bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4534: Theory and methodology for the design and analysis of PDX mouse clinical trials
Authors: Guo Sheng , Mao Binchen , Li Henry Q. 
Published: July 2017

Abstract
Patient-derived xenograft (PDX) is a well-accepted experimental cancer model mimicking original patients in histo- & molecular pathology, as well as drug response. Mouse clinical trials (MCT) using PDX becomes increasingly prevalent in oncology research, yet the theory and methodology for trial design and analysis is underdeveloped. By analyzing tumor growths of 34081 PDX mice, we showed that majority of them can be satisfactorily modeled by exponential growth kinetics, based on which we derived a new drug response readout called the AUC ratio that is superior to the tumor growth inhibition (TGI) and its variants. We outlined a bootstrap algorithm to calculate its confidence interval, and showed that a 4:4 (4 mice in both treatment groups) or up design sharply increases measurement accuracy over the lesser design. Next, we introduce three approaches for drug evaluation and biomarker discovery in MCTs. In the end-point based analysis, we used a cohort of gastric PDXs to show a positive correlation between EGFR mRNA expression and cetuximab efficacy, in agreement with clinical trial results. We then used linear mixed models (LMMs) to describe MCTs as clustered longitudinal studies that capture the growth and drug response heterogeneities across PDXs and among mice within a PDX. Further, LMMs can separate prognostic and predictive biomarker effects, quantify response difference to a drug for multiple cancers, or efficacy difference of multiple drugs to a cohort of PDXs. Thirdly, we used additive frailty models to perform survival analysis on MCTs. We defined survival endpoints of PFS and OS in PDXs, and showed that hazard ratios can be more accurately estimated. We revealed an inherent connection between frailty and growth rate for PDXs. We performed computational simulations for the last two methods to show that statistical power improves tremendously with a 3:3 or up design. This work lays the foundation for rational design and analysis of PDX mouse clinical trials.
Citation Format: Sheng Guo, Binchen Mao, Henry Q. Li. Theory and methodology for the design and analysis of PDX mouse clinical trials [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 4534. doi:10.1158/1538-7445.AM2017-4534
Abstract 4539: Novel feature selection strategies for enhanced predictive modeling and deep learning in the biosciences
Authors: Yang Pengwei , Abo Ryan , Liu Chang , Chen Zehua , Wu Haiguo , Cui Jike , Yandava Chandri , Bailey Shannon T. , Balch Curt , Gulcher Jeffery R. , Chittenden Thomas W. 
Published: July 2017

Abstract
Artificial Intelligence (AI) is the single most transformative technology in human history. Advancements in personalized medicine depend upon significantly furthering our current understanding of how genetic variation and somatic mutation regulate aberrant gene activity and subsequent disease biology, including the myriad of dysregulated molecular mechanisms of cancer. To this end, we have built a robust AI method to precisely assess pathogenicity for all genomic missense variants. Coupled with our advanced deepCODE feature selection strategy for constructing deep learning models, we can quantitatively integrate a priori pathway-based biological knowledge with multiple types of high-throughput omics data. This approach significantly improves performance of established classification methods via enhanced semantic interoperability for mapping between multiple biomedical ontologies and the subsequent identification of genes and molecular pathways more highly predictive of cancer type etiology. Specifically, our deepCODE AI methods greatly improve tumor subtype and drug-response classification accuracies by combining tumor DNA- and RNA-seq data. Our results indicate classification of human breast and lung cancer subtypes with 96% and greater than 99% accuracy, respectively. Our novel multinomial statistical-learning method, which was validated with 6 cancer type patient-derived tumor xenograft (PDTX) mouse models, achieved greater than 95% accuracy across 10,000 human tumors within the collection of 28 TCGA cancer types. Finally, our stepwise deepCODE drug target discovery approach systematically integrates our deep learning classification strategy with advanced Bayesian Network modeling to identify causative driver genes, representing probable novel drug targets. This stepwise machine learning approach also serves as a unique means to assess drug efficacy. Taken together, our advanced deepCODE AI tools greatly expand the means to fully understand the underlying molecular determinants of human cancer. We have developed user-friendly decision support and research tools for in-depth tumor analysis and large-scale case-control methods that afford investigators access to our deepCODE variant annotation algorithms.
Citation Format: Pengwei Yang, Ryan Abo, Chang Liu, Zehua Chen, Haiguo Wu, Jike Cui, Chandri Yandava, Shannon T. Bailey, Curt Balch, Jeffery R. Gulcher, Thomas W. Chittenden. Novel feature selection strategies for enhanced predictive modeling and deep learning in the biosciences [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 4539. doi:10.1158/1538-7445.AM2017-4539
Abstract 4584: High PD-1 expression on regulatory and effector T cells in lung cancer draining lymph nodes
Authors: Ven Rieneke Van De , Niemeijer Anna-Larissa N. , Stam Anita G. , Hashemi Sayed M. , Slockers Christian G. , Daniels Johannes M. , Thunnissen Erik , Smit Egbert F. , Gruijl Tanja D. de , Langen Adrianus J. de 
Published: July 2017

