tbuckley/cabot-search huggingface dataset:
Abstract 2759: Immune cell killing assay for analyzing the effects of immunomodulating agents <i>in vitro</i>
Authors: Jenni H. Mäki-Jouppila, Jussi M. Halleen, Katja M. Fagerlund
Journal: Cancer Research (2020)

Abstract Immuno-oncology has emerged as one of the most promising new approaches in cancer drug development. Greater cancer cell specificity of treatments can be achieved when the immune cells of a patient are used against tumors. Therefore, it is important to study the effects of immune cells on cancer cells using different models in vitro and in vivo. Our aim was to validate an in vitro T cell killing assay where activated peripheral blood mononuclear cells (PBMCs) target different cancer cells and increase their apoptosis. MCF-7 human breast carcinoma cells (ATCC) were used as target cells and were seeded on 96-well plates. 24 hours later, human PBMCs (Lonza) were added to the culture as effector cells. Simultaneously, the PBMCs were activated with 100 ng/ml anti-CD3 and 10 ng/ml IL2. Apoptosis was detected using IncuCyte Annexin V reagent, which was introduced to the cells at the same time with activators. Cell growth, proliferation and apoptosis were monitored with a live cell imager IncuCyte S3 (Sartorius) for three days. Cell viability was determined by CellTiter Glo (Promega) at the end of the study. The target-to-effector ratio of 1:5 and 1:10 both showed an increase in apoptosis of MCF-7 cells in the wells with activated PBMCs. This was detected with a confluence parameter (percentage) of IncuCyte S3. The T cell killing assay can be utilized for studying cancer therapeutics based on immune-oncology (e.g. pembrolizumab and atezolizumab) and to evaluate the potential of immune cells in killing cancer cells in the presence of drugs affecting the target-effector interaction. Citation Format: Jenni H. Mäki-Jouppila, Jussi M. Halleen, Katja M. Fagerlund. Immune cell killing assay for analyzing the effects of immunomodulating agents in vitro [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 2759.
Abstract 5183: The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity
Authors: Fei Teng, Yi Gu, Hui Chai, Huanhuan Guo, Hongjun Li, Xiwen Wu, Xinlai Yao, Fei Xu, Lei Shi, Zhenzhi Yan, Xiaoli Zi, Zheng Dai, Timethy Liao, Lisa Zheng, Francis Fan, Zhen Li, Jerry Yang, Xueming Qian
Journal: Cancer Research (2020)

Abstract Claudin-18 isoform 2 (CLDN18.2) is a member of the human claudin family of tetraspan membrane proteins that are crucial structural and functional components of tight junctions. Unlike other family members, CLDN18.2 expression is strictly limited to differentiated epithelial cells of gastric mucosa. Interestingly CLDN18.2 was ectopically expressed at a significant level in multiple tumor types including gastric, esophageal, pancreatic and lung cancers, which makes it as an attractive anti-cancer target. TST001 is a novel humanized IgG1 monoclonal antibody, which specifically binds to cells expressing human CLDN18.2 with high affinity but not to the closely related Claudin 18.1. TST001 can compete with IMAB362, the clinical stage anti-CLDN18.2 mAb, for its binding to CLDN18.2 yet engages distinct epitope for binding. By reducing fucosylation during cell culture process, TST001 has further enhanced binding affinity to FcγRIIIa, which translates into more potent ADCC activity. Indeed, TST001 showed sub-nanomolar ADCC activity against gastric cancer cells expressing medium to low CLDN18.2 in the presence of human PBMC and NK cells, which is significantly more potent than IMAB362. TST001 also showed more potent CDC and ADCP activities against CLDN18.2 expressing cells than IMAB362. In both Sprague Dawley Rat and Cynomolgus Monkey, the systemic exposure of TST001 increased proportionally in a dose-dependent manner. In gastric cancer cell line and patient derived xenograft tumor models, TST001 showed more potent anti-tumor activity as compared with IMAB362. Furthermore, the combination of TST001 with chemo agents resulted in synergistic anti-tumor effect in these tumor models. In addition, we have also generated and characterized an antibody that is suitable for IHC based detection and is selective to CLDN18.2 over CLDN18.1. Altogether, these preclinical findings warrant further clinical evaluation of TST001 in patients with CLDN18.2 positive tumors. Citation Format: Fei Teng, Yi Gu, Hui Chai, Huanhuan Guo, Hongjun Li, Xiwen Wu, Xinlai Yao, Fei Xu, Lei Shi, Zhenzhi Yan, Xiaoli Zi, Zheng Dai, Timethy Liao, Lisa Zheng, Francis Fan, Zhen Li, Jerry Yang, Xueming Qian. The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity [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 5183.
