bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1428: Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML cells
Authors: McEwan Brigid , Padalia Zinkal , Porras Ashley , Sagert Jason , Terrett Jonathan A. , Ho Tony , Kalaitzidis Demetrios 
Published: August 2019

Abstract
Acute myelogenous leukemia (AML) has a high mortality rate and remains difficult to treat, making new treatment approaches critical. Chimeric antigen receptor T (CAR-T) cell therapies have shown impressive clinical responses in B-cell neoplasia. However, comparable successes have not been reported to date in myeloid malignancies, potentially due to difficulty in manufacturing efficacious CAR-T cells from AML patients and lack of a suitable tumor antigen for AML. To address these issues, we have developed allogeneic CAR-T cells from healthy donors targeting the CD33/Siglec-3 antigen, a protein expressed on most AML cells and subpopulations in the majority of AML patients at presentation and relapse. Allogeneic anti-CD33 CAR-T cells were produced from healthy donor-derived T cells using CRISPR/Cas9 gene editing. In these cells, the TRAC locus was disrupted to reduce the risk of graft versus host disease (GvHD). At the same time, a CAR construct targeting CD33 was inserted site-specifically into the TRAC locus. In addition, the beta-2-microglobulin locus was disrupted to prevent clearance of the allogeneic CAR-T cells by the host immune system. These allogeneic anti-CD33 CAR-T cells showed potent effector activity in vitro against human AML-derived cell lines, as measured by both tumor cell lysis and effector cytokine secretion. The allogeneic anti-CD33 CAR-T cells also potently reduced AML tumors in vivo in xenograft mouse models.
Citation Format: Brigid McEwan, Zinkal Padalia, Ashley Porras, Jason Sagert, Jonathan A. Terrett, Tony Ho, Demetrios Kalaitzidis. Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML cells [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 1428.
Abstract 144: Characterization of glioma subtype-specific macrophage-tumor interactions using single-cell RNA-seq
Authors: Rao Rohit , Verma Ravinder , Wang Jincheng , Lu Qing Richard 
Published: August 2019

Abstract
Glioblastomas are malignant brain tumors that carry a poor prognosis. The tumor microenvironment has been identified as an important regulator of tumor growth and may represent a novel target for therapy. We have developed mouse models corresponding to two different glioma molecular subtypes, proneural and mesenchymal, to identify changes in microenvironment composition between glioma subtypes. We performed Drop-Seq on endpoint tumors from the proneural glioma model and found that tumor associated macrophages and microglia are the most prominent infiltrating microenvironmental population in proneural glioma. We profiled receptor-ligand interactions between tumor macrophages and tumor cells to identify the mechanisms by which macrophages regulate tumor growth. We identified several regulators previously published in the literature that regulate glioma growth such as pleiotrophin, Igf-1, and osteopontin, as well as some new candidate regulators prosaposin, oncostatin M and thrombospondin. Future directions include validation of tumor-microenvironment interactions using CRISPR activation in vitro, characterization of the tumor microenvironment in mesenchymal-like glioblastoma via single-cell RNA-sequencing, and changes in tumor microenvironment composition and function following treatment with chemotherapy or radiotherapy. A better understanding of tumor-microenvironment interactions in glioma will aid development of new therapies to promote tumor regression
Citation Format: Rohit Rao, Ravinder Verma, Jincheng Wang, Qing Richard Lu. Characterization of glioma subtype-specific macrophage-tumor interactions using single-cell RNA-seq [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 144.
Abstract 1458: Study on cervical cancer preventive effect of HPV vaccine in Japan
Authors: Nishimura Masato , Kagawa Tomohiro , Mineda Ayuka , Takiguchi Eri , Abe Akiko , Irahara Minoru 
Published: August 2019

