bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5651: A LAG-3/PD-L1 bispecific antibody inhibits tumor growth in two syngeneic colon carcinoma models
Authors: Kraman Matthew , Kmiecik Katarzyna , Zimarino Carlo , Everett Katy , Faroudi Mustapha , Wydro Mateusz , Doody Jacqueline 
Published: July 2017

Abstract
Combining immunotherapeutic antibodies in cancer treatment has shown benefits over single agents. An alternative to combining two antibodies is the development of bispecific antibodies that not only bring two biologies together but may result in novel mechanisms of action that are impossible to attain with combinations. Lymphocyte Activation Gene-3 (LAG-3) is a member of the Ig superfamily expressed on activated T cells, NK cells, pDCs, B cells, γδ T cells and participates in immune suppression. Programmed Cell Death receptor (PD-1) binds to its ligand PD-L1, expressed not only on activated immune cells to inhibit cellular immune responses but also on tumor cells. Expression of both these surface molecules therefore leads to T cell exhaustion allowing the tumor to escape immune surveillance. A mAb² TM (bispecific antibody) was engineered which binds murine LAG-3 and PD-L1 simultaneously and with nanomolar affinities. The anti-LAG-3/PD-L1 mAb² inhibits LAG-3 binding to MHCII and PD-L1 binding to PD-1 and CD80, resulting in T cell activation in vitro. This translates into in vivo efficacy, where the mAb² decreased tumor burden in the MC38 colon carcinoma tumor model. At the end of the study tumor-free animals were more numerous in the LAG-3/PD-L1 bispecific group than in the group given a combination of individual anti-LAG-3 and PD-L1 antibodies. The results were recapitulated in the CT26 murine colon cancer model, where the mAb² showed an increase of antitumor activity as compared to the antibodies given in combination. Thus, the preclinical data supports developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients.
Citation Format: Matthew Kraman, Katarzyna Kmiecik, Carlo Zimarino, Katy Everett, Mustapha Faroudi, Mateusz Wydro, Jacqueline Doody. A LAG-3/PD-L1 bispecific antibody inhibits tumor growth in two syngeneic colon carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5651. doi:10.1158/1538-7445.AM2017-5651
Abstract 5654: Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy
Authors: Arita Masashi , Watanabe Satoshi , Miho Takahashi , Sato Miyuki , Ohtsubo Aya , Ichikawa Kosuke , Kondo Rie , Abe Tetsuya , Tanaka Junta , Koya Toshiyuki , Kikuchi Toshiaki 
Published: July 2017

Abstract
Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) blockade therapy has demonstrated to enhance antitumor immunity. Recent evidence has shown that anti-PD-1/PD-L1 therapy restores the function of exhausted effector T cells and augments antitumor immune responses. The expression of PD-L1 has been best studied as a biomarker for the anti-PD-1/PD-L1 therapy. Because PD-L1 expression on tumor cells is induced by IFN-γ which is mainly produced by effector T cells, induction of antitumor effector T cells in cancer patients could be an important for the anti-PD-1/PD-L1 therapy. Indeed, previous studies have suggested that the increase of tumor-infiltrating lymphocytes is the predictive biomarker for PD-1/PD-L1 blockade therapy. We and others have demonstrated that lymphodepletive therapies, such as chemotherapy and radiotherapy, induce tumor-specific effector T cells from naïve T cells. Naïve T cells rapidly proliferate and elicit memory-like functions after lymphodepletion (homeostatic proliferation). These findings indicate that lymphodepletive regimens could augment the antitumor efficacies of the anti-PD-1/PD-L1 therapy. In the current study, we transferred naïve T cells into mice after whole-body irradiation or chemotherapy. These mice were inoculated s.c. with PD-L1+ B16F10 melanoma cells or PD-L1- MCA205 fibrosarcoma and then were treated with anti-PD-1 mAbs. Lymphodepletion by whole body irradiation, but not cytotoxic agents following the transfer of naïve T cells significantly enhanced antitumor immunity of anti-PD-1 mAbs. This augmentation required both of CD4+ and CD8+ T cells, but not NK cells. Further experiments revealed that immune cells infiltrating MCA205 expressed PD-L1. Transfer of naïve T cells from IFN-γ knockout mice abrogated the enhancement of antitumor effects of anti-PD-1 mAb therapy by lymphodepletion. These results suggest that lymphodepletion induces homeostatic proliferation of T cells and augments antitumor effects of PD-1/PD-L1 blockade therapy.
