bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4096: Clinical study of personalized neoantigen-based cancer vaccine in the treatment of advanced SCLC patients with brain metastasis: A case report
Authors: Gao Song , Li Yongchao , Ding Zhenyu , Xu Heng , Wang Jiaqian , Guo Xianling , Fang Juemin , Wei Guochao , Qin Huanlong , Wei Yuquan , Xu Qing , Yang Li 
Published: August 2019

Abstract
Background: Tumor neoantigens arising from somatic mutations are less likely to be subjected to central immune tolerance and therefore the attractive targets for designing cancer vaccine. The personalized neoantigen-based cancer vaccine, a passive immunotherapy based on the theory of adaptive immune responses, has been developed rapidly in recent years.
Case Presentation: A 75-year-old male small cell of lung carcinoma (SCLC) patient with brain metastasis, who have experienced multiple chemotherapy resistance, and disease relapse after PD-1 therapy, was enrolled in this study. Whole-exome sequencing (WES) and RNA-seq were used to evaluate patient’s mutation burden and to predict the potential neoantigens. Twelve neoantigen peptides were selected and then were synthesized to generate autologous dendritic cell (DC)-based neoantigen vaccine. At last, 1.5 × 108 DC-based neoantigen vaccine was subcutaneously injected into the patient’s body to evaluate the treatment efficacy. By following-up to 10 months after vaccination, we observed an objective response with all brain metastases regressed. The immunogenicity of each of the 12 neo-epitope administered in this study was analyzed by IFNγ ELISpot in CD4+ and CD8+ T cells in pre- and post-vaccination blood samples. Responses were detected against 66.67% (8/12) of the predicted neo-epitope.
Conclusions: The autologous DC-based neoantigen cancer vaccine can effectively trigger a positive immune response to patients’ tumor and prolong patients’ survival. The vaccination can also augment the anti-tumor response of T cells by targeting other nonsynonymous mutation-derived neoepitopes. Therefore, these data demonstrated that the autologous DC-based neoantigen cancer vaccine is safe and effective in eliciting a broad antitumor immunity. Moreover, our work has introduced a framework for testing neoantigen-based vaccine combinatorial strategies in patients with advanced recurrent cancers.
Citation Format: Song Gao, Yongchao Li, Zhenyu Ding, Heng Xu, Jiaqian Wang, Xianling Guo, Juemin Fang, Guochao Wei, Huanlong Qin, Yuquan Wei, Qing Xu, Li Yang. Clinical study of personalized neoantigen-based cancer vaccine in the treatment of advanced SCLC patients with brain metastasis: A case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4096.
Abstract 4099: Intrinsic Tumor Cell Consequences of Acquired Resistance to PD-L1 Blockade
Authors: Shi Yuhao , Mastri Michalis , Dolan Melissa , Oberst Michael , Ebos John 
Published: August 2019

Abstract
The use of immune checkpoint inhibitors (ICIs) that block programmed cell death protein ligand 1 (PD-L1) binding to PD-1 have led to durable responses in multiple cancer types; however, a subset of patients eventually stop responding. Currently, few preclinical models faithfully recapitulate clinically-relevant acquired ICI resistance that could help identify second-line treatments. Here we describe the in vivo derivation of cells from orthotopically implanted mouse mammary EMT-6 primary tumors in mice that were initially responsive to PD-L1 inhibition but eventually developed resistance. Transcriptomic comparisons of in vivo-derived parental (EMT6P) and anti-PD-L1 resistant (EMT6PDR) cells revealed alterations in multiple signaling pathways controlling secretory profiles that govern metastasis and angiogenesis. Using a small molecule screen of ~1500 FDA approved cancer drugs, we found that anti-proliferative activity in EMT6PDR cells was decreased for ~120 compounds, including numerous receptor tyrosine kinase inhibitors (RTKIs) currently being tested in ICI-refractory patient populations. Molecular analysis indicated resistance-mediated secretory changes may be linked to intrinsic functions of PD-L1 on the resistant tumor cell which, in turn, may explain differential RTKI sensitivity. Subsequent studies show that EMT6PDR secretory changes can be interferon (IFN) mediated. Together, these results reveal that acquired resistance to PD-L1 blockade can result in PD-L1-regulated intrinsic tumor cell changes involving secretory proteins and controlled, at least in part, by IFN signaling. Current studies seek to assess the impact of these cellular changes on RTKI responsiveness to identify secondary treatments after ICI failure.
Citation Format: Yuhao Shi, Michalis Mastri, Melissa Dolan, Michael Oberst, John Ebos. Intrinsic Tumor Cell Consequences of Acquired Resistance to PD-L1 Blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4099.
Abstract 410: Quantification and downstream analysis of circulating tumor cells isolated using CapioCyteTM liquid biopsy
Authors: Poellmann Michael J. , Bu Jiyoon , Moon Dominic , Wagner Kyle , Wang Andrew Z. , Hong Seungpyo 
Published: August 2019

