bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 654: The epigenetic landscape of T cell exhaustion
Authors: Sen Debattama 
Published: July 2017

Abstract
Exhausted T cells in cancer and chronic viral infection have distinctive patterns of gene expression, including sustained expression of the inhibitory receptor PD-1, but the regulation of gene expression in exhausted T cells is poorly understood. Here we define the accessible chromatin landscape in mouse and human exhausted CD8+ T cells and show that it is profoundly different from functional memory CD8+ T cells. Exhausted CD8+ T cells in a mouse model of chronic viral infection acquire an extensive, state-specific pattern of enhancers, which are organized into functional modules. One enhancer, -23.8kb from the Pdcd1 locus, is found only in exhausted T cells and other lymphocytes with sustained PD-1 expression. Genome editing shows it to be required for high PD-1 expression. Cas9-mediated in situ saturation mutagenesis of the enhancer pinpoints critical minimal sequences that correspond to bound transcription factor motifs for RAR, T-bet and Sox3 in exhausted CD8+ T cells. State-specific enhancer profiles identified in mouse exhausted CD8+ T cells are conserved in human exhausted antigen-specific CD8+ T cells responding to HIV and HCV infection. Detailed functional enhancer maps of T cell exhaustion reveal state-specific regulatory sequences and offer targets for genome editing that could alter gene expression preferentially in exhausted CD8+ T cells.
Citation Format: Debattama Sen. The epigenetic landscape of T cell exhaustion [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 654. doi:10.1158/1538-7445.AM2017-654
Abstract 661: Evaluating "harmonization" of PD-L1 assays using image analysis
Authors: Martin Nathan T. , Black Joshua C. , Pollack Zachary , Aeffner Famke , Krueger Joseph 
Published: July 2017

Abstract
The current diagnostics landscape for therapeutics that target the PD1/PD-L1 pathway is highly complex. Four different companion or complementary diagnostics have been developed for pembrolizumab in NSCLC, nivolumab in NSCLC and melanoma, and atezolizumab in urothelial carcinoma. The need to reconcile diagnostics for this class of targeted therapies has been recognized by the creation of the FDA-AACR-ASCO “PD-L1 Blueprint” working group to explore means to “harmonize” PD-L1 testing in tissue based IHC assays. The results reported from this working group noted similarities, but also several important discrepancies, between the current assays. Since each test uses a specific interpretation for each assay and indication, this creates a highly complex diagnostic landscape, which is likely to continue to increase in complexity as more PD-1/PD-L1 therapeutics and potentially novel diagnostics continue to be approved in additional indications.
To address the need for adaptive, sustainable harmonization for PD-L1 diagnostics, Flagship Biosciences evaluated the utility of image analysis-based methods to harmonize multiple PD-L1 tests. We executed a proof-of-concept study utilizing a cohort of serial tissue sections from the same NSCLC patients, stained with the FDA approved Dako PD-L1 tests (28-8 and 22C3 clones), and our in-house PD-L1 assays (SP142 and E1L3N clones) for comparison. We digitized the tissue slides using a whole slide scanner, and evaluated the samples with our tissue Image Analysis (tIA™) technology. As expected, the patient samples stained with the separate PD-L1 assays yielded differences in staining and, thus, the reported scores for PD-L1 expression based on each test used, despite serial sections being derived from the same patient. To attempt to harmonize the scoring approaches for each test, we leveraged our computational Tissue Analysis (cTA™) platform to create a mathematically-derived “virtual slide score” for each sample, which enabled calibration of the various tests to deliver cross PD-L1 comparative scores. Based on the proof-of-concept demonstrated in this study, the cTA™ approaches could enable harmonization of the various PD-L1 tests through use of a digital pathology platform. The data presented provides a foundation for potential application of the cTA™ platform in the clinical laboratory setting to achieve harmonization of multiple PD-L1 tests.
Citation Format: Nathan T. Martin, Joshua C. Black, Zachary Pollack, Famke Aeffner, Joseph Krueger. Evaluating "harmonization" of PD-L1 assays using image analysis [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 661. doi:10.1158/1538-7445.AM2017-661
Abstract 663: Clinical performance and utilization of 3 PD-L1 immunohistochemical assays
Authors: Anderson Steven M. , Horten Bruce , McCune Bryan , Paler Ronald 
Published: July 2017

