bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B059: Synergistic activation of antitumor immunity by an oncolytic virus VG161 armed with multiple immune-stimulating genes
Authors: Zhao Ronghua , Ding Jun , Choujenko Dmitry , Murad Yanal , Lee Erica , Liu Guoyu , Bu Luke , Jia William 
Published: February 2019

Abstract
Oncolytic viruses (OVs) are among the most powerful approaches in cancer immunotherapy. OVs not only cause cancer cell lysis but more importantly, their infection in tumors induces anti-tumor immune response from the host, resulting in lasting anti-tumor immunity. It has been recognized that anti-tumor immune response requires multiple immune regulatory factors that act synergistically and tumor microenvironment is critical for tumor to grow. Herpes simplex virus type-1 (HSV-1) has been approved by FDA as an oncolytic viral drug to treat melanoma. One advantage of HSV-1 is its large genomic capacity for carrying multiple exogenous genes.A HSV-1 oncolytic viral vector (VG161) was constructed to simultaneously express IL12, IL15 with its receptor alpha unit and a PDL-1 blocking peptide. Antitumor activity of VG161 was tested in both immune competent mice (CT26 and A20 tumor models) and nude mice for human tumor models (LNCaP and U87). Since CT26 and A20 are poorly permissive for HSV-1 replication, the mouse tumor models were able to demonstrate the antitumor immune response induced by VG161 while oncolytic activity of VG161 was demonstrated in LNCaP and U87 models since the immune system is compromised in those models.VG161 completely inhibited tumors in all the models tested and the animals survived tumor-free for many months till sacrificed. VG161 induced tumor oncolysis in both LNCaP and U87 tumors. In the CT26 model, animals were protected from the second challenging with CT26 cells following previous virally induced tumor regression. Furthermore, in a A20 double tumor model, intratumoral injection into the tumor on one side caused tumor regression on both sides. Transcriptome analysis showed significant change in tumor microenvironment. Finally, tumor specific memory T-cells were evident in the treated animals. The anti-tumor immune response by VG161 was significantly stronger than similar viruses that did not express any immune stimulating gene or only express GM-CSF. These results showed that intratumorally expressed multiple immune regulatory factors by an oncolytic virus may significantly change the tumor immune microenvironment to enhance efficacy of the oncolytic virus.
Citation Format: Ronghua Zhao, Jun Ding, Dmitry Choujenko, Yanal Murad, Erica Lee, Guoyu Liu, Luke Bu, William Jia. Synergistic activation of antitumor immunity by an oncolytic virus VG161 armed with multiple immune-stimulating genes [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B059.
Abstract B065: Tracking adipose-tissue Treg provenance, dependencies, and activities via T-cell receptor transgenic mice
Authors: Li Chaoran , DiSpirito Joanna R. , Zemmour David , Spallanzani Raul German , Kuswanto Wilson , Benoist Christophe , Mathis Diane 
Published: February 2019

Abstract
Recent epidemiologic and animal model studies indicate that overweight and obese individuals have increased risk of type-2 diabetes, cardiovascular diseases and certain types of cancer. It was suggested that chronic, low-grade inflammation of the adipose tissue, and eventually systemically, is one of the major causes for obesity-associated metabolic abnormalities and cancer. Regulatory T (Treg) cells located within parenchymal tissues safeguard tissue homeostasis and suppress inflammation. A paradigmatic “tissue-Treg” population is that found in visceral- adipose tissue (VAT) of male mice. VAT-Treg cells have a unique transcriptome, are clonally expanded, and promote metabolic health through effects on local immunocytes and adipocytes. Because of their rarity and inaccessibility, cardinal questions such as what factors control their accumulation in fat and when/where/how do they adopt their distinctive phenotype remained unanswered. We addressed these issues using VAT- Treg T-cell-receptor (TCR) transgenic mice and reporter mice for the diagnostic VAT-Treg transcription factor, PPARγ. Accumulation of VAT-Tregs was driven by combined effects of TCR specificity, Foxp3 expression, and a cell-intrinsic response to interleukin-33. Their characteristic phenotype emerged in two stages: a minority of splenic Treg cells weakly up-regulated a slice of the VAT-Treg transcriptional signature, reflecting cell activation, but the definitive phenotype, arming cells for fat survival, was manifest only in VAT. This deeper understanding of tissue-Treg generation should facilitate precision-targeting strategies.
Citation Format: Chaoran Li, Joanna R. DiSpirito, David Zemmour, Raul German Spallanzani, Wilson Kuswanto, Christophe Benoist, Diane Mathis. Tracking adipose-tissue Treg provenance, dependencies, and activities via T-cell receptor transgenic mice [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B065.
Abstract B078: Unbiased identification of CD4+ T-cell epitopes using novel MHC-based chimeric receptors
Authors: Kisielow Jan , Obermair Franz-Josef , Kopf Manfred 
Published: February 2019