Abstract
Objective: In Japan, side effects are emphasized and ingestion of HPV vaccine is not widespread. Meanwhile, the number of people suffering from cervical cancer has increased, and there is concern that deaths due to cervical cancer will increase. The objective of this study is to clarify the differences in the frequency of cytological abnormalities by presence or absence of HPV vaccination, sex hormone intake, and smoking history.
Methods: We examined each item described in medical questionnaire of a consultant who received cervical cancer screening in April 2015 - March 2016 and cytological diagnosis.
Results: There are 23,001 consultation examiners for 1 year. Of these, 3609 people aged 20-29, 6457 people aged 30-39 years old, 4433 people aged 40-49 years old were examined each item. With or without HPV vaccination, the frequency of cytological abnormalities (ASC-US and more) in 20-29 years old was 8/262 (3.1%), 121/3307 (3.7%), and there was no difference. Frequency of LSIL or more was significantly lower in vaccinates as 0/262 (0%) vs 70/3307 (2.3%) p&lt;0.05. There was no difference in the frequency of cytological abnormalities between the groups at 30-39 years old and 40-49 years old. With regard to the presence or absence of sex hormones, there was no difference in the frequency of cytological abnormalities in all ages. With smoking history, the frequency of LSIL or more was significantly higher in a group with smoking history, at the ages of 20-29 years (3.7% vs 1.4%) and 30-39 years (2.3% vs 1.2%).
Conclusion: If there is smoking history, it is important to undergo regular cervical cancer screening. In addition, HPV vaccination reduces the frequency of cytological abnormalities, so HPV vaccine is also important for the prevention of cervical cancer.
Citation Format: Masato Nishimura, Tomohiro Kagawa, Ayuka Mineda, Eri Takiguchi, Akiko Abe, Minoru Irahara. Study on cervical cancer preventive effect of HPV vaccine in Japan [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 1458.
Abstract 146: Multiple modalities of NanoString GeoMx™ Digital Spatial Profiler allow for spatially-resolved, multiplexed quantification of protein and mRNA distribution and abundance
Authors: Demirkan Gokhan , Viboch Elena , Merritt Chris , Ong Giang , Zevin Kristi , Sorg Kristina , Irving Lindy , Dunaway Dwayne , Geiss Gary K. , Beechem Joseph 
Published: August 2019

Abstract
Characterization of the spatial distribution and abundance of proteins and mRNAs with morphological context within tissues enables a better understanding of biological systems in many research areas, including immunology and oncology. However, it has proven difficult to perform such studies in a highly multiplexed manner. To address this unmet need, we have developed a novel optical-barcode based microscope and tissue-sampling platform designed to simultaneously analyze hundreds of proteins or mRNAs on a single FFPE section from distinct tissue spatial regions (GeoMxTM Digital Spatial Profiler, DSP).
Here, we present a series of modalities and associated applications for the GeoMxTM DSP platform and its integrated software. First, geometric profiling can be utilized by drawing automated circles, squares or even manual hand-drawn polygons as regions of interest (ROI) to characterize tissue heterogeneity. Second, gridded profiling offers high resolution unbiased tumor profiling by placing a grid on tissues and separately analyzing each segment in the grid. Third, contour profiling employs concentric rings, or any custom shape at a growing distance from a site of interest. Finally, segment and rare cell profiling exploits fluorophore-conjugated antibodies to profile specific cell types. These techniques can be used to discover drug mechanism of action or immune activation status, as well as to facilitate prediction of treatment response and disease progression or investigation of specific rare cell populations’ molecular profiles.
Using these multiple modalities, we spatially resolve protein and mRNA expression over 30 immune targets on FFPE tissue sections from various organs, including colon and tonsil. We demonstrate multiplexed detection from discrete regions within a tumor (tumor center and immune invasive margin), enabling systematic interrogation of immune activity in FFPE samples. Finally, we present the utility of each modality under different scenarios.
Citation Format: Gokhan Demirkan, Elena Viboch, Chris Merritt, Giang Ong, Kristi Zevin, Kristina Sorg, Lindy Irving, Dwayne Dunaway, Gary K. Geiss, Joseph Beechem. Multiple modalities of NanoString GeoMx™ Digital Spatial Profiler allow for spatially-resolved, multiplexed quantification of protein and mRNA distribution and abundance [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 146.
Abstract 1460: Generation of a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine, improves anti-tumor immunity and long-term memory T-cell generation
Authors: Tahiliani Vikas , Miriyala Jayalakshmi , Dillon Patrick , Rose Jason , Giffin Louise , Hutchins Jeff , Seavey Matthew M. 
Published: August 2019