Abstract
Three different PD-L1 immunohistochemical (IHC) assays have recently been approved to help guide treatment decisions regarding anti-PD-1 (Keytruda®, Opdivo®) and anti-PD-L1 (Tecentriq®) immuno-oncology based therapies. The three assays differ in the primary monoclonal antibodies used, the assay platform (Dako, Ventana), scoring and interpretation criteria, and intended use. Our clinical laboratories currently offer all 3 assays (pharmDx™ 22C3, pharmDx™ 28-8, and SP142) because they are associated with different intended uses, companion and complementary diagnostics for non-small-cell lung cancer (NSCLC), and complementary diagnostic for urothelial carcinomas (UC). In the NSCLC samples evaluated in the first year since the approval of the two pharmDx™ assays, we have noted a higher percentage of positive samples with the pharmDx™ 28-8 assay (50%) compared to the pharmDx™ 22C3 assay (30%). This difference is mainly due to the use of different assay cutoffs associated with the two assays, as there is good correlation between the overall staining patterns, including the distribution of the percentage of tumor cells exhibiting positive staining. For the SP142 assay tested on UC samples, 22% of the cases were considered positive. All 3 assays are robust, with a limited number of samples considered inconclusive (&lt;10%), mainly due to an inadequate number of tumor cells. The companion diagnostic PD-L1 assay (pharmDx™ 22C3) has had the greatest utilization of the 3 assays, as it is required for the use of the Keytruda® in NSCLC samples. The performance features of the 3 different PD-L1 assays in the clinical laboratory setting has shown that all assays are robust and can be readily scored and interpreted by the pathology team. The utilization of the 3 assays correlates with respective intended use, tumor type and companion versus complementary diagnostic application, for each assay.
Citation Format: Steven M. Anderson, Bruce Horten, Bryan McCune, Ronald Paler. Clinical performance and utilization of 3 PD-L1 immunohistochemical assays [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 663. doi:10.1158/1538-7445.AM2017-663
Abstract 694: TK-216: a novel, first-in-class, small molecule inhibitor of EWS-FLI1 in early clinical development, for the treatment of Ewing Sarcoma
Authors: Selvanathan Saravana P. , Moseley Eric , Graham Garrett T. , Jessen Katti , Lannutti Brian , Üren Aykut , Toretsky Jeffrey A. 
Published: July 2017

Abstract
One of the most significant challenges in creating more potent, less toxic treatments for patients is to identify new cancer therapeutic targets that distinguish the malignant from normal cells. EWS-FLI1 is a well-established Ewing sarcoma (ES) oncogene that has the potential to be an ideal therapeutic target by directly impacting malignant cells. We have previously reported the discovery and characterization of YK-4-279, an enantiomer-specific inhibitor of EWS-FLI1, which has been demonstrated to induce apoptosis, inhibit EWS-FLI1 transcription, block RNA helicase A co-immunoprecipitation with EWS-FLI1, and result in alternative splicing to mimic EWS-FLI1 knockdown. Continuous efforts in structure-guided medicinal chemistry has yielded TK-216, an analog of YK-4-279 inhibitor of EWS-FLI1, which is 3-4 fold more potent with excellent drug-like properties. TK-216 potently inhibits the proliferation of ES cells. Induces apoptosis in a dose -dependent manner as measured by caspase-3 activity in multiple ES cell lines with distinct translocation variants. The effects of TK-216 on alternative splicing (AS) were further validated using genes including ARID1A, CLK1, CASP3, PPFIBP1 and RUNX2. The splicing pattern was similar between TK-216 and YK-4-279. In addition to the in vitro activity of TK-216 , we show that TK-216 displays anti-tumor activity in a number of ES xenograft models. In summary, TK-216, a novel, first-in-class therapeutic which directly inhibits EWS-FLI1, offers a promising approach for the treatment of Ewing Sarcoma and is currently in Phase 1 clinical trials in patients with relapsed or refractory Ewing Sarcoma (clinicaltrials.gov - NCT02657005).
Citation Format: Saravana P. Selvanathan, Eric Moseley, Garrett T. Graham, Katti Jessen, Brian Lannutti, Aykut Üren, Jeffrey A. Toretsky. TK-216: a novel, first-in-class, small molecule inhibitor of EWS-FLI1 in early clinical development, for the treatment of Ewing Sarcoma [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 694. doi:10.1158/1538-7445.AM2017-694
Abstract 982: Development of homogeneous dual-drug ADCs: Application to the co-delivery of auristatin payloads with complementary antitumor activities
Authors: Levengood Matthew R. , Zhang Xinqun , Emmerton Kim K. , Hunter Joshua H. , Senter Peter D. 
Published: July 2017