P267 The S2PLIT-UG score, a novel system identifying patients with a high risk of all-cause mortality following acute decompensation of heart failure, correlates with levels of sST2, hs-cTnI and NT-proBNP
Authors: Josip Anđelo Borovac, Domenico D'Damario, Duška Glavaš, Zora Sušilović Grabovac, Daniela Šupe Domić, Katarina Novak, Anteo Bradarić, Davor Miličić, Darko Duplančić, Joško Božić
Journal: European Journal of Heart Failure (2020)
Abstract LB-379: Dominant negative PD1 armored CAR-T cells induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients
Authors: Yan Yuan, Liansheng Huang, Yang Su, Chengfei Pu, Tianling Ding, Xibin Xiao, Lina Jin, Zhiyuan Cao, Ting Wu, Tong Chen, Luying Ding, Xiaohong Zhang, Haifeng Lan, Zhao Wu, Lei Xiao
Journal: Cancer Research (2020)

Abstract The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to treat relapsed/refractory B cell malignancy. However, tumor microenvironment influences and affects the efficacy of CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated programmed cell death protein 1 (PD1) after T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy.Here, we generated CAR T expressed an anti-CD19 CAR molecule and a dominant-negative PD1 molecule. Compared with conventional CART cells, these “armored” CART cells showed the enhanced capability of tumor-killing and more “memory-like” phenotypes after multiple-round tumor challenging. These results suggest dominant-negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment.Further, we reported the findings of a clinical trial for six relapsed or refractory B-cell non-Hodgkin lymphoma (NHLs) patients treated using our armored CAR T cells. These six patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous CAR T cells range from1×106/kg to 8×106/kg. PET/CT showed significant tumor shrinkage and SUV max declines in all six patients, and the ongoing responses were monitored. The best overall response rate (ORR)was 100%. Conclusion: The results of these six patients in the clinical trial showed that our armored CAR T cells achieved the significant anti-bulky lymphoma response while causing limited and tolerated cytokine release syndrome and central nervous system toxicity. Thus, dominant-negative PD1 molecules may increase CAR T cells persistence in patients, enhancing the efficacy of CAR T cells for treating blood cancer. Finally, dominant-negative PD1 can be used as a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to monitor current patients and recruit more patients for the clinical trial. Citation Format: Yan Yuan, Liansheng Huang, Yang Su, Chengfei Pu, Tianling Ding, Xibin Xiao, Lina Jin, Zhiyuan Cao, Ting Wu, Tong Chen, Luying Ding, Xiaohong Zhang, Haifeng Lan, Zhao Wu, Lei Xiao. Dominant negative PD1 armored CAR-T cells induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients [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 LB-379.
