bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract NT-105: ANTI-TUMOUR EFFECTS OF ALL-TRANS RETINOID ACID, AN ANNEXIN A2-S100A10 PATHWAY INHIBITOR ON SEROUS OVARIAN CANCER
Authors: Lokman Noor A , Ho Rachel , Gunasegaran Kavyadharshini , Bonner Wendy M , Oehler Martin K , Ricciardelli Carmela 
Published: June 2021

Abstract
Annexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis. In combination with S100A10, annexin A2 plays an important role in the plasminogen activator system regulating plasmin production. The aim of this study was to investigate the potential utility of all-trans retinoid acid (ATRA), an inhibitor of the annexin A2-S100A10 signalling pathway, as a new therapeutic against serous ovarian cancer. Survival of serous ovarian cancer cells (OVCAR-3, OV-90, & OAW28) was significantly decreased by ATRA treatment (1-5µM). ATRA (1µM) also significantly decreased proliferation (Ki67 positivity, p=0.0034), S100A10 protein levels (p=0.0273), and increased cell apoptosis (cleaved caspase-3 positivity, p=0.0024) in serous ovarian cancer tissues using an ex vivo explant assay. In OAW28 cells, reduced cell survival following ATRA treatment was associated with a reduction of S100A10 protein levels, S100A10 and annexin A2 membrane localization, plasmin generation, motility and invasion. In contrast, ATRA inhibited OV-90 cell survival and invasion but did not affect plasmin activation or S100A10 and annexin A2 membrane localization or protein levels. These findings suggest that ATRA inhibits serous ovarian cancer proliferation and invasion via both S100A10 dependant and S100A10 independent mechanisms. Our results show that ATRA has promising potential as a novel therapy against serous ovarian cancer that warrants further evaluation.
Citation Format: Noor A Lokman,Rachel Ho, Kavyadharshini Gunasegaran, Wendy M Bonner , Martin K Oehler, Carmela Ricciardelli. ANTI-TUMOUR EFFECTS OF ALL-TRANS RETINOID ACID, AN ANNEXIN A2-S100A10 PATHWAY INHIBITOR ON SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-105.
Abstract TMIM-072: COMBINATIONAL TARGETING OF HDAC6 AND PD-1/PD-L1 IMMUNE CHECKPOINT IN ARID1A-MUTATED OVARIAN CANCERS
Authors: Fatkhutdinov Nail , Fukumoto Takeshi , Zhang Rugang 
Published: June 2021

Abstract
Ovarian clear cell carcinoma (OCCC) typically has a low response rate to platinum-based standard of care, and has no effective therapy for advanced stage disease. About 50% OCCCs harbor a mutation in ARID1A, a subunit of a SWI/SNF chromatin remodeling complex. We have previously demonstrated the dependence of ARID1A-mutated OCCCs on HDAC6 activity. In addition, ARID1A inactivation impairs mismatch repair, thus sensitizing ARID1A-mutated tumors to checkpoint blockade. However, anti-PD-L1 treatment only marginally improved the survival of ARID1A-deficient mice. We sought to determine whether combinational approach will improve efficacy of checkpoint blockade therapy in ARID1A-mutated OCCC. We combined HDAC6 inhibitor ACY1215 and PD-1/PD-L1 immune checkpoint blockade utilizing Arid1a-/-/Pik3caH1047R genetic ovarian clear cell model. Combination further prolonged mice survival as compared to single treatments and observed effects correlated with an increase in the activity of anti-tumor cytotoxic T-cells. In addition, we observed increase in dendritic cell infiltration following HDAC6 inhibition, suggesting of an increase in antigen presentation. Our findings indicate that combination of HDAC6 inhibition with PD-L1 checkpoint blockade could be a potential strategy for ARID1A-mutated OCCCs, not only eliminating ARID1A-mutated tumor cells but also restoring anti-tumor immunity.
Citation Format: Nail Fatkhutdinov, Takeshi Fukumoto, and Rugang Zhang. COMBINATIONAL TARGETING OF HDAC6 AND PD-1/PD-L1 IMMUNE CHECKPOINT IN ARID1A-MUTATED OVARIAN CANCERS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-072.
Abstract TMIM-083: A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER
Authors: Layek Buddhadev , Shetty Mihir , Starr Tim , Prabha Swayam 
Published: June 2021

