bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1502: KRAS RNAi therapy in preclinical models of pancreatic cancer sensitizes tumors to checkpoint blockade by affecting the tumor microenvironment
Authors: Ganesh Shanthi , Shui Serena , Craig Kevin , Wang Weimin , Brown Bob D. , Abrams Marc 
Published: August 2019

Abstract
KRAS is one of the most frequently mutated oncogenes in pancreatic cancer. Recent research has revealed that activation of KRAS in cancer cells causes recruitment of immunosuppressive molecules to the tumor microenvironment (TME) and blocks T-cell mediated cytotoxicity. Despite huge progress in our understanding of KRAS and its role in tumorigenesis, direct pharmacological targeting of KRAS has thus far not been achieved. In these studies, we inhibited KRAS directly in tumor-bearing mice, using a potent and specific Dicer substrate siRNA (DsiRNA) formulated in tumor-selective lipid nanoparticles. We demonstrate that intravenously-dosed KRAS DsiRNA treatment results in reduction of multiple immunosuppressive signaling molecules, affecting recruitment of myeloid cells and regulatory T cells (Tregs) to the TME. In addition, effective KRAS inhibition reversed MEK-inhibitor-induced resistance in a model of KRAS mutant human PDAC. These data suggest that KRAS DsiRNA has potential to sensitize treatment-refractory PDAC tumors to both immune checkpoint blockade as well as conventional targeted therapeutics
Note: This abstract was not presented at the meeting.
Citation Format: Shanthi Ganesh, Serena Shui, Kevin Craig, Weimin Wang, Bob D. Brown, Marc Abrams. KRAS RNAi therapy in preclinical models of pancreatic cancer sensitizes tumors to checkpoint blockade by affecting the tumor microenvironment [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 1502.
Abstract 151: Comprehensive characterization of gastric cancer at single-cell resolution
Authors: Chen Jiamin , Sathe Anuja , Grimes Sue , Greer Stephanie , Lau Billy , Renschler Ann , Poultsides George , Suarez Carlos , Ji Hanlee 
Published: August 2019

Abstract
The gastric carcinoma cells have complex interactions with diverse cell types in the associated tumor microenvironment. The tumor microenvironment plays important roles on gastric cancer development, progression and therapy response. In this study, we leveraged high-throughput single-cell RNA sequencing (scRNAseq) to characterize the diverse cell population in gastric tumors.
In total, we analyzed more than 30,000 single cells from eight gastric tumors and matched normal tissues. Cells were sequenced at an average depth of 70000 reads/cell to guarantee sufficient coverage for downstream analysis. Using graph-based cell clustering methods and known cell markers, we identified heterogenous epithelial cells (PGC+, MUC5AC+, TFF1+, EPCAM+, CDH1+), fibroblasts (ACTA2+, THY1+, COLA1+), endothelial cells (VWF+, PECAM1+), and a variety of immune cells including M1 and M2 macrophages (IL1A+, IL1B+, TNF+, MARCO+, MSR1+, CD68+), CD4 T cells (CD3D+, CD4+), CD8 T cells (CD8A+), Gamma Delta T cells (TRGC2+, TRDC+), B cells (CD79+), and plasma cells (CD19+, CD20+, IgG+). Specifically, gastric epithelial cancer cells demonstrated distinct CNVs inferred from single cell transcriptome files.
We established and characterized patient derived gastric cancer organoids from single tumor cells. The organoids recapitulate CNVs found in the original gastric tumors and displayed varied degree of drug responses. We identified specific molecular features of the tumor microenvironment that modulate cell growth and immune responses. For example, we identified heterogenous myofibroblast populations with distinct chemokine secretory profiles compared to normal gastric tissue. We characterized gene signatures associated with immune checkpoints on T cells and targetable molecules in innate cells. Using cell type specific expression profiles, we were able to establish a comprehensive signaling network of tumor-tumor, tumor-stromal, stromal-stromal and stromal-tumor signaling via receptor-ligand pairing.
Citation Format: Jiamin Chen, Anuja Sathe, Sue Grimes, Stephanie Greer, Billy Lau, Ann Renschler, George Poultsides, Carlos Suarez, Hanlee Ji. Comprehensive characterization of gastric cancer at single-cell resolution [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 151.
Abstract 1524: CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation
Authors: Vidard Laurent , Dureuil-Sizaire Christine , Baudhuin Jérémy , Vescovi Lionel , Durand Laurence , Sierra Véronique , Parmantier Eric 
Published: August 2019