Abstract
A common theme in treating cancer is the use of combination chemotherapy, where multiple drugs with different mechanisms of action are combined to elicit synergistic activity or overcome differential drug sensitivities. Antibody-drug conjugates (ADCs) have emerged as a powerful approach for treating cancer, combining the tumor targeting specificity of monoclonal antibodies with the potent cell-killing activity of cytotoxic drugs. Like other therapies, these agents are increasingly being tested in combination with unconjugated, clinically approved anticancer agents. In addition, emerging data demonstrates that insensitivity to a particular ADC can be overcome through delivery of a different payload using the same antibody. For these reasons, the development of ADCs that can deliver two complementary payloads to a tumor would likely be a significant advancement in ADC technology. To enable dual-drug conjugation, we utilized a multiplexing drug carrier that contains cysteine residues with orthogonal protecting groups and identified novel conditions for utilization of these protecting groups on a folded protein. Sequential cysteine unmasking enables discrimination between conjugation sites to allow for site-specific drug conjugation. This strategy provides homogeneous ADCs bearing 16 total drugs per antibody, split evenly between the two drug linkers. Importantly, this strategy is flexible, as it does not require engineered antibodies or custom enzymes for drug-linker conjugation. To demonstrate the potential benefits of ADC dual drug delivery, this strategy was applied to the construction of ADCs bearing two classes of auristatin drug linkers that have different physiochemical properties and complementary anti-cancer activities. Dual-auristatin ADCs were tested in cell line and xenograft models that have differential sensitivities to the individual auristatin components, including those with heterogeneous antigen expression or high levels of drug efflux transporters. The data from these studies demonstrate that the dual-auristatin ADCs were active on cells and tumors that are refractory to treatment with either of the individual component drugs. This work highlights the potential for delivering two synergistic or complementary payloads on a single ADC and presents a flexible method for constructing dual-drug ADCs with site-specific and homogeneous drug loading.
Citation Format: Matthew R. Levengood, Xinqun Zhang, Kim K. Emmerton, Joshua H. Hunter, Peter D. Senter. Development of homogeneous dual-drug ADCs: Application to the co-delivery of auristatin payloads with complementary antitumor activities [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 982. doi:10.1158/1538-7445.AM2017-982
Abstract CT041: The clinical study on CD19-directed chimeric antigen receptor-modified T cells in patient with Richter Syndrome
Authors: Xia Leiming , Chen Qian , Li Qiao , Li Tan , Wang Yi , Bao Yangyi 
Published: July 2017