Abstract
Current tumor targeted drug delivery systems suffer from a lack of selectivity for tumor cells. We propose a two-step tumor targeting strategy to improve the delivery of therapeutic agents to metastatic ovarian cancer. The two-step targeting approach relies on the introduction of non-natural targets (azide functional groups) in the tumor tissue, followed by the delivery of drug-loaded polymeric nanoparticles that are surface modified (with dibenzyl cyclooctyne; DBCO) and have high affinity for these synthetic targets. The objective of the present study was to determine the in vivo efficacy of two-step targeting in a clinically-realistic, patient-derived xenograft (PDX) model of ovarian cancer. The DBCO functionalized, paclitaxel (PTX)-loaded nanoparticles (16.2% w/w PTX; diameter 320 ± 10 nm; and zeta potential -11.5 ± 1.3 mV) were formulated using the FDA approved, biodegradable and biocompatible polymer, poly (DL-lactide-co-glycolide) (PLGA), by emulsion-solvent evaporation method. Glycoengineered mesenchymal stem cells (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Anticancer efficacy of MSC-Az mediated two-step targeting strategy was evaluated in female athymic nude mice bearing PDX tumors. Mice with generation 2 tumors were randomly divided into four groups receiving intravenous injection of saline, PTX solution, DBCO-PTX nanoparticles, and intravenous injection of MSC-Az followed by intravenous injection of DBCO-PTX nanoparticles (MSC-Az + DBCO-PTX). We observed significantly reduced tumor growth (p &lt;0.05) and improved survival in the group receiving MSC-Az + DBCO-PTX compared to all other groups. Furthermore, immunohistochemical analysis of the tumor tissues demonstrated that the animals treated with MSC-Az + DBCO-PTX had extensive necrosis compared to other groups, suggesting the potential of MSCs for improved tumor targeting and inhibition. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance tumor specific delivery of conventional chemotherapeutic drugs resulting in significantly improved anti–cancer efficacy.
Citation Format: Buddhadev Layek, Mihir Shetty, Tim Starr, Swayam Prabha. A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-083.
Abstract A37: Engineering armored TCR-modified T cells to enhance anti-tumor efficacy
Authors: Drakes Dylan J. , Rafiq Sarwish , Purdon Terence , Brentjens Renier 
Published: June 2021

Abstract
Clinical trials utilizing T cells genetically engineered to express a tumor-targeted T-cell receptor (TCR) illustrate the promise of this therapy in treating cancer patients. However, there are obstacles that must be overcome to improve the efficacy of TCR gene therapy. Two separate signals are needed to completely activate T cells and drive T-cell proliferation and differentiation. Co-stimulatory molecules present on the surface of cancer cells can become downregulated as an escape mechanism, thus depriving the T cells of complete activation and leading to T-cell apoptosis or anergy. This project aims to armor tumor-associated antigen-specific T cells with proinflammatory cytokines, specifically IL-12 and IL-18. We hypothesize that this genetic modification will provide an alternate form of co-stimulation that will augment antitumor efficacy. Tumor-associated antigen specific pmel-1 T cells transduced with retroviral constructs were shown to be more functional through increased secretion of IFNγ when co-cultured with antigen-positive tumor cells. Additionally, the armored pmel T cells were able to significantly enhance lysis of the B16F10 melanoma cell line in vitro. Subsequently, the in vivo efficacy of the armored T cells was assessed in a syngeneic, immune-competent B16F10 melanoma mouse model. The armored pmel T cells were confirmed to significantly delay the B16F10 tumor progression and enhance the survival of these mice in comparison to control pmel T cells. These results provide future insight into applying the concept of armored TCR T cells to a therapeutically relevant human tumor target to enhance TCR-modified T-cell antitumor responses.
Citation Format: Dylan J. Drakes, Sarwish Rafiq, Terence Purdon, Renier Brentjens. Engineering armored TCR-modified T cells to enhance anti-tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A37.
Abstract A46: Degradation of hyaluronan from the tumor extracellular matrix increases infiltration of CD8+ T cells and natural killer cells in an orthotopic pancreatic tumor model
Authors: Lee Jisook , Kimbler Trevor , Thompson Curtis , Thompson Benjamin J. 
Published: June 2021