Abstract 4298: The gut microbiome is associated with clinical responses to anti-PD-1 immunotherapy in gastrointestinal cancer patients in China
Authors: Zhi Peng, Siyuan Cheng, Quan Zhang, Yan Kou, Ziqi Wang, Rong Jin, Han Hu, Xiaotian Zhang, Jifang Gong, Jian Li, Ming Lu, Xicheng Wang, Jun Zhou, Zhihao Lu, Dongtao Bi, Yan Tan, Lin Shen
Journal: Cancer Research (2020)

Abstract We report the first and largest cohort, to the best of our knowledge, on the gut microbiome of 126 gastrointestinal (GI) cancer patients in China receiving the immune checkpoint inhibitors (ICI) targeting PD-1. The cohort included 31 patients with colon cancer, 23 with esophageal carcinoma, 47 with gastric cancer, and 25 with other cancer types. 43 of the patients had samples collected before treatment. 35 of patients were assessed as microsatellite-instability-High (MSI-High) and 71 as non-MSI-High. 408 fecal samples from the patients were collected. We performed 16s rRNA amplicon sequencing (V4 region) of the patients' samples to investigate the relationship between microbial profiles and patients' immunotherapy treatment response (RECIST 1.1). Principal coordinate analysis (PCoA) showed a subgroup of responders exhibiting a microbiome profile which was enriched in Prevotella. Hierarchical clustering of patients' microbiome profiles also suggested that for each gastric and colon cancer, patients with the same response tend to share similar microbiome profiles. By comparing the microbiome profiles between R and NR group using samples collected before treatment or within 3 weeks since the start of treatment, we identified 16s rRNA V4 sequences from Prevotella enriched in R group for each tumor type, which suggests positive association between Prevotella and tumor response. Our data also suggested that MSI as good marker for tumor response, although more data is required to achieve the significance level. Besides, no significant difference in alpha diversity was observed between R and NR group for each tumor type. In sum, we studied the microbiome profiles of 126 GI cancer patients and evaluated their association with anti-PD-1 immunotherapy. Patients with the same tumor type and response tend to share similar microbiome profiles, where Prevotella and a few other taxa contributed to the pattern. Citation Format: Zhi Peng, Siyuan Cheng, Quan Zhang, Yan Kou, Ziqi Wang, Rong Jin, Han Hu, Xiaotian Zhang, Jifang Gong, Jian Li, Ming Lu, Xicheng Wang, Jun Zhou, Zhihao Lu, Dongtao Bi, Yan Tan, Lin Shen. The gut microbiome is associated with clinical responses to anti-PD-1 immunotherapy in gastrointestinal cancer patients in China [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 4298.
Abstract 3619: High quality library preparation and accurate sequencing from highly damaged matched patient sample sets
Authors: Margaret R. Heider
Journal: Cancer Research (2020)

Abstract Preparation of high quality next-generation sequencing (NGS) libraries is critical for accurate identification of disease-causing mutations, but clinical scientists are often limited by the input DNA quality. In cancer genomics, a common source of DNA is formalin-fixed, paraffin-embedded (FFPE) tissue from patient biopsy, and in most cases high quality fresh or frozen tissue samples are not available. FFPE DNA poses many notable challenges for preparing NGS libraries, including low input amounts and extensive damage from fixation, storage, and extraction methods. Sequencing artifacts arising from damaged DNA bases raise the level of apparent mutations, making it more difficult to discern true, low frequency, disease-related variants from noise. We developed a second-generation, multi-enzyme DNA repair mix (V2) that is designed to repair the most prevalent damage types found in FFPE DNA including cytosine deamination, oxidative damage, abasic sites, nicks, and gaps. We tested the application of the V2 enzymatic repair mix in Illumina library preparation for DNA samples extracted from a series of matched patient sample sets, which included: FFPE normal and tumor tissue, and frozen normal and tumor tissue for each patient. Following this, we performed target enrichment, deep sequencing, and variant calling analyses. Our library preparation workflow integrates enzymatic repair upstream of Illumina library preparation without an additional bead purification step, maximizing library yield and complexity from precious FFPE samples. Rescue of damaged DNA molecules for library conversion and repair of damaged DNA bases improved on-target rate, coverage uniformity, and duplication rates. With a matched frozen sample for each FFPE specimen, we demonstrate that repair of damaged DNA bases improves sequencing accuracy by reducing the number of false-positive variant calls. We propose that enzymatic repair enables researchers to capture as much useable, accurate data from poor quality FFPE samples as possible. Citation Format: Margaret R. Heider. High quality library preparation and accurate sequencing from highly damaged matched patient sample sets [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 3619.