Citation Format: Masashi Arita, Satoshi Watanabe, Takahashi Miho, Miyuki Sato, Aya Ohtsubo, Kosuke Ichikawa, Rie Kondo, Tetsuya Abe, Junta Tanaka, Toshiyuki Koya, Toshiaki Kikuchi. Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5654. doi:10.1158/1538-7445.AM2017-5654
Abstract 566: A pathway based drug selection for cancer precision medicine
Authors: Vasudevaraja Varshini , Cheng Lijun , Inavolu Sai Mounika , Radovich Milan 
Published: July 2017

Abstract
Background and Purpose:
Precision medicine tailors the right therapy to the right patient based on his/her tumor molecular profiles. In clinic and ongoing clinical trials, drug-targeted selection schemes depends more or less on drug targets’ mutations or expression status. However, there is a lack of systematic pathway based method to connect individual genomics information with properly drug target and treatment in precision medicine. The paper aims to integrate various knowledge-bases, including cancer drugs, drug-targets and gene-gene regulatory pathway, to construct a drug target and properly drug selection algorithm for individual patient in precision medicine.
Materials and Methods:
In the drug selection algorithm, drug targets and properly drugs recommendation are based on the patient specific molecular profile data, including copy number variation, mutation, and gene expression. Our target and drug selections are based on whether these drug targets act as hub genes that either regulate or control the signaling pathways for many other genes in the biological pathways. Only those patients whose molecular profiles do not show targets, the usual chemotherapy treatment will be recommended. This novel algorithm is applied to individual Pancreatic Adenocarcinoma (PAAD) for drug target and drug selection. All of patients’ genomic data obtained from the Cancer Genome Atlas (TCGA). The pathway information is from Pathway Commons and FDA approved cancer drugs and their targets is from DrugBank. The Cancer Cell Line Encyclopedia (CCLE) 46 pancreases cancer cell line are used to validate the algorithm result reliability.
Results:
Our algorithm identifies targets, such as ERBB2, CDK2, SRC, CDK9, SMAD2, CDK4, HDAC1, PPP1CA, AKR1B1, EGFR, IGF1R, AKT and MEK, for pancreatic adenocarcinoma cancer patients. In which, they cover the clinic first line effective drug targets, such as Gemcitabine for the Akt-mTOR signaling pathway (AKT) and CDK4/6 inhibitor and Erlotinib for HER2 Kinase Family (ERBB2, EGFR) activation inhibitor. In addition, new inhibitors include Src inhibitors (dasatinib, saracatinib and bosutinib), TGF beta inhibitor for target SMAD2 (galunisertib) and IGF-1R/insulin receptor inhibitors (ceritinib, brigatinib) are recommended accordingly and validated in pancreatic cancer cells.
Conclusion:
This novel algorithm might act as a better source for off-label drug selection and further cell line validations may help in providing a better treatment strategy in precision medicine.
Note: This abstract was not presented at the meeting.