Abstract
Background: Circulating tumor cells (CTCs) have great potential as biomarkers for the diagnosis and prognosis of many cancers. The CapioCyteTM chip isolates live CTCs through a unique combination of biomimetic cell rolling and nanoparticle-mediated multivalent immunorecognition. Recently-published work reported the highly sensitive and specific CTC capture from 24 patients in a pilot study [Myung et al., Clinical Cancer Research 2018, 24(11):2439-2547]. Here, we report results from additional cohorts of patients and demonstrate downstream analysis of captured CTCs.
Methods: Peripheral blood samples were collected from patients undergoing radiotherapy (RT) (n=12; oligometastic n = 5, head and neck cancer n = 1, non small cell lung cancer n = 2, prostate cancer n = 3, cervical cancer n = 1) or immunotherapy (n=4). Samples were processed the next day by CapioCyteTM chips designed for the immunoisolation cells expressing epithelial cell adhesion molecule (EpCAM), human epidermal growth factor-2 (HER-2), and epidermal growth factor receptor (EGFR). Captured CTCs were identified by immunocytochemistry as containing round nuclei, positive expression of cytokeratin, and negative expression of CD45. Select samples were recovered from the capture surface and submitted for single cell gene expression assays (RNASeq) using 10X Genomics Chromium barcoding and Illumina next-generation sequencing.
Results: Immunocytochemical staining identified CTCs in all pre-treatment blood samples from patients undergoing RT (mean 95 CTC/ml whole blood, SE 54, range 4-680) and immunotherapy (mean 70 CTC/ml whole blood, SE 16, range 39-104). CTC counts decreased with time points collected during and post-treatment, consistent with other measures of treatment progress. Single cell RNASeq confirmed the presence of tumor-derived cells in select samples and, importantly, demonstrated the ability to conduct downstream analysis of CTCs isolated on the CapioCyteTM chip.
Conclusions: The CapioCyteTM chip effectively captures CTCs for quantification and downstream analysis requiring viable cells such as RNASeq. The liquid biopsy technology has great potential to contribute to diagnosis and personalized treatment of cancer.
Citation Format: Michael J. Poellmann, Jiyoon Bu, Dominic Moon, Kyle Wagner, Andrew Z. Wang, Seungpyo Hong. Quantification and downstream analysis of circulating tumor cells isolated using CapioCyteTM liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 410.
Abstract 4102: DNA methylation and repressive histones in the promoters of immune checkpoints in tumor tissues and peripheral blood of breast and colorectal cancer patients
Authors: Elkord Eyad , Nair Varun Sasidharan , Toor Salman M. 
Published: August 2019