Abstract
αβT-cell receptors (TCRs) bind peptide-major histocompatibility complexes (pMHC) with low affinity, posing a considerable challenge for direct identification of αβT-cell cognate peptides (epitopes). Here, we describe a platform for the discovery of MHC class-II presented epitopes, based on screening of engineered reporter cells expressing novel pMHC-TCR (MCR) hybrid molecules carrying cDNA-derived peptides. This technology identifies natural epitopes of CD4 T-cells in an unbiased and efficient manner and allows detailed analysis of TCR cross-reactivity providing recognition patterns on top of discrete epitopes. We identify cognate peptides of virus- and tumor-specific T-cells in mouse disease models and present a proof of concept for human T-cells. Furthermore, we show that vaccination with a peptide naturally recognized by TILs can efficiently protect from tumor challenge. Thus, the MCR technology holds promise for basic research and clinical applications allowing personalized identification of T-cell antigens in patients.
Citation Format: Jan Kisielow, Franz-Josef Obermair, Manfred Kopf. Unbiased identification of CD4+ T-cell epitopes using novel MHC-based chimeric receptors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B078.
Abstract B079: Evaluation of tools for predicting mutated tumor antigens from exome and RNA sequencing
Authors: Kodysh Julia , Finnigan John P. , Rubinsteyn Alex 
Published: February 2019

Abstract
Neoantigen vaccination is an emerging modality of cancer immunotherapy with many ongoing trials. One central question of neoantigen vaccination is the method for selecting which mutated tumor-specific antigens to include in a patient’s vaccine. Many in-silico pipelines for neoantigen selection have been published in the past few years, but no comprehensive evaluation has compared them directly on the same tumor/normal sequencing data. We evaluate several publicly available commonly used neoantigen pipelines (pVACtools [1], MuPeXI [2], TIminer [3], OpenVax [4]) on both murine and human cancer samples. Our evaluation highlights the salient differences between these pipelines and shows the divergent results they achieve. References: 1. Kiwala S, Hundal J, …, Griffith M. pVACtools: Computational selection and visualization of neoantigens for personalized cancer vaccine design. Cancer Genetics 2018. 2. Bjerregaard A-M, Nielsen M, ..., Eklund AC. MuPeXI: Prediction of neo-epitopes from tumor sequencing data. Cancer Immunology Immunotherapy 2018. 3. Tappeiner E, Finotello F, ..., Trajanoski Z. TIminer: NGS data mining pipeline for cancer immunology and immunotherapy. Bioinformatics 2017. 4. Rubinsteyn A, Kodysh J, …, Hammerbacher J. Computational pipeline for the PGV-001 Neoantigen Vaccine Trial. Frontiers in Immunology 2018.
Citation Format: Julia Kodysh, John P. Finnigan, Alex Rubinsteyn. Evaluation of tools for predicting mutated tumor antigens from exome and RNA sequencing [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B079.
Abstract B131: Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer
Authors: Schmidt Sarah , ElGazzar Ahmed , Bonilla Weldy V. , Pauzuolis Mindaugas , Reiter Andrea , Kleissner Theresa , Oeler Daniel , Stemeseder Felix , Berka Ursula , Kiefmann Bettina , Schulha Sophie , Matushansky Igor , Merkler Doron , Pinschewer Daniel , Orlinger Klaus 
Published: February 2019