Abstract
T-cell migration and infiltration in solid tumors is a critical step for maximizing the efficacy of many cancer immunotherapies. Hyaluronan (HA) is a glycosaminoglycan that accumulates in the extracellular matrix (ECM) of a range of solid tumors, including pancreatic ductal adenocarcinoma (PDA). PEGylated recombinant human hyaluronidase PH20, pegvorhyaluronidase alfa (PEGPH20; PVHA), is a novel, first-in-class biologic that enzymatically degrades HA in the tumor microenvironment (TME) and is in clinical development in combination with chemotherapy for the treatment of HA-accumulating tumors. Previously, in a murine PDA tumor model, we demonstrated that accumulation of HA restricts T-cell infiltration and promotes immunosuppression. In the present study, we hypothesized that degradation of HA by PEGPH20 would increase access of CD8+ T cells to the tumor. To test this hypothesis, Pan02 murine PDA cells were engineered to overexpress hyaluronan synthase 3 (Pan02-HAS3) and were implanted orthotopically into the pancreas. In Pan02-HAS3 tumors, HA accumulation was 53-fold higher (2606 ng/mg) compared with Pan02 parental tumors (50 ng/mg) as determined by HA ELISA. Degradation of HA in Pan02-HAS3 tumors with intravenous PEGPH20 as a single agent inhibited tumor growth by 58% at a dose of 0.0375 mg/kg and 73% at a dose of 1 mg/kg. Flow cytometric analysis of tumor-infiltrating immune cells in PEGPH20-treated tumors demonstrated a significant increase in the numbers of cytotoxic CD8+ tumor-infiltrating lymphocytes and natural killer (NK) cells versus control tumors. However, no changes in CD8+ T-cell proliferation were detected, as measured by Ki67 expression or bromodeoxyuridine (BrdU) incorporation. Degradation of HA in the TME was also associated with an increased frequency of CD103+ dendritic cells and a decreased frequency of immunosuppressive CD206+ tumor-associated macrophages. These data support prior reports that accumulation of HA in the TME restricts T-cell infiltration and promotes immunosuppression, and that PEGPH20 treatment may facilitate access of CD8+ T cells and NK cells into tumors. These findings are consistent with prior studies and support the ongoing clinical evaluation of combining PEGPH20 with immune checkpoint inhibitors to improve antitumor efficacy in HA-accumulating tumors.
Citation Format: Jisook Lee, Trevor Kimbler, Curtis Thompson, Benjamin J. Thompson. Degradation of hyaluronan from the tumor extracellular matrix increases infiltration of CD8+ T cells and natural killer cells in an orthotopic pancreatic tumor model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A46.
Abstract A79: Myeloid-lymphatic endothelial progenitors significantly contribute to lymph node metastasis in clinical breast cancer
Authors: Volk-Draper Lisa , Patel Radhika , Bhattarai Nihit , Yang Jie , Ran Sophia 
Published: June 2021

Abstract
Introduction: Lymph node (LN) metastasis, a key prognostic factor for poor survival of breast cancer (BC) patients, directly depends on lymphangiogenesis, i.e., formation of new lymphatic vessels. Using orthotopic BC models, we previously showed that lymphangiogenesis is strongly promoted by tumor-mobilized myeloid-derived lymphatic endothelial cell (LEC) progenitors (M-LECP) and that M-LECP density correlates with lymphatic metastasis. The goal of this study was to examine the density and a prometastatic role of M-LECP in clinical human BC.
Methods: Circulating CD14+ cells from BC patients (N=25) and healthy donors (N=24) were analyzed for expression of lymphatic-specific markers. Specimens from BC patients (N=104) along with normal mammary tissues (N=6) were co-stained with antibodies against myeloid and lymphatic markers including CD68, CD14, CD18 as well as LYVE1, podoplanin, and VEGFR-3. Sections were also double stained to identify LYVE1+ cells expressing lymphoid, M2-type macrophage, immunosuppressive, and stem cell markers. Densities of tumor CD68+ macrophages, LYVE1+ vessels, and CD68+/LYVE1+ double-stained M-LECP were quantified and correlated with node status and other parameters. Prometastatic potential of experimentally produced mouse M-LECP was determined by injecting in vitro differentiated myeloid-lymphatic cells into mice bearing syngeneic EMT6 breast tumors.
Results: 92% of BC patients had monocytes expressing at least one lymphatic marker compared to 2% of healthy donors. More than 70% of breast tumors contained M-LECP with density ranging from 2 to 50 cells per high-power field. Tumor-recruited M-LECP expressed specific markers of myeloid but not lymphoid lineages as well as M2-type, immunosuppressive and stem cell markers. Tumors with high density (&gt;20 cells/field) of M-LECP were significantly more likely to belong to aggressive subgroups (HER2+ and TNBC) and present with lymph node metastasis (P-value &lt;0.02).
Conclusion: These data show for the first time that human breast tumors recruit significant amounts of immature myeloid cells with immunosuppressive and lymphatic-promoting properties. Such cells are largely absent in normal breast tissues. Statistical analyses indicate that M-LECP can significantly contribute to formation of new lymphatic vessels and promote metastasis.
Citation Format: Lisa Volk-Draper, Radhika Patel, Nihit Bhattarai, Jie Yang, Sophia Ran. Myeloid-lymphatic endothelial progenitors significantly contribute to lymph node metastasis in clinical breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A79.
Abstract A93: Development of blocking antibodies to human CD47 with lower side effects on RBCs and platelets
Authors: Zhang Richard , Lin Haishan 
Published: June 2021