Abstract 5882: Genomic correlates of differential response to EGFR-directed tyrosine kinase inhibitors
Authors: Natalie Vokes, Tom Nguyen, Christine Lydon, Emily Chambers, Lynette Sholl, Mizuki Nishino, Eliezer Van Allen, Pasi Janne
Journal: Cancer Research (2020)

Abstract Background: Oncogenic mutations in EGFR are powerful biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, there remains significant heterogeneity in duration of response to therapy and overall survival. TP53 mutations have been linked with worse outcomes, thought to be due to increased likelihood of small cell transformation. Methods: We identified NSCLC patients at our institution with sensitizing oncogenic EGFR mutations who had been treated with EGFR TKI(s) and who had at least one tumor specimen profiled via targeted next generation sequencing (OncoPanel). Progression free survival (PFS) on first-line EGFR TKI, overall survival (OS), and resistance mechanism were assessed. Patients were defined as TP53 mutant positive (TP53+) or wild type (TP53-). Pathogenic TP53 mutations were identified and associated with outcome and resistance mechanism. Results: We identified 270 patients for inclusion in our cohort. 70% were female (190/270), 60% were never smokers (163/270), and median age was 62 (range 29-93). Sensitizing EGFR mutations were predominantly exon 19 deletion (51%, 138/270) or L858R (38%, 103/270). 94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). TP53+ patients were as likely to achieve objective radiographic response as TP53- (p=0.615), but had shorter PFS (HR 1.56, CI 1.1-2.2, p=0.011). TP53+ patients were no more likely to develop SCLC transformation (p=0.637). Among patients with T790M as their resistance mechanism, TP53+ patients still had shorter PFS compared to TP53- (HR 1.9, CI 1.2-3, p=0.003). Pre-treatment TP53 mutations were associated with a higher tumor mutational burden (p=0.017) and copy number burden (p=0.0026). Conclusion: While TP53 mutations associate with shorter PFS, there is no association with baseline TP53 mutation status and small cell transformation, and TP53+ patients also develop the T790M resistance mutation earlier than TP53- patients. Higher mutation and copy number burden in TP53+ patients suggests greater genomic instability and may act as a mechanism of earlier resistance development. Citation Format: Natalie Vokes, Tom Nguyen, Christine Lydon, Emily Chambers, Lynette Sholl, Mizuki Nishino, Eliezer Van Allen, Pasi Janne. Genomic correlates of differential response to EGFR-directed tyrosine kinase inhibitors [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 5882.