Citation Format: Varshini Vasudevaraja, Lijun Cheng, Sai Mounika Inavolu, Milan Radovich. A pathway based drug selection for cancer precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 566. doi:10.1158/1538-7445.AM2017-566
Abstract 5668: CCL2/CCR2-driven monocyte recruitment to the tumor following radiotherapy influences the outcome of the treatment of head and neck cancer
Authors: Mondini Michele , Loyher Pierre L. , Berthelot Kevin , Clémenson Céline , Boissonnas Alexandre , Deutsch Eric 
Published: July 2017

Abstract
Local radiotherapy is the major treatment to control locally advanced head and neck cancer. Evidence supporting the importance of immune response in the response to radiation therapy is growing and the possibility to potentiate the effects of radiotherapy by modulating the function of the immune system offers new exciting therapeutic perspectives. Preclinical findings suggest that immunomodulatory agents may synergize with radiotherapy, increasing local response rates and inducing sustained systemic responses. The role of monocytes/macrophages in the response to radiotherapy is under extensive investigation. Among the many cytokines secreted by tumor cells, CCL2 is involved in inflammatory monocyte recruitment from bone marrow to the inflammatory site. We have recently developed a model of human papillomavirus (HPV)-related head and neck cancer using immunocompetent mice and validated its usefulness to evaluate the tumor response to radiotherapy. Using the same model, based on the injection of TC1/luciferase cells in the inner lip of C57Bl/6 mice, we show that local radiotherapy induces an increase of CCL2 levels in the bloodstream and intratumorally accompanied by a neo-infiltration of monocytes in the tumor that subsequently differentiate into tumor-associated macrophages (TAM). When TC1/Luc cells were engrafted in CCL2-/- or CCR2-/- mice, the tumor response to radiotherapy and survival were improved. This was accompanied by an impaired infiltration of inflammatory monocytes, and a subsequent decrease of TAM levels at later time points. In vitro, exposure to ionizing radiation increased the secretion of CCL2 by TC1/Luc cells, and such increase was significantly enhanced when tumor cells were co-cultured with irradiated RAW 264.7 macrophage-derived cells. This data suggests interplay between tumor and TAM that can amplify the effects of radiotherapy on the immune system. We propose that reducing radiation-induced monocyte recruitment may yield improved results in the treatment of HPV-related head and neck squamous cell carcinomas by radiotherapy. Immunologically-augmented radiotherapy could allow reduction of the delivered radiation dose, thus minimizing the risk of treatment sequelae while maintaining optimal tumor control.
Citation Format: Michele Mondini, Pierre L. Loyher, Kevin Berthelot, Céline Clémenson, Alexandre Boissonnas, Eric Deutsch. CCL2/CCR2-driven monocyte recruitment to the tumor following radiotherapy influences the outcome of the treatment of head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5668. doi:10.1158/1538-7445.AM2017-5668
Abstract 5669: Targeting post-surgical breast cancer metastasis through combining natural killer T cell immunotherapy and low dose chemotherapy
Authors: Gebremeskel Simon , Tanner Kaitlyn , Lobert Lynnea , Johnston Brent 
Published: July 2017

Abstract
Breast cancer is the most common cancer in Canadian women and the second leading cause of cancer deaths. Given that most mammary tumors are surgically resectable and over 90% of breast cancer-associated deaths are due to metastasis, new therapeutic strategies targeting metastasis are required. Natural killer T (NKT) cells are a rare population of immune cells that have been shown to limit primary tumor growth and target distant metastatic disease in various animal models. We have shown that NKT cell activation improves survival in a model of post-surgical metastatic breast cancer. We are now expanding this work to determine whether NKT cell activation can be combined with chemotherapies to improve outcomes. In our model, 4T1 mammary carcinoma cells were injected into the mammary fatpad of syngeneic BALB/c mice. Tumors were resected at day 12, and mice were treated with cyclophosphamide or gemcitabine. On day 17, NKT cells were activated by transfer of dendritic cells loaded with the glycolipid antigen α-GalCer. We also examined whether gemcitabine or mafosphamide (active component of cyclophosphamide) would induce immunogenic cell death of 4T1 cells in culture. Chemotherapeutics did not affect NKT cell activation as measured by serum IFNγ levels. Treatment with cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cells alone reduced metastasis and prolonged survival. Combined treatments significantly enhanced survival. NKT cell activation decreased the frequency and immunosuppressive function of myeloid derived suppressor cells (MDSCs). Treatments resulted in enhanced tumor specific immunity as surviving mice exhibited slower tumor growth following secondary tumor challenge. Gemcitabine and mafosphamide also increase the immunogenicity of cancer cells in vitro by increasing the exposure/release of MHCI, MHCII, CD1d, Calreticulin, HMGB1 and ATP. NKT cell activation therapy can successfully be combined with low doses of gemcitabine or cyclophosphamide to enhance protection against tumor metastasis and recurrence. This work provides a clear rationale for combining chemotherapy with NKT cell immunotherapy to target metastatic disease in the clinical setting.