Abstract
The treatment of advanced non-small cell lung cancer (NSCLC) with PD-1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find biomarkers that will identify patients likely to benefit from this therapy. In this study we assessed the difference of T cell subsets and PD-1 expression levels on T cells in tumor-draining lymph nodes (TDLN), non-TDLN (NTDLN) and peripheral blood mononuclear cells (PBMC).
To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine-needle aspirates (FNA) from TDLN and NTDLN of patients with NSCLC and compared to PBMC.
Our data show that the frequency of PD-1+ CD4+ and CD8+ T cells, as well as the PD-1 expression level on activated regulatory T (aTreg) and CD4+ and CD8+ T cells, are higher in TDLNs as compared to NTDLNs or PBMC.
These elevated PD-1 expression levels in TDLN may reflect tumor-specific T cell priming and may serve as a predictive or early response biomarker during PD-1 checkpoint blockade.
Citation Format: Rieneke Van De Ven, Anna-Larissa N. Niemeijer, Anita G. Stam, Sayed M. Hashemi, Christian G. Slockers, Johannes M. Daniels, Erik Thunnissen, Egbert F. Smit, Tanja D. de Gruijl, Adrianus J. de Langen. High PD-1 expression on regulatory and effector T cells in lung cancer draining lymph nodes [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 4584. doi:10.1158/1538-7445.AM2017-4584
Abstract 4605: Efficient targeting of BCMA-positive multiple myeloma cells by antibody-coupled T-cell receptor (ACTR) engineered autologous T cells in combination with an anti-BCMA antibody
Authors: Cheema Tooba , Hickman Taylor , O'Callaghan Katie , Westendorf Lori , Manlove Luke , Gardai Shyra , Nelson Allison , Boomer Ryan , McGinness Kathleen , Schultes Birgit , Ettenberg Seth , Sussman Django , Huet Heather 
Published: July 2017

Abstract
B cell maturation antigen (BCMA) has recently emerged as an attractive therapeutic target in multiple myeloma. BCMA has restricted expression on plasma cells with little to no expression on other normal tissues, but is upregulated on the surface of multiple myeloma cells. BCMA can regulate proliferation and survival of myeloma cells via binding to its ligands APRIL and BAFF and induce downstream signaling pathways. Thus, several approaches to target BCMA are currently under clinical investigation, including chimeric antigen receptor (CAR) T cell therapies, bispecific antibodies and antibody drug conjugates.
The Antibody-Coupled T cell Receptor (ACTR) technology is a universal, engineered T cell therapy consisting of the extracellular domain of human CD16 and the intracellular T cell co-stimulatory and signaling domains. ACTR is designed to engage the Fc domain of therapeutic antibodies opsonized to target cells to mediate anti-tumor activity. Previous work has demonstrated ACTR T cell activity in combination with rituximab, trastuzumab, and hu14.18 K322A against CD20, Her2, and GD2 expressing cell lines, respectively (Kudo et al. Cancer Res 2014; 74:93-103). Currently ACTR is being evaluated in Phase I clinical trials with rituximab to treat relapsed refractory B cell lymphoma.
Here we demonstrate a humanized afucosylated anti-BCMA antibody, SEA-BCMA, binds to ACTR expressing T cells with high affinity and mediates T cell activation, potent cytotoxicity, cytokine release and proliferation across a wide range of BCMA expressing myeloma cells. ACTR activity was specific to SEA-BCMA - opsonized target cells, dose dependent and had no activity on BCMA negative tumor lines. Furthermore, the SEA-BCMA antibody has additional properties that might contribute to a therapeutic effect, including blocking the binding of ligands to BCMA and driving natural killer cell mediated ADCC effects. These preclinical studies demonstrate a promising multi-faceted activity of ACTR T cells in combination with the anti-BCMA antibody, SEA-BCMA, for clinical consideration in multiple myeloma patients.
Citation Format: Tooba Cheema, Taylor Hickman, Katie O'Callaghan, Lori Westendorf, Luke Manlove, Shyra Gardai, Allison Nelson, Ryan Boomer, Kathleen McGinness, Birgit Schultes, Seth Ettenberg, Django Sussman, Heather Huet. Efficient targeting of BCMA-positive multiple myeloma cells by antibody-coupled T-cell receptor (ACTR) engineered autologous T cells in combination with an anti-BCMA antibody [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 4605. doi:10.1158/1538-7445.AM2017-4605
Abstract 4614: Upregulation of memory T cell population and enhancement of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade
Authors: Kato Yu 
Published: July 2017