Abstract
To understand and dissect the mechanisms driving NK cell proliferation, we took advantage of the methodology used in cell therapy to numerically expand NK cells in the presence of K562-derived artificial Antigen Presenting Cells (aAPCs) and cytokines. For 9 consecutive weeks, high expression of CD137L by a K562-derived aAPC cell line was able to sustain NK cell expansion by 100 million-fold whereas low expression of CD137L by the parental K562 cell line supported the expansion by only 40,000-fold. The level of expression of CD137L, however, did not modulate the sensitivity of the K562 cell line to the intrinsic cytotoxicity of NK cells. Similarly, the low NK cell proliferation in the presence of the parental K562 cell line and cytokines was increased by adding agonistic anti-CD137 antibodies to levels similar to CD137L-expressing K562-derived aAPCs. Finally, the synergy between IL-15 and IL-21 was observed only upon CD137 engagement and the presence of aAPCs. Therefore, we conclude that NK cell proliferation requires cell-to-cell contact, the activation of CD137 axis, the presence of IL-15 (or its membranous form) and IL-21. By analogy with the three signals model required to activate T cells, we speculate, that the cell-to-cell contact represents “signal 1”, CD137 would be “signal 2” and cytokines would be “signal 3”. The precise nature of signal 1 remains to be defined.
Citation Format: Laurent Vidard, Christine Dureuil-Sizaire, Jérémy Baudhuin, Lionel Vescovi, Laurence Durand, Véronique Sierra, Eric Parmantier. CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation [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 1524.
Abstract 2302: Natural killer cell cancer therapy in mouse model
Authors: Huang Shih-Wen , Lai Yein-Gei , Wu Jen-Qi , Liou Yae-Huei , Liao Nan-Shih 
Published: August 2019

Abstract
Natural killer (NK) cells exert anti-tumor function through direct killing of tumor cells and indirect modulation of the function of other immune cells, such as T cells, dendritic cells and macrophages. However, the efficacy of adoptive NK cell transfer in cancer treatment has been limited, and only found in certain myeloid leukemia under allogeneic setting. The functional heterogeneity of NK cells and the immunosuppressive tumor microenvironment likely contribute to the limited efficacy. We establish a method to condition ex vivo expanded murine NK cells with anti-tumor activity. The conditioned NK cells are EOMES+CD127-DX5-CD49a+and CD11b+CD27+. Encountering with solid tumor cell lines in vitro enhances the production of IFN-γand triggers killing of the tumor cells by conditioned NK cells. In a syngeneic orthotopic EO771 breast cancer model, adoptive transfer of conditioned NK cells into tumor-bearing mice slows tumor progression and alters the composition and function of intra-tumor immune cells. To better imitate clinical condition, we transfer conditioned NK cells into tumor-resected mice, and found the therapy improved survival rate. We are investigating the anti-tumor mechanism of the conditioned NK cells.
Citation Format: Shih-Wen Huang, Yein-Gei Lai, Jen-Qi Wu, Yae-Huei Liou, Nan-Shih Liao. Natural killer cell cancer therapy in mouse model [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 2302.
Abstract 2328: BiTE-T cell: A novel design for solid tumor
Authors: Luo Feifei , Wang Yuedi , Liu Jie , Chu Yiwei 
Published: August 2019