Abstract
Our technology is focused on developing a next generation cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-cell costimulation (OX40L-Ig), into a single tumor cell line that secretes both. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma cell line, stably transfected to express gp96-Ig is being tested in a phase 1/2 clinical trial (NCT#02439450) with checkpoint inhibition for NSCLC. A similar line is being generated that will complement HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines and established an analogous system, that treats tumor-bearing animals with tissue-matched irradiated cancer cell lines (B16F10) expressing gp96-Ig (mHS-110) and OX40L-Ig (mHS-130) both expressing ovalbumin, as our model tumor-associated antigen. Single dose vaccination with mHS-110 identified that 1 to 10 million cells (290 ng to 2,900 ng of secreted gp96-Ig) provided sufficient anti-tumor CD8+ T-cell expansion, in vivo (*p&lt;0.01; 1-way ANOVA), with the greatest expansion observed on day 7, post-immunization. To identify the best ratio of mHS-110 to mHS-130; a dose ratio study was performed. Fixed numbers of mHS-110 (1 million cells, 290 ng of secreted gp96-Ig) were matched with different ratios of mHS-130. Similar to our single dose vaccination study, our results demonstrated that the peak CD8+ T-cell expansion occurred on day 7 post-immunization, and that the addition of mHS-130 further boosted anti-tumor CD8+ T-cell expansion by 3-fold when the ratios of mHS-110 to mHS-130 were at a 1-to-1 ratio (290 ng of secreted gp96-Ig to 290 ng of secreted OX40L-Ig) (*p&lt;0.05, Mann-Whitney). These animals were subsequently boosted 14-days post-immunization, and we similarly found that the 1-to-1 ratio of mHS-110 to mHS-130 gave the maximum expansion of CD8+ T cell responses, peaking on day 21 and contracting thereafter (*p&lt;0.05; Mann-Whitney). Importantly, these ratios led to high frequencies of IFNγ+ antigen-specific CD8+ T cells at both priming and boosting, which enhanced rejection of established B16F10 tumors and increased overall survival.
Citation Format: Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Jason Rose, Louise Giffin, Jeff Hutchins, Matthew M. Seavey. Generation of a novel, allogeneic cell-based, Gp96-Ig/OX40L cancer vaccine, improves anti-tumor immunity and long-term memory T-cell generation [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 1460.
Abstract 1466: Combination immunotherapy successfully control tumor growth in a transgenic mouse model
Authors: Lim Kue Peng , Zainal Syafinaz , Zulaziz Natasha , Gan Chai Phei , Chai San Jiun , Lye Bryan Kit Weng , Wang Chuan , Sutavani Ruhcha V. , Ottensmeier Christian , King Emma , Thomas Gareth , Savelyeva Natalia , Cheong Sok Ching 
Published: August 2019

Abstract
The use of checkpoint inhibitor anti-PD1 has achieved significant clinical benefit, in recurrent and metastatic head and neck cancer patients, where the overall response rate is between 16-20%. The use of antigen-specific cancer vaccine to increase the level of cytotoxic T cells is believed to work synergistically with anti-PD1. In this study, we evaluated the efficacy of antigen-specific DNA vaccine when it’s used in combination with anti-PD1. The B6.Cg-Tg(HLA-A/H2-D)2Enge/J mice bearing established tumours overexpressing the tumour antigen were vaccinated either with anti-PD1, DNA vaccine or anti-PD1 in combination with DNA vaccine. Tumour volume was monitored and antigen-specific immune responses were evaluated at the endpoint. Our data demonstrated DNA vaccine induced antigen-specific immune responses and animals vaccinated with DNA vaccine harboured smaller tumour volume compared to controls. Significantly, animals that received DNA vaccine expressed consistently higher levels IFN-γ and resulted in the upregulation of PD1 compared to control animals. We then demonstrated mice vaccinated with both DNA vaccine and anti-PD1 had near to complete tumour control, indicating a synergistic effect of DNA vaccine with anti-PD1. Animals treated with DNA vaccine in combination with anti-PD1 also have better overall survival. Importantly, these animals showed increased antigen-specific responses by the ELISPOT assay. In summary, our data suggest antigen-specific DNA vaccine works synergistically with anti-PD1 and conferred an excellent tumour control; this opens up a new opportunity of combinatory immunotherapy that might benefit a wider population of patients in an antigen-specific manner.
Citation Format: Kue Peng Lim, Syafinaz Zainal, Natasha Zulaziz, Chai Phei Gan, San Jiun Chai, Bryan Kit Weng Lye, Chuan Wang, Ruhcha V. Sutavani, Christian Ottensmeier, Emma King, Gareth Thomas, Natalia Savelyeva, Sok Ching Cheong. Combination immunotherapy successfully control tumor growth in a transgenic 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 1466.
Abstract 1468: Synergistic cancer immunotherapy combination of MVA-CD40L with tumor targeting antibodies or checkpoint blockade to achieve strong antitumor immune responses against large, established tumors
Authors: Medina-Echeverz Jose , Hinterberger Maria , Giessel Raphael , Bathke Barbara , Kassub Ronny , Fiore Giovanna , Chaplin Paul , Hochrein Hubertus , Lauterbach Henning 
Published: August 2019