Abstract 439: Withaferin A attenuates the induction of cardiac cachexia by ovarian cancer
Authors: Natia Q. Kelm, Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar
Journal: Cancer Research (2020)

Abstract The purpose of this study was to investigate whether cardiac cachexia occurs in the context of ovarian cancer and whether Withaferin A could ameliorate the cachectic phenotype. We believe that treatment with Withaferin A can ameliorate cancer-induced cachexia and preserve heart function. Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Cachexia is a common syndrome in advanced cancer patients and accounts for approximately 20% of all cancer-related fatalities. Withaferin A is a steroidal lactone with anti-inflammatory properties that is known to inhibit the growth of ovarian cancer and was recently demonstrated to attenuate the skeletal muscle cachectic phenotype induced by a xenograft model of ovarian cancer. The ovarian cancer cell line A2780 was xenografted into severely immunodeficient female NSG mice via an intraperitoneal (i.p.) injection. Tumor-free control groups received an equivalent volume of sterile saline. Following an engraftment period of 8 days, tumor-free and tumor-bearing mice were treated with vehicle or Withaferin A at one of two doses (2 mg/kg or 4 mg/kg) via i.p. injections every 3 days until the end of the study (4 weeks). Bodyweight and grip strength were assessed on a weekly basis. Heart function was evaluated at the terminal week of the study by echocardiography using Vevo3100 system (FUJIFILM VisualSonics Inc.), followed by histological assessment of the heart for evidence of fibrosis and cardiomyocyte size changes. Cancer induced heart failure in female NSG mice (Systolic dysfunction: FS - 35±3.2; diastolic dysfunction: E/A - 0.45±0.12, IVRT - 22±1.2 msec) and reduced cardiac mass (normalized cardiac mass 9±1.1 (tumor-bearing, vehicle-treated) compared to 13±1.3 (tumor-free, vehicle-treated). Treatment with Withaferin A preserved systolic function in tumor-bearing mice (FS - 58±5.2), but diastolic dysfunction was only modestly improved (E/A - 0.83±0.98, IVRT -17±1.2 msec). Further, Withaferin A ameliorated the reduction in myofibrillar cross-sectional area induced by ovarian cancer. Lastly, treatment with Withaferin A ameliorated fibrotic depositions in the hearts in the tumor-bearing animals. In conclusion, ovarian cancer was shown to induce cardiac cachectic phenotype. Further, it was demonstrated that WFA treatment preserved systolic function, reduced diastolic dysfunction, and attenuated the atrophying and fibrotic effects of the xenografted tumors. Citation Format: Natia Q. Kelm, Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar. Withaferin A attenuates the induction of cardiac cachexia by ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 439.
Abstract 1251: Epigenetics in early onset colorectal cancer (EOCRC)
Authors: Karen Riggins, Benjamin Musher, Michael Scheurer, Li Yang, Patricia Castro, Neda Zarrin-Khameh, Lanlan Shen
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) incidence rates have increased among young adults while the rates have decreased among older adults over 50 years of age. While the etiology of the growing prevalence of young adults with newly diagnosed CRC is unknown, there has been growing interest in the roles implicated for diabetes, obesity, environmental changes, and epigenetics. Among the epigenetic marks implicated in EOCRC, the most widely studied are the global DNA hypomethylation. Using mouse studies, our group has demonstrated that DNA methylation as an epigenetic mechanism to control gene expression is essential to postnatal development. We have discovered a key set of genes that undergo epigenetic changes in colonic epithelial stem cells, and these changes are stable over a lifetime. We have shown that the gut microbiome influences this process. Importantly, perturbation of established intestinal DNA methylation leads to accelerated intestinal tumor development. To translate our mechanistic studies in the animal model to humans, we have confirmed these CpG loci that are concordant between the two species (i.e. homologous regions and/or conserved CpG islands). Here, we hypothesize that the dysregulation of developmentally programmed intestinal DNA methylation is associated with enhanced susceptibility to colon cancer in young adult. We have identified a population of patients within the Harris Health and Baylor College of Medicine system under the age of 50 with mismatch repair stable colorectal adenocarcinoma. Patient characteristics including age, sex, race, and primary tumor profile (stage at diagnosis, histology, and RAS status) have been defined. Using a panel of 6 genes and bisulfite pyrosequencing for quantitative assessment of DNA methylation, we compared the level of methylation in EOCRC tumors to paired normal adjacent tissues as well as normal adult tissue (age 50 or greater) to traditional CRC tumors. Our preliminary data suggest hypermethylation patterns are distinct in patients of EOCRC relative to traditional CRC. Our ultimate goal is to better understand the etiology of EOCRC in order to devise better prevention and treatment strategies for EOCRC. Citation Format: Karen Riggins, Benjamin Musher, Michael Scheurer, Li Yang, Patricia Castro, Neda Zarrin-Khameh, Lanlan Shen. Epigenetics in early onset colorectal cancer (EOCRC) [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 1251.