Citation Format: Simon Gebremeskel, Kaitlyn Tanner, Lynnea Lobert, Brent Johnston. Targeting post-surgical breast cancer metastasis through combining natural killer T cell immunotherapy and low dose chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5669. doi:10.1158/1538-7445.AM2017-5669
Abstract 5677: Performance of a robust and sensitive liquid biopsy workflow for mutation detection in plasma
Authors: Choi Jonathan , Choi Cindy , Dinis Jorge , Li Jingchuan , Chien Sean , Min Bosun , Munoz Abraham , Jin Janet , Pati Amrita , Feng Liang , Wu Johnny , Singh Ashla , Casey Fergal 
Published: July 2017

Abstract
The discovery of circulating tumor DNA (ctDNA) and the development of highly sensitive technologies have made the utility of liquid biopsies in clinical practice more feasible. Potential applications for liquid biopsies include early cancer detection, tumor genotyping in the absence of tissue biopsies, disease monitoring, and identification of drug resistance markers. However, there is a multitude of technical challenges to accurately detect ctDNA with high sensitivity and reproducibility. Various methods have been established by research centers and companies, each with its advantages and limitations. We have developed a sensitive NGS-based liquid biopsy assay, called the AVENIO ctDNA Analysis Kits (research use only), which includes three panels targeting biomarkers for solid tumors. The AVENIO ctDNA Analysis Kits include cfDNA extraction from up to 5ml plasma input, optimized reagents and workflow for NGS library preparation and target enrichment. It is accompanied with an intuitive software and data analysis package to easily obtain results. The assay sensitively detects 4 cancer relevant mutation classes - single nucleotide variations (SNVs), insertions/deletions, copy number variations and structural rearrangements.
We conducted a study with 200+ samples of plasma-derived cfDNA, cell line blends containing relevant cancer mutations, and clinical samples, with which we demonstrate the analytical sensitivity of the three distinct AVENIO gene panels (covering 17, 77 and 197 genes). We demonstrate &gt;95% sensitivity for SNVs at 0.5% mutant allele frequency; &gt;95% sensitivity for 1% indels; &gt;95% sensitivity for 1% structural variants. We also demonstrate assay robustness through multiple replicates, day-to-day, and operator-to-operator reproducibility.
In conclusion, the AVENIO ctDNA Analysis Kits for solid tumors encompasses a comprehensive assay and analysis workflow aimed to provide researchers with robust, reliable, highly sensitive and ease to use liquid biopsy assays to conduct the necessary studies to demonstrate the utility of circulating biomarkers in routine clinical testing.
Citation Format: Jonathan Choi, Cindy Choi, Jorge Dinis, Jingchuan Li, Sean Chien, Bosun Min, Abraham Munoz, Janet Jin, Amrita Pati, Liang Feng, Johnny Wu, Ashla Singh, Fergal Casey. Performance of a robust and sensitive liquid biopsy workflow for mutation detection in plasma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5677. doi:10.1158/1538-7445.AM2017-5677
Abstract 5683: Evaluation of the utilization of blood collection tubes for cell-free DNA research
Authors: Endo Fumitaka , Iwaya Takeshi , Chiba Takehiro , Yaegashi Mizunori , Sato Kei , Kume Kohei , Arisue Atsuhiro , Nishinari Yutaka , Kawagishi Ryoko , Segawa Takenori , Nishizuka Satoshi , Sasaki Akira 
Published: July 2017

Abstract
Many studies have been conducted investigating cell-free DNA (cfDNA) for disease diagnosis. To prevent cellular DNA release into the plasma, plasma separation within 2 hours of blood collection is required, when utilizing the most commonly used type of tube (BD Vacutainer® CPTTM; CPT). These temporal restrictions render operations requiring plasma separation a laborious task. It has been demonstrated that Cell-Free DNA BCT® tubes (Streck Inc; BCTs) prevented nucleated cell disruption. The use of BCTs may enable us to separate plasma without temporal restrictions. The aim of this study was to evaluate changes in DNA levels in plasma after preservation using two types of collection tubes. Samples were drawn from 7 healthy donors into CPTs and BCTs, and stored at room temperature. Plasma was separated immediately (d0), and on days 3, 6, 9, 12, and 14 after blood collection. The concentrations of DNA in the extracted plasma samples were measured. Blood stored in CPTs showed increases in plasma DNA concentrations over time. The mean DNA concentrations at each time-point were 0.39 (d0), 2.96 (d3), 40.4 (d6), 84.9 (d9), 91.4 (d12), and 94.9 ng/μl (d14). However, plasma DNA levels remained stable in BCTs from 6 days. There were significant differences between the DNA concentrations in BCTs on d0 (0.74 [0.43-1.44] ng/µl) and d14 (1.78 [0.63-4.20] ng/µl) (p = 0.0378). Although significant differences were only observed between d0 and d14 in BCTs, the amount of plasma DNA gradually increased after d6. Furthermore, obvious color changes in the plasma were observed, and the boundary between plasma and PBMCs became unclear over time. These results indicate that BCTs may yield stable cfDNA samples for up to 6 days after blood collection. BCTs may be a novel collection tube for cfDNA research, including liquid biopsies in cancer patients.