Abstract
Higher expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and progression of cancer patients. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints (ICs) in cancer. We investigated transcriptomic expression of different ICs and some ligands including PD-L1 and galectin-9 in the tumor microenvironment (TME) and in circulation of primary breast cancer (PBC) and colorectal cancer (CRC) patients. We found that transcriptomic expressions of PD-1, CTLA-4, TIM-3 and LAG-3 in PBC and PD-1, CTLA-4, TIM-3, TIGIT, PD-L1 and galectin-9 in CRC were significantly upregulated in tumor tissues (TT), compared with normal tissues (NT). Additionally, expressions of TIM-3, TIGIT, and PD-L1 were significantly upregulated, while LAG-3 was downregulated in peripheral blood of both PBC and CRC patients. We then investigated the epigenetic modifications beyond this upregulation of immune checkpoint genes. Interestingly, we found that CpG islands in the promoters of PD-1, CTLA-4 and TIM-3 in PBC, and CTLA-4 and TIGIT in CRC patients were significantly hypomethylated in tumor compared with normal tissues. Notably, CpGs in PD-L1 promoter were completely hypomethylated in PBC and CRC in both TT and NT. In addition, PD-L1 was hypomethylated in in peripheral blood of both PBC and CRC patients, while TIGIT was hypomethylated only in circulation of CRC patients, compared with healthy donors. Next, we checked the abundance of repressive histones (H3K9me3 and H3K27me3) in the promoter regions of ICs/ligands. We found that in PBC TT, distribution of both H3K9me3 and H3K27me3 was lower in the promoters of PD-1, CTLA-4 and LAG-3, while distribution of only H3K27me3 was lower in TIM-3 promoter, compared with NT. Furthermore, in CRC TT, the distribution of H3K9me3 was lower in PD-1 and TIGIT promoters, and H3K27me3 was lower in CTLA-4 promoter, while both H3K9me3 and H3K27me3 were lower in TIM-3 promoter, compared with NT. Our data demonstrate that both DNA methylation and repressive histones are involved in upregulation of ICs and their ligands in the tumor microenvironment and peripheral blood of breast and colorectal cancer patients. These epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast and colorectal cancers.
Citation Format: Eyad Elkord, Varun Sasidharan Nair, Salman M. Toor. DNA methylation and repressive histones in the promoters of immune checkpoints in tumor tissues and peripheral blood of breast and colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4102.
Abstract 4113: Quantitative cell-based bioassays to advance immunotherapy programs targeting immune checkpoint receptors
Authors: Grailer Jamison , Gilden Julia , Stecha Pete , Garvin Denise , Wang Jun , Beck Michael , Hartnett Jim , Krishnan Gopal , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: August 2019

Abstract
The human immune system is comprised of a complex network of immune checkpoint receptors that are promising new immunotherapy targets for the treatment of a variety of cancers and autoimmune disorders. The Nobel prize for Medicine in 2018 was awarded for seminal studies on the role of immune checkpoint targets in T cell activation and furthermore, combining different strategies to release the brakes on the immune system with the aim of eliminating tumor cells even more efficiently. Immunotherapies designed to block co-inhibitory receptors (e.g. PD-1, CTLA-4, TIGIT) are showing unprecedented efficacy in the treatment of cancer. However, not all patients and tumor types respond to this approach. This has resulted in broadening of immunotherapy research programs to target additional co-inhibitory (e.g. LAG-3, TIM-3) and co-stimulatory (e.g. 4-1BB, GITR, OX40, ICOS) receptors individually and in combination.
A major challenge in the development of antibody-based biologics is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable and fail to yield data required for drug development in a quality-controlled environment. To address this need, we have developed a suite of cell-based functional bioassays to interrogate modulation of immune checkpoint receptors individually (e.g. PD-1, LAG-3, TIM-3, GITR, 4-1BB) and in combination (e.g. PD-1+CTLA-4, PD-1+LAG-3). These assays consist of stable cell lines that express luciferase reporters driven by response elements under the precise control of mechanistically relevant intracellular signals. Thus, the bioassays reflect mechanisms of action for the drug candidates designed for each immune checkpoint receptor and demonstrate high specificity, sensitivity and reproducibility. Here we describe the application of MoA-based immune checkpoint receptor bioassays as tools for biologics drug discovery, development, potency and stability studies.
Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays to advance immunotherapy programs targeting immune checkpoint receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4113.
Abstract 4116: Immune cell checkpoint profiling of solid tumors by multiplex immunofluorescence
Authors: Finan Amanda , Goulange Nicolas , Motte Manon , Tliba Maroua , Mace Alexandra , Coton Jean-Philippe , Lazzaro Domenico , Burrer Renaud 
Published: August 2019