Abstract
Genetically engineered T cells therapy is a promising strategy in cancer immunotherapy. Chimeric antigen receptor (CAR)-T cells therapy, as one successful strategy, has achieved the breakthrough and been approved in non-solid tumor but not solid tumor, which might be limited partially by CARs-restricted on cell surface and side effects of retrovirus. Meanwhile, bispecific T cell engager (BiTE), as another successful strategy, has been approved in non-solid tumor, the therapeutic limitation of which in solid tumor might be the short half-life of antibodies, the lack of endogenous effector T cells in patients with advanced cancer, and severe adverse effects. In this study, we developed a novel glypican-3 (GPC3)-targeting BiTE, αGPC3/CD3. These GPC3-BiTE engineered human T cells persistently produced GPC3-BiTE fusion proteins, which were released extracellularly to help both engineered T cell and bystander T cells to exhibit GPC3-specific activity. As a result, GPC3-BiTE-T cells could possess the capability of both CAR-T cells and BiTE, and even aid more than conventional CART cells in the CART-like function. In addition, GPC3+ tumor-bearing mice treated with the secretable GPC3-BiTE-T cells got a significant tumor growth inhibition and prolonged survival without observed adverse effect. Compared with control groups, more GPC3-BiTE-T cells with less PD-1 expression were detected at tumor site, which was similar to the GPC3-CART cell therapy. And the accumulation of GPC3-BiTE-T cells was positively related with the inhibition of tumor growth. Moreover, GPC3-BiTE-T cells assisted bystander T cells accumulated into tumor site in vivo, which was lack in GPC3-CART cell therapy. Thus, the novel GPC3-BiTE-T cells have the characteristics of high potency, long term and low toxicity, which might supply an attractive GPC3-targeting immunotherapy for solid tumors.
Citation Format: Feifei Luo, Yuedi Wang, Jie Liu, Yiwei Chu. BiTE-T cell: A novel design for solid tumor [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 2328.
Abstract 2358: Porphyromonas gingivalis promotes colorectal cancer development by regulating NLRP3 inflammasome signaling
Authors: Wang Zhi , Wang Xi , Jia Yiqun 
Published: August 2019

Abstract
Metagenomic analyses indicate that Porphyromonas spp. is associated with human colorectal carcinoma (CRC), however, whether this is an indirect or causal link remains unclear. We found that Porphyromonas gingivalis (P. gingivalis) were enriched in human stool or FFPE samples from colorectal carcinoma patients compared to colorectal adenoma or healthy subjects. Two colorectal cohort studies demonstrated that P. gingivalis infection was associated with poor prognosis of CRC. Moreover, in the ApcMin/+ mouse model of colorectal tumorigenesis, P. gingivalis increases tumor counts and in the orthotopic rectal MC38 carcinoma model increases tumor growth. Furthermore, tumors from orthotopic MC38 model exposed to P. gingivalis exhibited a tumor-infiltrating myeloid cells recruiting signature that was confirmed in human P.gingivalis-positive colorectal carcinomas. We next evaluated the role of NLRP3 in P. gingivalis promoting on CRC progression. When comparing with wild type mice, the increased tumor growth was subtracted in Nlrp3-/- mice by the same orthotopic MC38 model exposed to P. gingivalis. To determine relevant cell compartment responsible for NLRP3 function, we generated Nlrp3-/- chimeric mice with adoptive bone marrow transplantation by using the same orthotopic tumor model. The results showed the effect of NLRP3 on P. gingivalis pathogenesis was from both hematopoietic and non-hematopoietic sources. Additionally, we performed expression profile to show that NLRP3 attenuates multiple pathways associated with P. gingivalis promoting colorectal cancer development. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells by regulating NLRP3 inflammasome activity, P. gingivalis generates a proinflammatory microenvironment that is conductive for colorectal neoplasia progression.
Note: This abstract was not presented at the meeting.
Citation Format: Zhi Wang, Xi Wang, Yiqun Jia. Porphyromonas gingivalis promotes colorectal cancer development by regulating NLRP3 inflammasome signaling [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 2358.
Abstract 2367: Enhancing the efficacy of liver cancer immunotherapy by specific inhibition of histone deacetylase 8
Authors: Yang Wei-Qin , Zhou Jingying , Feng Yu , Cheung Ka Wing , Cheng Alfred Sze-Lok 
Published: August 2019