Citation Format: Fumitaka Endo, Takeshi Iwaya, Takehiro Chiba, Mizunori Yaegashi, Kei Sato, Kohei Kume, Atsuhiro Arisue, Yutaka Nishinari, Ryoko Kawagishi, Takenori Segawa, Satoshi Nishizuka, Akira Sasaki. Evaluation of the utilization of blood collection tubes for cell-free DNA research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5683. doi:10.1158/1538-7445.AM2017-5683
Abstract 569: Dexamethasone inhibits T-cell proliferation through a CTLA-4 mediated pathway
Authors: Hutchinson Marsha-Kay N. , Giles Amber J. , Sonnemann Heather M. , Reid Caitlin M. , Park Deric M. , Gilbert Mark 
Published: July 2017

Abstract
BACKGROUND: The use of corticosteroids for therapeutic benefit has to be weighed against the risks of adverse consequences associated with these drugs. Brain tumor patients in particular, are routinely prescribed dexamethasone (a glucocorticoid) to reduce edema associated with their lesion. Checkpoint blockade, a type of immune therapy, is currently being investigated as a potential treatment for brain tumors. However, glucocorticoid signaling has been shown to attenuate the immune response through several mechanisms including the repression of transcription of genes controlling pro-inflammatory cytokines and chemokines.
HYPOTHESIS: Here, we propose that dexamethasone’s ability to upregulate inhibitory T-cell molecules such as CTLA-4 and PD-1 might be an additional immunosuppressive mechanism.
METHODS: Healthy donor T cells were tested for response to dexamethasone. T cell proliferation, cell cycle analysis, apoptosis, and protein expression were assessed with flow cytometry. Protein expression was also measured with Western blots. Transcriptional changes were assessed with qPCR. A monoclonal antibody, ipilimumab, was used to block CTLA-4 binding.
RESULTS: Unexpectedly, dexamethasone did not elicit a direct lymphotoxic effect on T cells as measured by absolute cell number. However, we found that dexamethasone significantly reduced T cell entry into the cell cycle, but did not impact cells already undergoing mitosis. Checkpoint molecules CTLA-4 and PD-1 were increased with dexamethasone treatment when cells are stimulated. Blockade of CTLA-4 with Ipilimumab resulted in a substantial reversal of cell cycle entry inhibition that was induced by dexamethasone.
CONCLUSIONS: These results suggest that dexamethasone impairs T cell expansion by inhibiting cell cycle entry. Upregulated CTLA-4 expression contributes to cell cycle entry blockade which is reversed by inhibiting CTLA-4 with ipilimumab. These findings indicate that administration of ipilimumab before dexamethasone diminishes the negative proliferative effect on anti-tumor T cells suggesting that when needed, corticosteroids can be used after immune checkpoint blockade has been established.
Citation Format: Marsha-Kay N. Hutchinson, Amber J. Giles, Heather M. Sonnemann, Caitlin M. Reid, Deric M. Park, Mark Gilbert. Dexamethasone inhibits T-cell proliferation through a CTLA-4 mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 569. doi:10.1158/1538-7445.AM2017-569