Abstract
Immune checkpoint proteins are important regulators in self-tolerance. However, these same molecules also allow cancer cells to evade immune destruction. Checkpoint inhibitor (CKI) blockade therapies that aim at restoring antitumoral immunity have resulted in long-lasting remission in patients with cancers that were previously seen as incurable. However, only a fraction of the patients respond to these treatments. Research is currently focusing on identifying biomarkers that can predict a response to CKI therapies and stratify patient populations. As it is likely that several CKI need to be targeted at once to restore immune responses, numerous clinical trials associating more than one CKI are under evaluation. We have developed a multiplex immunohistochemistry panel, validated by in-depth image analysis, for immune cell checkpoint profiling. The base of the panel consists of CD3/CD8/PD-1/PD-L1 with the capability of adding additional targets including other immune checkpoint (e.g. TIGIT, SIRPα, CTLA-4) or tumor markers. Here we present our validation assay which uses the base panel and the ability to interchange the additional targets. Assay conditions for the individual biomarkers, including antigen retrieval, antibody concentration, panel position, and efficiency of stripping, are optimized. Simplex protocols are analyzed to ensure accuracy and specificity of the staining, success of stripping, and a balance of signal intensities. Validation includes the comparison of staining (% positive cells or % positive area) between a reference protocol and the position of interest. Multiplex optimization consists of staining serial, single stained slides of the individual biomarkers and the multiplex slide in parallel. The staining concordance (% positive cells) is evaluated with imaging software. Repeatability and robustness of the panels are validated by image analysis. This technique gives clinicians the potential to determine candidate patients for CKI single or double therapies and their progress during treatment. The established, rigorous workflow that we have developed allows our customers to adapt the panels to their needs and to have the highest confidence in the consequent images and results related to the profiling of immune cell checkpoints in solid tumors.
Citation Format: Amanda Finan, Nicolas Goulange, Manon Motte, Maroua Tliba, Alexandra Mace, Jean-Philippe Coton, Domenico Lazzaro, Renaud Burrer. Immune cell checkpoint profiling of solid tumors by multiplex immunofluorescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4116.
Abstract 4122: The regulatory mechanism of PD-L1 level through ER-associated degradation
Authors: Cha Jong-Ho , Yang Wen-Hao , Xia Weiya , Wei Yongkun , Chan Li-Chuan , Li Chia-Wei , Lee Heng-Huan , Hung Mien-Chie 
Published: August 2019

Abstract
Programmed death ligand-1 (PD-L1) is an important immune checkpoint molecule that allows cancer cells to evade immune surveillance. Further, the PD-L1 level is relatively higher in tumor tissues compared to normal tissues. Thus, the PD-L1/PD-1 axis has served as primary target for cancer immunotherapy. However, the regulatory mechanisms of PD-L1 level are not fully understood.
Here, we demonstrated that the ER-associated degradation (ERAD) mechanism of PD-L1 through cross-talking between phosphorylation and glycosylation. We discover that AMP-activated protein kinase (AMPK) activated by metformin directly binds with PD-L1 in the ER lumen and phosphorylates Ser 195 of PD-L1. The Ser 195 phosphorylation induces abnormal mannose-rich glycan structures of PD-L1 through excessive ER trimming process. PD-L1 with abnormal glycan structures is occupied by ER quality check components in the ER and finally degraded through ERAD pathway.
We provide new insights to understand cancer immune checkpoints by identifying a new regulatory mechanism of PD-L1 and these findings can be used to improve the efficacy of previous cancer immunotherapy for the PD-L / PD-1 axis.
Citation Format: Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Yongkun Wei, Li-Chuan Chan, Chia-Wei Li, Heng-Huan Lee, Mien-Chie Hung. The regulatory mechanism of PD-L1 level through ER-associated degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4122.
Abstract 4123: Clinical significance and the difference between programmed death-1 ligand-1 and ligand-2 in patients with esophageal cancer
Authors: Okadome Kazuo , Baba Yoshifumi , Yagi Taisuke , Kiyozumi Yuki , Eto Kojiro , Hiyoshi Yukiharu , Nagai Yohei , Ishimoto Takatsugu , Iwatsuki Masaaki , Iwagami Shiro , Miyamoto Yuji , Yoshida Naoya , Baba Hideo 
Published: August 2019