Abstract
CD47 is a major immune “checkpoint” molecule for macrophage activation. It is highly expressed on many types of cancers, including human acute myeloid leukemia (AML), non-Hodgkin’s lymphoma (NHL), and solid tumors such as small-cell lung cancer (SCLC). Binding of CD47 to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. CD47 overexpression is considered to be one of the mechanisms cancer cells employ to evade immune surveillance and correlates with poor prognosis in cancers. Several strategies have been used to block CD47 binding to SIRPα, including anti-CD47 blocking antibodies and SIRPα Fc proteins. However, since CD47 is also expressed on normal cells, a major concern is that these anti-CD47 antibodies may also induce platelet aggregation and red blood cell hemagglutination. In addition, since anti-CD47 antibodies bind to many different cell types in the peripheral circulation, the half-life for these antibody drugs could be lower. Here we report the generation and characterization of a panel of high-affinity anti-human CD47 blocking antibodies. The lead antibodies bound to human CD47 with sub-nanomolar affinities and displayed a range of activities in blocking CD47/SIRPα interaction. These antibodies showed robust activities in stimulating macrophage-mediated phagocytosis of cancer cells. Importantly, our antibodies did not induce red blood cell hemagglutination in in vitro assays. One of the lead antibodies demonstrates pH- dependent binding to human CD47. It has lower binding affinity to human CD47 at neutral pH but higher binding affinity to CD47 at more acidic pH, suggesting that this antibody may preferentially bind to CD47 in tumor microenvironment. Currently we are evaluating these anti-CD47 antibodies in preclinical efficacy and safety models.
Citation Format: Richard Zhang, Haishan Lin. Development of blocking antibodies to human CD47 with lower side effects on RBCs and platelets [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A93.
Abstract A95: A genome-wide CRISPR screen identifies novel ligands for the Siglec family of glyco-immune checkpoint receptors
Authors: Wisnovsky Simon , Bertozzi Carolyn 
Published: June 2021

Abstract
Cancer cells are frequently characterized by extensive remodeling of their cell surface glycocalyx, the complex pattern of sugar modifications that decorate cell surface proteins. In particular, cancer cells often overexpress an unusually high density of sialic acid glycans on their plasma membrane. This modification shields tumors from immune detection through engagement of inhibitory Siglec (Sialic acid-binding immunoglobulin-type lectin) receptors, which are widely expressed in innate immune cells. Blockade of these Siglec-based immune checkpoints has shown the potential to increase immune activity against highly sialylated cancer cells. The specific glycosylated ligands that serve as counter-receptors for Siglecs, however, are not well characterized. Here we describe a strategy for better defining these immune checkpoints using a CRISPR-based genetic screening approach. A library of gRNAs was screened using FACS to identify genes whose ablation significantly reduced cell-surface binding of recombinantly expressed, fluorescently labeled Siglecs. We thereby generated a list of genes with putative roles in driving the cell-surface expression of sialic acid-containing Siglec ligands. Our screen correctly identified known genes involved in sialic acid biosynthesis, validating the specificity of this approach. Additionally, this screen revealed that knockdown of a single heavily O-glycosylated protein plasma membrane protein dramatically reduced binding of Siglec7, the Siglec receptor expressed specifically in NK cells. Follow-up work has shown that Siglec7 binds to this ligand with high affinity and that genetic blockade of this interaction potentiates NK cell killing activity in vitro. This study has thus defined a novel and specific glyco-immune interaction with potential significance in driving tumor escape from innate immune surveillance.
Citation Format: Simon Wisnovsky, Carolyn Bertozzi. A genome-wide CRISPR screen identifies novel ligands for the Siglec family of glyco-immune checkpoint receptors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A95.
Abstract A96: Antigen-specific human CD4+ T cell clones as tools to characterize immunomodulatory receptor antibodies for immunotherapy
Authors: Li Sophie (Ying) , Le Saux Sabine , Shields Robert , de Waal Malefyt Rene 
Published: June 2021

