic tool for lung cancer having the practicality and cost effectiveness of conventional serological screening. Elevated serum AABH in conjunction with CT scanning may greatly facilitate earlier diagnosis of lung cancer at a stage in which cure rates are significantly higher and thus may contribute to increased patient survival.
Neutrophil to lymphocyte ratio, PD-L1 expression, and survival in patients with advanced non-small cell lung cancer receiving first-line immune checkpoint inhibitor therapy.
Authors: Li Mingjia , Zhao Songzhu , Spakowicz Daniel , Burkart Jarred Thomas , Patel Sandip H. , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Wei Lai , Presley Carolyn J , Otterson Gregory Alan , Owen Dwight Hall 
Published: February 2020

46 Background: Neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with various types of cancer, including those who are treated with immune checkpoint inhibitors (ICI). We evaluated NLR at baseline and during early phase of treatment for patients with advanced non-small cell lung cancer (NSCLC) who received ICI to evaluate its prognostic value in first line ICI therapy and its relationship to programmed death-ligand 1 (PD-L1) expression. Methods: We retrospectively evaluated patients with advanced NSCLC who received ICI as first line therapy from 2016 to 2018. NLR was calculated as ratio of absolute neutrophil/lymphocyte counts and was consider elevated if ≥5. PD-L1 expression by immunohistochemistry was performed as standard of care with 22C3 antibody. Kaplan Meier analysis was used for survival. Wilcoxon-Mann-Whitney test was used to evaluate PD-L1 expression between groups. All Calculation was performed using SAS V9.4. Results: A total of 78 patients were included in this study; 28 received pembrolizumab monotherapy, 45 received pembrolizumab, carboplatin, and pemetrexed, and 5 received other pembrolizumab combinations. Patients with baseline NLR < 5 before initiating ICI had median estimated OS of 46.1 months (79.4% patient still alive and 95% CI not reached) compare to median OS of 10.7 months (95% CI lower limit 6.4 and upper limit not reached) for patients with NLR ≥5, P < 0.001. Similar association between NLR and OS can be seen when NLR were repeated immediate before the cycle 2 with P = 0.001. We observed an association between baseline NLR and PD-L1 expression. The median PD-L1 tumor proportion score (TPS) was 60% (Interquartile Range 1-80) for patients with baseline NLR < 5 vs 20% (IQR 0-60) for patients with NLR ≥5, P = 0.037. Conclusions: We confirmed the prognostic value of NLR for patients with advanced NSCLC at baseline and during early treatment in patients with NSCLC receiving first line ICI treatment. We also found an association between elevated NLR and lower PD-L1 expression. Future study with larger cohort is still needed to further delineate these relationships.
Association of immune microenvironment to response in treatment-naïve non-small cell lung cancer (NSCLC) samples with follow-up second-line immunotherapy data.
Authors: Cumberbatch Marie , Elliott Nathan , Warren Sarah , Kim Woo Ho , Womack Christopher , Bhagat Milan , Colarossi Lorenzo , Memeo Lorenzo 
Published: February 2020

49 Background: Archival specimens collected months or years prior to starting immunotherapy are often used to identify patients for second line immune checkpoint inhibitor (ICI) treatment. PD-L1 expression and the immune microenvironment in these patients may have altered over time following multiple lines of failed standard of care (SOC) treatments. Methods: Formalin fixed paraffin embedded (FFPE) tumor samples, taken during resection performed as first line surgical treatment from a cohort of NSCLC patients (n = 18), were evaluated by Nanostring using the IO360 gene expression panel, and by immunohistochemistry (IHC) for CD3, CD8, PD-L1, CD68 and CD163. The resultant immune profiles were correlated with the clinical follow-up data for radiotherapy, SOC chemotherapy, and second line immunotherapy with the aim of understanding whether immune signatures predictive of response to ICI therapy may be identified in such samples. Results: Of the 18 cases, clinical follow-up data indicated objective response to ICI therapy for 4 patients, with the mean time from initial diagnosis to ICI treatment being 2.8 years (range: 0.4 to 8.5 years). Although pathologist PD-L1 IHC scores were not predictive of response, IHC image analysis data revealed significant increases in CD3 (2.3-fold) and CD8 (2.7-fold) T cell numbers in the responder population. In addition, although CD68+ macrophage frequencies did not differ significantly between responder and non-responder populations, reduced M2-like CD163+ macrophage/monocyte numbers were evident for responders. While the Tumor Inflammation Signature was not predictive of response, several gene expression signatures were significantly associated with response including increased abundance of CD8 T cells, cytotoxic cells, cytotoxicity, MHC class II antigen presentation and Melanoma-Associated Antigens (MAGE). Conclusions: Despite these patients having received various lines of radiotherapy and SOC chemotherapy prior to receiving immunotherapy, immune profiles associated with response to second line immunotherapy were detected in surgical first line resection samples.