Abstract
The heterogeneous responses to immune-checkpoint blockade (ICB) therapy e.g. anti-programmed death-ligand 1 (PD-L1) antibody are attributable to the complex interplay between a range of cancer-cell-autonomous cues and the immunosuppressive tumor microenvironment. Two recent phase I/II trials of checkpoint inhibitors in patients with advanced hepatocellular carcinoma (HCC) have produced promising results, yet the objective response rates were relatively low (17-20%) as compared to other solid tumors such as melanoma and lung cancer (~40-60%). Accumulating evidence is underscoring the fundamental importance of epigenetic regulation in tumor immune evasion. We have previously elucidated a critical role of histone deacetylase 8 (HDAC8) in hepatic carcinogenesis (Cancer Research 2015;75:4803-16). Here, we aim to investigate the therapeutic potential of a HDAC8-specific inhibitor PCI-34051 in preclinical hepatocellular carcinoma (HCC) models. PCI-34051 significantly reduced HCC tumorigenicity in immunocompetent but not immunodeficient mice. Immune profiling revealed specific reduction in tumor-infiltrating regulatory T cells, which was associated with significant increase in CD8+ T cells. Notably, combined PCI-34051 and anti-PD-L1 treatment resulted in complete tumor eradication in all of the co-treated mice. Moreover, the combination therapy promoted long-term survival, which was associated with elevated CD8+ T effector and central memory cells. Our data suggest that selective chromatin modifications by HDAC8 alter the tumor immune surveillance program and demonstrate the potential of rational combinatorial epigenetic immunotherapy to fully unleash T-cell responses, leading to long-term remission of HCC. Acknowledgement: This work is supported by the RGC CRF (C4017-14G) and the Focused Innovations Scheme-Scheme B from the Chinese University of Hong Kong (1907309).
Citation Format: Wei-Qin Yang, Jingying Zhou, Yu Feng, Ka Wing Cheung, Alfred Sze-Lok Cheng. Enhancing the efficacy of liver cancer immunotherapy by specific inhibition of histone deacetylase 8 [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 2367.
Abstract 2368: Domatinostat increases apoptosis, G2M cell-cycle arrest and immunogenicity of Merkel cell carcinoma
Authors: Song Lina , Bretz Anne Catherine , Gravemeyer Jan , Spassova Ivelina , Hamm Svetlana , Muminova Shakhlo , Bartz Rene , Becker Juergen C. 
Published: August 2019

Abstract
Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer prevalent in elderly and immunocompromised patients. MCC is highly immunogenic as it is either associated with Merkel cell polyoma virus (MCPyV) integration or UV-associated mutations in non-viral cases. Indeed, immune checkpoint inhibitors (CPI) like PD-1/PD-L1 blocking antibodies exert a strong clinical activity; however, primary or secondary resistance often occurs. Domatinostat (4SC-202) is an orally available small molecule inhibitor targeting histone deacetylases (HDAC) class I currently in clinical evaluation to improve response to CPI (SENSITIZE, NCT03278665). In syngeneic tumor mouse models domatinostat treatment demonstrated immune-modulatory effects by increasing the intra-tumoral infiltration of cytotoxic CD8+ T cells (CTLs) and enhancing gene expression of a CPI response signature.
Immune escape mechanisms described for MCC include low intra-tumoral levels of CTLs and reduced expression of antigen-presenting MHC class I molecules. Our previous data suggest that low MHC-I levels are reversible and involve epigenetic silencing of genes encoding the antigen-processing machinery (APM). Here, we present novel preclinical data about the efficacy and mode of action of domatinostat in MCC. Global gene expression by single cell RNA-seq revealed regulation of genes involved, among others, in apoptosis and antigen presentation. Importantly, domatinostat additionally inhibited proliferation of MCC cell lines by induction of a G2M cell-cycle arrest and apoptosis. Moreover, expression of MCPyV-encoded transforming early genes, particularly during the G1-phase, was inhibited by domatinostat. Thus, it exerts also a direct anti-tumoral effect. In viable cells, domatinostat increases their susceptibility to immune responses, as qPCR and immunoblot analysis confirmed the induction of APM and MHC-I expression by domatinostat. APM and MHC-I expression has been reported to be restored by an epigenetic drug combination (vorinostat plus mithramycin). In contrast, we now provide evidence that the single agent treatment with domatinostat alone is sufficient for increasing immunogenicity of MCC cells.
In summary, domatinostat counteracts immune escape of MCC in many aspects suggesting a combination treatment of the HDACi domatinostat with CPI as a promising therapeutic strategy. Prospective clinical trials are needed to confirm this hypothesis.
Citation Format: Lina Song, Anne Catherine Bretz, Jan Gravemeyer, Ivelina Spassova, Svetlana Hamm, Shakhlo Muminova, Rene Bartz, Juergen C. Becker. Domatinostat increases apoptosis, G2M cell-cycle arrest and immunogenicity of Merkel cell carcinoma [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 2368.
Abstract 2390: FcgR co-engagement by anti-TIGIT monoclonal antibodies enhances T cell functionality and antitumor immune responses
Authors: Chand Dhan , Waight Jeremy D. , Paltrinieri Elena , Dietrich Sylvia , Bushell Mark , Costa Mathew , Gombos Randi , Wilson Nicholas S. , Buell Jennifer S. , Stein Robert B. , Duncan Alexander , Savitsky David A. 
Published: August 2019