Abstract
Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma (mostly DLBCL). RS is a rare complication with unfavorable clinical outcome. There is no effective treatment for it currently. As a new type of cell-based immune therapy, chimeric antigen receptor modified T (CAR-T) cell treatment is now widely used in treating hematological malignancies, especially in CD19+ B cell malignancy. Therefore, CD19-directed chimeric antigen receptor modified T cells (CART-19) treatment is worthwhile to be developed as a new method for Richter Syndrome’s patients. In this study, the patient with Richter Syndrome expressing high level of CD19 was enrolled in a clinical trial. The patient had received a series of standard treatments with no therapeutic effect before 4.55 x 108 autologous CART-19 cells were infused, of which approximately 50% were transduced with the CAR. After CART-19 infusion, the main side effects were repeated fever, pancytopenia and significant rises of serum cytokines, including IFN-γ, IL-6 and IL-10. However, before discharge, the level of cytokines reduced to normal level. In addition, we detected K+, Ca2+, creatinine and glutamic-pyruvic transaminase, and found all of these were normal, which suggested that there was no significant tumor necrosis after treatment. The treatment included two courses. During the first course, the patient was infused with 4 x 107 CART-19 cells twice, followed by 1 x 108 cells in the 3rd infusion and then 1x106 cells in the 4th infusion. After these infusions, the proportion of B cells in the patient’s peripheral blood decreased from 72% to 40%, accompanied by reduced size of cervical, mediastinal and axillary lymph nodes. Eighteen days later, the patient was infused in the second course with 3.7x107 CART-19 cells twice, followed by 1x108 cells twice. After the second course, the proportion of B cells maintained at approximate 85%, and the lymph nodes enlargement was observed as disease progression. Based on the recent therapeutic landscape for hematological malignancies including B cell lymphomas, CD19-CAR T cell therapy may offer a new therapeutic option for RS, which aims to reduce the patients’ tumor burden, prolong their survival time, and provide opportunities for combined therapy with chemotherapy and bone marrow transplantation.
Note: This abstract was not presented at the meeting.
Citation Format: Leiming Xia, Qian Chen, Qiao Li, Tan Li, Yi Wang, Yangyi Bao. The clinical study on CD19-directed chimeric antigen receptor-modified T cells in patient with Richter Syndrome [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 CT041. doi:10.1158/1538-7445.AM2017-CT041
Abstract DDT01-02: AZD5991: A potent and selective macrocyclic inhibitor of Mcl-1 for treatment of hematologic cancers
Authors: Hird Alexander W. , Secrist J. Paul , Adam Ammar , Belmonte Matthew A. , Gangl Eric , Gibbons Frank , Hargreaves David , Johannes Jeffrey W. , Kazmirski Stephen L. , Kettle Jason G. , Kurtz Stephen E. , Lamb Michelle L. , Packer Martin J. , Peng Bo , Stewart Craig R. , Tyner Jeffrey W. , Yang Wenzhan , Ye Qing , Zheng XiaoLan , Clark Edwin A. 
Published: July 2017

Abstract
Mcl-1, a member of the Bcl/Mcl family, is a key protein involved in evasion of apoptosis in a wide variety of tumors. Its amplification and overexpression have also been implicated in innate and acquired resistance to anticancer drugs. Mcl-1 is capable of preventing induction of apoptosis, both by binding and inactivating the pro-apoptotic executioner Bcl-2 protein, Bak, as well as by sequestering other pro-apoptotic BH3-only proteins such as Bim and Noxa. AZD5991 is a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1. It demonstrates all the hallmarks of a true Mcl-1 inhibitor: 1. potent, selective, and rapid apoptosis in Mcl-1-dependent cell lines (e.g., GI50 as low as 10 nM in multiple myeloma cell lines); 2. loss of activity upon overexpression of Bcl-xL or siRNA-mediated knockout of Bak; 3. Mcl-1:Bak complex disruption as demonstrated by co-immunoprecipitation. AZD5991 is active in vivo, with complete (100%) tumor regression demonstrated in several mouse xenograft models after a single tolerated dose. We have also demonstrated synergistic in vivo efficacy in combination with standard-of-care agents. Analysis of ex vivo activity in primary samples from leukemia patients indicates that a high percentage of leukemia patients should respond to drug treatment, which supports our plan for a phase I trial of AZD5991 in patients with hematologic cancers.
Citation Format: Alexander W. Hird, J. Paul Secrist, Ammar Adam, Matthew A. Belmonte, Eric Gangl, Frank Gibbons, David Hargreaves, Jeffrey W. Johannes, Stephen L. Kazmirski, Jason G. Kettle, Stephen E. Kurtz, Michelle L. Lamb, Martin J. Packer, Bo Peng, Craig R. Stewart, Jeffrey W. Tyner, Wenzhan Yang, Qing Ye, XiaoLan Zheng, Edwin A. Clark. AZD5991: A potent and selective macrocyclic inhibitor of Mcl-1 for treatment of hematologic cancers [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 DDT01-02. doi:10.1158/1538-7445.AM2017-DDT01-02
Abstract LB-033: The transcriptional landscape of p53 signaling pathway
Authors: Matsuda Koichi , Tanikawa Chizu 
Published: July 2017