Abstract
T-cell activation requires co-stimulatory signals that are provided by the interaction between Immuno-Modulatory Receptor (IMR) receptors and ligands expressed on the T cells and APC or tumor cells. Hence, an antigen (Ag)-specific human T-cell clone system was developed. It has been applied not only to study the biology of IMRs, but also to characterize the different biologics targeting those molecules as single agents or in combination to test improved efficacy. Data shown will include the establishment of alloreactive human CD4+ T-cell clones, FACS profiling IMRs of T-cell clones, engineering of different antigen presenting cells transfected with IMR ligands, and application of T-cell clones in characterization of anti-PD1 and anti-Lag3 antibodies
Citation Format: Sophie (Ying) Li, Sabine Le Saux, Robert Shields, Rene de Waal Malefyt. Antigen-specific human CD4+ T cell clones as tools to characterize immunomodulatory receptor antibodies for immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A96.
Abstract A99: Management of advanced melanoma: improved survival and barriers to access in a national cohort following the approvals of checkpoint blockade immunotherapies and targeted therapies
Authors: Dobry Allison , Zogg Cheryl , Hodi Stephen , Smith Timothy , Ott Patrick , Iorgulescu Bryan 
Published: June 2021

Abstract
Background: Immune checkpoint blockade (ICB) and BRAFV600-targeted therapy have demonstrated substantial clinical efficacy for patients with stage 4 melanoma in clinical trials; however, their impact on survival and barriers to treatment in the “real-life” setting remains unknown.
Methods: Patients who presented with cutaneous melanoma during 2004-2015 using the National Cancer Database, which comprises &gt;70% of all newly-diagnosed cancers in the U.S., were evaluated for predictors of presenting with stage 4 disease and receiving ICB, and the associated unadjusted and risk-adjusted overall survival (OS).
Results: 17,975 patients presented with stage 4 metastatic cutaneous melanoma. Overall, patients who presented after the FDA’s initial approvals (starting in 2011) for ICB and BRAFV600-targeted therapy demonstrated a 31% relative improvement in 4-yr OS (p&lt;0.001), compared to pre-2011. Following the initial approvals in 2011, improved OS was associated in risk-adjusted analyses with ICB (HR 0.57, 95CI: 0.52-0.63). ICB demonstrated improved median and 4-yr OS of 16.9 months (95CI: 15.6-19.3; vs. 7.7 months, 95CI: 7.2-8.4) and 32.4% (95CI: 29.5-35.3; vs. 21.0%, 95CI: 19.6-22.2, all p&lt;0.001), respectively; improved OS was persistent in unadjusted and risk-adjusted landmark survival analyses. Uninsured patients and management in the community setting were less likely to receive ICB in multivariable analyses.
Conclusions: In a national “real-life” treatment population, we show that the wide availability of the novel treatment modalities ICB and BRAFV600-targeted therapy has significantly improved the survival of patients with stage 4 melanoma. Our findings additionally suggest that there are opportunities for expanding coverage and access to these novel immunotherapies in community practice.
Citation Format: Allison Dobry, Cheryl Zogg, Stephen Hodi, Timothy Smith, Patrick Ott, Bryan Iorgulescu. Management of advanced melanoma: improved survival and barriers to access in a national cohort following the approvals of checkpoint blockade immunotherapies and targeted therapies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A99.