Abstract
Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. In the present study, we exploit both innate and adaptive immune responses triggered by recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against large, established tumors in different combinatory settings. Therapeutic treatment with rMVA-CD40L resulted in the control or eradication of solid tumors in several unrelated tumor models. The expansion of non-exhausted, tumor-specific cytotoxic CD8+ T cells was essential for the therapeutic activity and was partially dependent on CD8α+ cross-presenting dendritic cells. Combination of rMVA-CD40L with PD-1 checkpoint blockade further enhanced the therapeutic activity of MVA virotherapy in colorectal carcinoma. In addition, rMVA-CD40L combined with antibodies targeting Tumor-Associated Antigens (TAA) resulted in increased therapeutic antitumor efficacy against two unrelated tumor models. We describe a translationally relevant therapeutic synergy between viral vaccination and CD40L costimulation. We show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combining immunotherapeutic regimes, such as checkpoint blockade and TAA targeting antibodies. This novel immunotherapeutic approach could translate into clinical cancer therapies where ADCC competent TAA targeting antibodies PD-1 checkpoint blockade are employed.
Citation Format: Jose Medina-Echeverz, Maria Hinterberger, Raphael Giessel, Barbara Bathke, Ronny Kassub, Giovanna Fiore, Paul Chaplin, Hubertus Hochrein, Henning Lauterbach. Synergistic cancer immunotherapy combination of MVA-CD40L with tumor targeting antibodies or checkpoint blockade to achieve strong antitumor immune responses against large, established tumors [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 1468.
Abstract 147: Deletion of the RNA regulator HuR in microglia/macrophages promotes an anti-tumor microenvironment in glioblastoma
Authors: Wang Jiping , Leavenworth Jianmei , Hjelmeland Anita , Borg Ben , King Peter H. 
Published: August 2019

Abstract
Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are a prime target, being drawn into the tumor and stimulated to produce factors that support tumor growth and immune system evasion. Here we show that the RNA regulator, HuR, plays a key role in the tumor-promoting response of microglia/macrophages. Knockout of HuR in microglia/macrophages led to reduced tumor growth and prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor associated macrophages were decreased, more polarized toward an M1-like phenotype, and had attenuated PD-L1 expression. There was a concomitant reduction in tumor-associated polymorphonuclear myeloid-derived suppressor cells, but an increase in Treg cells. In vitro assays showed reduced migration of HuR-/- microglia toward secreted factors derived from glioblastoma cells, and a decrease in migration of glioblastoma cells toward secreted factors derived from HuR-/- microglia. The molecular response of HuR-/- microglia was altered including reduced CXCL1, 2, MMP2, PD-L1 and VEGF expression and an increase in CXCL10 and several MMPs. There was a mixed effect on cytokines and other factors associated with both proinflammatory and alternatively activated phenotypes. In summary, HuR is a key modulator of the tumor microenvironment in glioblastoma, promoting tumor progression through its molecular regulation of factors produced by microglia/macrophages. These findings underscore the relevance of HuR as a therapeutic target in glioblastoma.
Citation Format: Jiping Wang, Jianmei Leavenworth, Anita Hjelmeland, Ben Borg, Peter H. King. Deletion of the RNA regulator HuR in microglia/macrophages promotes an anti-tumor microenvironment in glioblastoma [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 147.
Abstract 1473: Dual oncolytic viral immunotherapy generates large polyfunctional tumour-specific CD8 + T cell responses that infiltrate immunosuppressive tumors
Authors: Stojdl David 
Published: August 2019

Abstract
Generating effective T cell mediated clearance of solid tumors remains an unmet challenge in cancer therapy. Suppressive tumor microenvironments limit the generation of significant numbers of tumor specific T effector cells, their migration to tumor beds, and their subsequent functionality within tumors, thereby blocking the patient’s normally potent acquired immune response from contributing to tumor control.
In an effort to meet this challenge, we have developed novel oncolytic viruses that were bioselected and engineered to cause cancer cell death through two distinct and complementary mechanisms-of-action, direct cancer lysis and tumor-antigen specific T cell generation. Specifically, we have selected and engineered MG1 Maraba virus which both infects tumor tissue to reverse immune suppressive programs while simultaneously delivering vector encoded tumor antigens to the spleen to vaccinate against the patient’s tumor. The result is a large increase in peripheral and tumor infiltrating CD8+ T effectors cells, strong intratumoral inflammatory signatures and ultimately curative efficacy in preclinical solid tumor models. This first-in-class therapeutic strategy is currently being evaluated in Phase 1 and Phase 2 clinical trials.
In this new study, we describe the development of a novel viral immunotherapy platform based on Farmington virus that is: (1) oncolytic in solid tumor models, (2) a potent inducer of highly-functional antigen-specific T cells (expanding tumor specific CD8+ T effector pools over 1000 fold from pre-existing T central memory) and is (3) immunologically distinct from our clinical MG1 Maraba platform. We show that when used sequentially in a heterologous boosting regimen, T cell responses to encoded tumor antigens, either foreign (HPV E7), self (TRP2) or multi-neoantigen, can exceed greater than 50% of all CD8+ T cells in the periphery. The majority of these CD8+ T effectors show markers of polyfunctionality with little expression of the PD-1 exhaustion marker. We will describe our current data assessing the phenotype, localization and potency of these T cell responses in preclinical models of solid tumors and propose strategies to deploy our novel dual oncolytic viral immunotherapy boosting paradigm to the clinic.
Citation Format: David Stojdl. Dual oncolytic viral immunotherapy generates large polyfunctional tumour-specific CD8 + T cell responses that infiltrate immunosuppressive tumors [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 1473.