Abstract
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) has emerged as an important regulator of the cancer-immunity cycle. Preclinical studies have demonstrated that TIGIT antibodies can enhance T and NK cell anti-tumor immunity, and therapeutic antibodies targeting TIGIT are advancing in the clinic. Nonetheless, questions on the optimal format for TIGIT therapeutics remain unresolved. Preclinical studies have demonstrated that anti-TIGIT antibodies enhance anti-tumor immunity by (1) blocking inhibitory signaling downstream of TIGIT/PVR and TIGIT/PVRL2 receptor-ligand interactions and (2) redirecting PVR/PVRL2 ligand binding to the co-stimulatory receptor CD226. Here we describe a novel and unanticipated mechanism of action of anti-TIGIT antibodies in which interactions between the antibody Fc domain and select FcγRs, particularly FcγRIIIA, dramatically improve T cell activation and effector function. In mouse tumor models, TIGIT antibodies that promote FcγR interactions enhance anti-tumor responses, whereas Fc-inert TIGIT antibodies show no such benefit. Moreover, TIGIT antibodies that enhance binding to human FcγRIIIA or mouse FcγRIV promote superior single agent activity and combination activity with other checkpoint modulators in antigen-stimulation assays and mouse tumor models respectively. Notably, this mechanism of action is independent of regulatory T cell depletion. Our findings support a dependence on Fc-FcγR interaction for promoting T cell responsiveness and effector function upon TIGIT antagonism. We further demonstrate that this novel mechanism also extends to anti-CTLA-4, but not anti-PD-1 or anti-LAG-3 antibodies. Altogether, our data describe a novel FcγR-dependent mechanism of action that may enhance the therapeutic activity of anti-TIGIT antibodies, deepen our understanding of this class of therapies, and inform on the optimal design for a new class of Fc-engineered antibodies that could be leveraged to potentially enhance antitumor immune responses.
Citation Format: Dhan Chand, Jeremy D. Waight, Elena Paltrinieri, Sylvia Dietrich, Mark Bushell, Mathew Costa, Randi Gombos, Nicholas S. Wilson, Jennifer S. Buell, Robert B. Stein, Alexander Duncan, David A. Savitsky. FcgR co-engagement by anti-TIGIT monoclonal antibodies enhances T cell functionality and antitumor immune responses [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 2390.
Abstract 2397: Pre-clinical evaluation of PE0116: A potent cross-linking depednet 4-1BB agonist antibody
Authors: Song Ningning , Li Zhengwu , He Shan , Yang Teddy , Duan Qing 
Published: August 2019

Abstract
4-1BB is a member of the tumor necrosis factor superfamily and plays a critical role in activation of cytotoxic T cells to promote anti-tumor immunity. As a co-stimulatory molecule, it is ideally suited for activation via agonist therapeutic antibodies in order to reactivate the immune system and promote cytolytic activity through CD8+ T cells. Clinical trials of two agonist antibodies (Urelumab and Utomilumab) are ongoing. Urelumab has shown clinical efficacy but been hampered by inflammatory liver toxicity at doses above 1 mg/kg, suggesting potential safety concerns at higher doses. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist. Hence, it may be necessary to achieve potent immune activation while avoiding limiting immune-related adverse events. PE0116 is a fully human monoclonal antibody generated from immunization of Harbour H2L2 human transgenic mice with recombinant human 4-1BB protein. It blocks the binding of 4-1BB to its ligand 4-1BBL and its activity in T cell activation is crosslinking dependent. After crosslinking, PE0116 strongly increases IFNg secretion from T cells in the presence of anti-CD3 antibody and its activity is superior to Utomilumab analog. More importantly, PE0116 has demonstrated robust anti-tumor activity and better potency than both benchmark antibodies in MC38 tumor model with human 4-1BB KI mice. PE0116 has also demonstrated good safety profile in a non-GLP safety study in cyno monkey. Currently the antibody is under late stage IND-enabling study. Its safety and efficacy will be further tested in patients.
Citation Format: Ningning Song, Zhengwu Li, Shan He, Teddy Yang, Qing Duan. Pre-clinical evaluation of PE0116: A potent cross-linking depednet 4-1BB agonist antibody [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 2397.