Abstract
Introduction: Lenvatinib (LEN) selectively inhibits the kinase activity of VEGFR1-3, FGFR1-4, KIT, PDGFRα, and RET, which are involved in tumor angiogenesis and tumor cell proliferation in several cancer types. Currently, Phase 1b/2 clinical trials of the combination of LEN and pembrolizumab (a monoclonal antibody [mAb] that blocks the interaction between PD-1 and its ligands) are ongoing for selected types of cancer including renal cell carcinoma, melanoma and non-small cell lung carcinoma. We have reported that tumor associated macrophage and regulatory T cell population were downregulated by treatment of LEN. In this study, mechanism of LEN and PD-1 mAb combination was investigated by flow cytometory and RNA-seq analyses.
Experimental Procedure: We examined antitumor activity of combination treatment of LEN (10mg/kg, qd) and anti-mouse PD-1 mAb (500μg/mouse, twice weekly) in Ct26 and B16F10 syngeneic mouse models. In order to investigate tumor-specific memory T cell response, re-inoculation of fresh CT26 cells into tumor-free mice was conducted. For immune cell population analyses, tumor or spleen samples were analyzed by flow cytometry. Changes of molecular immune response in tumors were examined by RNAseq followed by weighted gene co-expression network analysis (WGCNA).
Summary of data: Combination of LEN with PD-1 mAb showed more potent anti-tumor growth activity in CT26 and B16F10 models compared with either treatment alone. Notably, complete tumor regression was detected in a portion of mice that received combination treatment only. Re-inoculation of fresh CT26 cells into these tumor-free mice did not grow tumor; in contrast, all naïve animals grew tumor aggressively in the same experimental condition. RNAseq analysis of treated CT26 tumors indicated that combination of LEN with PD-1 mAb synergistically up-regulates IFN signaling-related genes. Flow cytometory analysis revealed that LEN increased memory T cell population compared with vehicle treatment.
Conclusions: The results indicate that the combination of LEN with PD-1 mAb was more effective than either single agent alone in multiple syngeneic tumor models and was accompanied with a potent antitumor immune response, especially the up-regulation of memory T cell and Th1 activation by LEN.
Citation Format: Yu Kato. Upregulation of memory T cell population and enhancement of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade [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 4614. doi:10.1158/1538-7445.AM2017-4614
Abstract 4615: Development of an antibody-drug conjugate with broad anticancer activity
Authors: Lin Siang-Yo , Szekely Zoltan , Lin Chen-Yong , Bertino Joseph R. , Rather Gulam Mohmad 
Published: July 2017