Abstract
Background: Immunotherapies targeting the PD-1/PD-L1 pathway have emerged as promising therapeutic strategies for many cancers. PD-L1 and PD-L2 are ligands of PD-1 on T-cells and prevent T-cells activation and proliferation. There have been reported that PD-L1 and PD-L2 are expressed on not only antigen-presenting cells but also some types of tumors. Clinical and prognostic features of the PD-L1 have been widely reported for many types of cancers but those of PD-L2 remain unclear in esophageal cancer. The aim of this study was to analyze the clinical significance and the difference between PD-L1 and PD-L2 in esophageal cancer.
Methods: Using a database of 437 curatively resected esophageal cancer from April 2005 to March 2016, we evaluated PD-L1 and PD-L2 expression in tumor cells by immunohistochemical staining and analyzed the association between those with clinicopathological features. Double immunohistochemical staining for PD-L1 and PD-L2 was performed to confirm the localization of each positive cell.
Results: Out of 437 cases of esophageal cancer, 69 cases (15.8%) showed PD-L1 positive and 71 cases (16.2%) showed PD-L2 positive expression. There was no significant relationship between PD-L1 and PD-L2 positive cases (p=0.18). In both PD-L1 and PD-L2 positive cases, double immunohistochemical staining for PD-L1 and PD-L2 showed that there was a heterogeneity for PD-L1 and PD-L2 positive tumor cell. PD-L1 positive cases were significantly associated with tobacco use (p=0.013), pathological stage (p=0.001), and preoperative therapy present cases (p=0.015). In the other hand, PD-L2 positive cases were significantly associated with younger age (p=0.029). Thus PD-L1 and PD-L2 patient characteristics were likely different. Overall survival rates of the patients with PD-L1 or PD-L2 positive were significantly worse than those with PD-L1 or PD-L2 negative (p=0.009 and p=0.013, respectively).
Conclusion: There was no significant relationship between PD-L1 and PD-L2 expression, and patient characteristics of those were different in patients with esophageal cancer. But both PD-L1 and PD-L2 expression were significantly associated with prognosis, supporting their roles as prognostic biomarkers.
Citation Format: Kazuo Okadome, Yoshifumi Baba, Taisuke Yagi, Yuki Kiyozumi, Kojiro Eto, Yukiharu Hiyoshi, Yohei Nagai, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Clinical significance and the difference between programmed death-1 ligand-1 and ligand-2 in patients with esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4123.
Abstract 4127: RX-5902 exhibits direct and immunomodulatory anti-tumor activities in melanoma PDX models
Authors: Eisen Andrew 
Published: August 2019

Abstract
Background: Nuclear β-catenin promotes deleterious processes in tumors and their microenvironment. Diminishing nuclear β-catenin attenuates these oncogenic processes. RX-5902 is an oral, small molecule inhibitor of β-catenin nuclear translocation mediated by phosphorylated p68 (DDX5). RX-5902 exhibits potent anti-cancer activity in many cancer cell lines, xenograft models in immunodeficient mice and immune competent mice and in patients. This study examines the relative contribution and context of the direct and immunomodulatory effects on the anti-tumor activities of RX-5902.
Methods: Four patient-derived melanoma xenograft models were implanted into either immunodeficient nude mice or NOG mice “humanized” with HLA unmatched CD34+ stem cells with average humanization of 36%. The PDX models were derived from 2 tumors that were clinically unresponsive to an anti-PD-1 agent and 2 tumors obtained prior to any immune treatment. In each category one tumor had BRAF WT and one a V600E mutation. Mice were randomized to receive either vehicle or RX-5902 at 5, 15 or 50 mg/kg po QDx5/Off x2 when implanted tumors reached 100-120 mm3 and began treatment when tumors reached 200mm3. Treatment lasted for 28 days and animals were observed for an additional 14 off therapy.
Results: The tumor growth inhibition data at 50 mg/kg is found in the table below. There was evidence of an immune contribution to the TGI in those tumors derived from subjects who did not benefit from I/O (Nivolumab) therapy. In each category the response was greater in tumors with WT BRAF.
Conclusion: RX-5902 provided greater TGI in the two melanoma PDX models derived from subjects who were resistant to I/O therapy compared to the models from I/O naïve subjects and, regardless, is greater in BRAF WT vs mutant tumors. The RX-5902 immune-mediated anti-tumoral activity may benefit the majority of melanoma subjects with limited response to BRAF-directed and/or I/O therapy.
Citation Format: Andrew Eisen. RX-5902 exhibits direct and immunomodulatory anti-tumor activities in melanoma PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4127.