Abstract
Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53+/+ or p53-/- mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3,551 genes in one or more of the 24 tissues only in p53+/+ mice, while 2,576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation. Annotation using TCGA (The Cancer Genome Atlas) database revealed that p53 negatively regulated mRNA expression of several cancer therapeutic targets or pathways such as BTK, SYK, and CTLA4 in breast cancer tissues. In addition, stomach exhibited the induction of Krt6, Krt16, and Krt17 as well as loricrin, an epidermal differentiation marker, after the X-ray irradiation only in p53+/+ mice, implying a novel mechanism to protect damaged tissues by rapid induction of differentiation. Our comprehensive transcriptome analysis elucidated tissue specific roles of p53 and its signalling networks in DNA-damage response that will enhance our understanding of cancer biology.
Citation Format: Koichi Matsuda, Chizu Tanikawa. The transcriptional landscape of p53 signaling 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 LB-033. doi:10.1158/1538-7445.AM2017-LB-033
Abstract LB-053: Next-generation sequencing of T-cell receptor-beta gene rearrangements reveals dramatic expansion of T-cell clonotypes after CART-EGFRvIII therapy for glioblastoma
Authors: O'Rourke Donald M. , Chen Fang , Binder Zev A. , Kulikovskaya Irina , Gupta Minnal , Finklestein Jeffrey , Ambrose David E. , Nasrallah MacLean P. , June Carl H. , Lacey Simon F. , Melenhorst J. Joseph 
Published: July 2017

Abstract
We are interested in the T cell repertoire in glioblastoma (GBM) patients who have been administered peripherally infused CART-EGFRvIII adoptive T cell therapy for recurrent EGFRvIII-positive GBM. On neuropathologic evaluation following GBM tumor resection, we noticed that several subjects had a robust lymphocytic infiltrate in their tumors following CART-EGFRvIII infusion, which was out of proportion to the level of CART-EGFRvIII genomic sequences observed. We sought to quantify the T cell infiltrate in five subjects whose tumors were resected at different time points following CART infusion (days 6-104). In these five subjects, we analyzed the T cell clonotypic repertoire in the infusion product and in pre- and post-infusion brain tumor specimens by deep sequencing the T cell receptor (TCR) Vβ chain of tumor-infiltrating T cells. Data analysis was performed using ImmunoSeq and exported data were further examined using Graphpad Prism. The infusion products in these patients were highly polyclonal with no clones represented above 1%. We found that in all five of these subjects, the number and frequency of unique TCRVβ clonotypes increased by several thousand (~20-fold) in post-infusion GBM specimens, and only a small portion of these unique TCRs were shared with pre-existing tumor-infiltrating specific T cells (TILs). A consistent finding in these patients was that the clonotype compositional diversity of T cells in the tumor bed post-infusion was considerably larger than the pre-CART vs. infusion product sharing frequency. These data indicate there was a significant increase in the number and clonotypic diversity of tumor-infiltrating T cells following intravenous CART-EGFRvIII infusion, but only a small proportion appears to be derived from the infusion product. Collectively, these results show that CART infusion can trigger accumulation of TILs. Whether or not these TILs respond to GBM neoantigens remains to be investigated.
Citation Format: Donald M. O'Rourke, Fang Chen, Zev A. Binder, Irina Kulikovskaya, Minnal Gupta, Jeffrey Finklestein, David E. Ambrose, MacLean P. Nasrallah, Carl H. June, Simon F. Lacey, J. Joseph Melenhorst. Next-generation sequencing of T-cell receptor-beta gene rearrangements reveals dramatic expansion of T-cell clonotypes after CART-EGFRvIII therapy for glioblastoma [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 LB-053. doi:10.1158/1538-7445.AM2017-LB-053