Abstract
Treatment for patients with advanced solid tumors that include triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and castrate resistant prostate cancer (CRPC), as well as Mantle Cell Lymphoma (MCL), while increasing survival is not curative. We have identified a membrane bound protease, “activated” matriptase, as an attractive target antigen for highly selective antibody delivery of cytotoxins as activated matriptase expression is restricted to epithelial tumors and some B-cell lymphomas. We generated a novel ADC by linking M69, a mouse antibody specific to activated matriptase, to monomethyl auristatin E (MMAE) via a PEGylated, releasable di-peptide linker as a proof-of-principle prototype. Both in cell lines and in human xenograft models of TNBC, NSCLC, CRPC and MCL, the conjugate was found to exhibit potent anticancer activity against all of these tumor types without toxicity. Encouraged by these results, we are also exploring the use of this ADC against gastric and pancreatic cancer, and in combination with chemotherapy and immunotherapy. As this is a mouse antibody, we are also generating a chimeric antibody for toxicity studies in primates.
Citation Format: Siang-Yo Lin, Zoltan Szekely, Chen-Yong Lin, Joseph R. Bertino, Gulam Mohmad Rather. Development of an antibody-drug conjugate with broad anticancer activity [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 4615. doi:10.1158/1538-7445.AM2017-4615
Abstract 4661: Omentin as an adjunct to CA-125 in detecting recurrent ovarian cancer
Authors: Lewis Kelsey , Yeung Chi Lam Au , Mok Samuel , Lu Karen 
Published: July 2017

Abstract
Omentin (Intestinal Lactoferrin Receptor ITLN1) is an adipokine that is mainly secreted by the mesothelial cells lining visceral adipose tissues. It has been shown in previous studies that ovarian cancer cells down-regulate omentin which allows increased proclivity to spread to the omentum. Levels of serum omentin are decreased in patients with high-grade serous ovarian cancer (HGSOC) compared with patients with benign gynecologic diseases. Moreover, survival correlation studies showed that patients with lower serum omentin level at the time of first treatment experienced significantly shorter survival times than those with higher levels of omentin. CA-125 is currently the only biomarker used to monitor progression and re-occurrence of ovarian cancer. To our best knowledge, the relationship between omentin and CA-125 has not been investigated previously. We hypothesize that omentin may be a clinically useful adjunct to CA-125 in detecting recurrent ovarian cancer.
92 serum samples were collected prospectively from 27 HGSOC patients during the postoperative period until recurrence was detected. Patients had an average of 3.37 follow up visits and CA-125 levels were concurrently established. Recurrence was determined by imaging or an increase from baseline in CA-125 level. Samples were stored frozen at -80 degrees Celsius until use for this study. Circulating omentin levels were quantified using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The results showed that 24 patients experienced a rise in CA-125 level during the postoperative period and 12 of these patients had an associated decrease in serum omentin level (average = 127.8 ng/mL). A significant negative correlation between omentin and CA-125 levels was observed (p = 0.02).
This study provides the first evidence that omentin may be a clinically useful adjunct to CA-125 in detecting recurrent ovarian cancer and warrants further investigation.
Citation Format: Kelsey Lewis, Chi Lam Au Yeung, Samuel Mok, Karen Lu. Omentin as an adjunct to CA-125 in detecting recurrent ovarian 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 4661. doi:10.1158/1538-7445.AM2017-4661
Abstract 4687: Characterization of the cryoablation-induced immune response in kidney cancer patients
Authors: Kato Taigo , Iwasaki Tomoyuki , Uemura Motohide , Nagahara Akira , Higashihara Hiroki , Osuga Keigo , Ikeda Yuji , Kiyotani Kazuma , Park Jae-Hyun , Nonomura Norio , Nakamura Yusuke 
Published: July 2017

Abstract
Cryoablation is one of promising treatment modalities for kidney cancer and expected to induce strong local immune response as well as systemic T cell-mediated immune reaction that may lead to regression of distant metastatic lesions. In this study, we collected tumor tissues from 14 kidney cancer patients, at the time points of pre-cryoablation and 3 months after cryoablation. In addition, blood samples were collected from 8 kidney cancer patients at the same time points. We applied a next generation sequencing approach to characterize T cell receptor beta (TCRB) repertoires using mRNA isolated from tumor tissues and peripheral blood mononuclear cells. To assess clonality of T cells, the diversity index of TCRB was calculated according to complementarity-determining region 3 sequences. Through TCRB repertoire analysis, we demonstrated expansion of certain T cell clones in tumor tissues by cryoablation. In addition, we found that proportions of abundant TCRB clonotypes (≥ 1% frequency among total TCRB reads) were significantly increased in the post-cryoablation tissue samples than those of pre-cryoablation tumor samples, suggesting that cryoablation could induce strong immune reactions in tumors with oligoclonal expansion of anti-tumor T cells. Interestingly, some of these TCRB clonotypes were also increased in peripheral blood, indicating that certain numbers of T cell clones may also circulate systemically and then attack tumor cells in distant regions. We also measured mRNA expression levels of immune-related genes in the tissue samples of pre- and post- cryoablation and found significantly elevated expression levels of CD8, CD4, Granzyme A, and CD11c along with high CD8/FOXP3 ratio in the post-cryoablation tissue samples. Furthermore, immunohistochemical analysis confirmed infiltration of a large number of CD11c-positive cells, probably representing macrophages and dendritic cells into the post-cryoablation tissues. Collectively, our findings revealed that cryoablation could induce both local and systemic immune responses associated with CD11c-positive cells infiltration and oligoclonal expansion of anti-tumor T cells. For the translation into clinics, unique TCR sequences identified in post-cryoablation tissues in individual patients can be applied to personalized TCR-engineered T cell therapy.
Citation Format: Taigo Kato, Tomoyuki Iwasaki, Motohide Uemura, Akira Nagahara, Hiroki Higashihara, Keigo Osuga, Yuji Ikeda, Kazuma Kiyotani, Jae-Hyun Park, Norio Nonomura, Yusuke Nakamura. Characterization of the cryoablation-induced immune response in kidney cancer patients [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 4687. doi:10.1158/1538-7445.AM2017-4687
Abstract 4688: AVID200: a novel computationally-designed TGF beta trap promoting anti-tumor T cell activity
Authors: O'Connor-McCourt Maureen D. , Lenferink Anne E. , Zwaagstra John , Sulea Traian , Collins Catherine , Singh Renu , Durocher Yves , Cantin Christiane , Koropatnick James 
Published: July 2017

Abstract
AVID200 is a computationally-designed, avidity-enhanced, receptor ectodomain-based trap that binds and neutralizes TGF-beta 1 and 3 with low pM potency. Of the three TGF-beta isoforms, blockade of TGF-beta 2 has been shown to promote cancer metastasis. Therefore, AVID200 is designed to inhibit TGF-beta 1 and 3 only. TGF-beta is a strongly immunosuppressive molecule that, when expressed by cancers, mediates escape from immune surveillance. Increased TGF-beta ligand promotes cancer progression by suppressing anti-tumor immunity, predominantly by suppressing recruitment and activation of anti-tumor T cells. Consequently, TGF-beta is an important therapeutic target in cancer.AVID200 immunotherapy blocks the capacity of TGF-beta 1 and 3 ligands to interact with their receptors. That blockage induces T cell infiltration into tumors, thereby promoting a "T cell-inflamed" tumor state. Multiple trap formats with differing in vitro blocking potency, biophysical traits, and circulating half-lives in rodents have been designed, synthesized, and tested. On the basis of favorable characteristics, the AVID200 molecule was selected for in vivo assessment of efficacy in inhibiting growth of syngeneic 4T1 triple negative breast cancer (TNBC) homografts in immunocompetent host mice. In addition, CD4+ and CD8+ T cells isolated from draining lymph nodes of 4T1 tumor-bearing mice, treated and untreated with AVID200 and other candidate TGF-beta traps, were assessed for activities important in anti-tumor immune activity. We report that AVID200 immunotherapy decreased T-cell apoptosis, stimulated T-cell proliferation in response to tumor cell lysate-loaded dendritic cells, and enhanced the capacity of T-cells to specifically recognize and kill 4T1 tumor cells in ex vivo 2D cultures. The effect of combining AVID200 with immune checkpoint inhibitors in the treatment of syngeneic homografts in immune-competent mice is being assessed. AVID200 is a promising new immunotherapy to selectively inhibit the TGF-beta 1 and 3 isoforms, thereby enhancing desirable anti-tumor immunity while avoiding the tumor-promoting effects resulting from TGF-beta 2 neutralization.
Citation Format: Maureen D. O'Connor-McCourt, Anne E. Lenferink, John Zwaagstra, Traian Sulea, Catherine Collins, Renu Singh, Yves Durocher, Christiane Cantin, James Koropatnick. AVID200: a novel computationally-designed TGF beta trap promoting anti-tumor T cell activity [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 4688. doi:10.1158/1538-7445.AM2017-4688