Abstract
Active immunization against cancer requires the induction of exquisitely potent tumor-specific CD8+ T-cell (CTL) responses, which can be repeatedly boosted and reactivated. Hookipa Pharma engineered a replication-attenuated viral vector platform (TheraT®) based on the arenavirus lymphocytic choriomeningitis virus (LCMV), which meets these aforementioned criteria. Here, we present a preclinical data package of Hookipa´s lead immunotherapy product HB-201, targeting HPV16-driven head and neck cancer. It encodes a non-oncogenic version of the human papilloma virus 16 (HPV16) oncoproteins E7 and E6 (TheraT®-E7E6). Attenuation and safety of TheraT®-E7E6 were demonstrated by i) rapid viral clearance after systemic administration of the vector and ii) reduced neurovirulence in mice. TheraT®-E7E6 treatment was shown to induce substantial CD8+ T-cell expansion and high frequencies of E7- and E6-specific CTL responses with a balanced effector / central memory profile. These responses were boosted and reactivated upon TheraT®-E7E6 re-administration. TheraT®-E7E6 eradicated palpable TC-1 tumors, a syngeneic mouse tumor model of HPV-driven cancer. Even in mice with large tumors (~300mm3), TheraT®-E7E6 afforded significant tumor control and improved survival, with high frequencies of E7-specific CTLs persisting for several weeks. Furthermore, the efficacy of TheraT®-E7E6 can be potentiated in combination therapies, e.g., with PD-1 checkpoint inhibitors. In conclusion, replication-attenuated TheraT®-E7E6 is safe, highly immunogenic and shows excellent therapeutic efficacy as mono- or combination therapy in a preclinical model of HPV-induced cancer. Clinical trials for the treatment of HPV16+ cancers will be initiated in 2019.
Citation Format: Sarah Schmidt, Ahmed ElGazzar, Weldy V. Bonilla, Mindaugas Pauzuolis, Andrea Reiter, Theresa Kleissner, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Doron Merkler, Daniel Pinschewer, Klaus Orlinger. Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B131.
Abstract B138: Cancer immunotherapy with APOBEC3B-induced heteroclitic library tumor cell vaccines and immune checkpoint blockade
Authors: Vile Richard , Evgin Laura , Kottke Timothy , Schuelke Matthew , Driscoll Christopher B. , Huff Amanda L. , Thompson Jill , Molan Amy , Harris Reuben S. , Pulido Jose S. , Wongthida Phonphimon 
Published: February 2019

Abstract
We have previously shown that a vesicular stomatitis virus-based cDNA library expressing xenogeneic altered self-epitopes led to T-cell mediated rejection of prostate cancer, glioma and melanoma. The use of a library of altered self-peptides which reflects the transcriptome of the tumor circumvents the necessity for a priori knowledge of which antigens may be immunogenic in a patient, and primes a polyclonal T-cell response that provides strong cumulative antitumor selective pressure. We have expanded this concept of altered-self library vaccination using tumor vaccines modified by the overexpression of APOBEC3B, a cytosine deaminase that generates C to T transition mutations. A freeze-thawed whole tumor cell vaccine prepared from B16 melanoma cells stably overexpressing human APOBEC3B treated established subcutaneous parental B16 tumors and, when combined with PD-1 checkpoint blockade, cured between 75%-100% of mice. T-cells from mice treated with the vaccine and anti-PD1 produced high levels of IFN-γ when restimulated with parental unmodified B16 melanoma cells in vitro. Whole-genome sequencing of B16APOBEC3B overexpressing cells identified 301 C to T or G to A missense mutations unique to the APOBEC3B line. Using an in silico MHC binding affinity algorithm, we identified and experimentally validated a short list of 10 APOBEC3B- induced heteroclitic peptides. We have also shown that this approach can be extended to an orthotopic brainstem model of high grade glioma. GL261 tumors stereotactically implanted into the brainstem were significantly responsive to treatment with an APOBEC3B- modified GL261 vaccine in combination with anti-PD-1 checkpoint blockade. In summary, when overexpressed in tumor cells, APOBEC3B generates a library of heteroclitic sequences that primes both CD4 and CD8 T-cells that have escaped central tolerance and that recognize both newly mutated antigens from the vaccine, and the corresponding unaltered self epitopes expressed on the tumor cells.
Citation Format: Richard Vile, Laura Evgin, Timothy Kottke, Matthew Schuelke, Christopher B. Driscoll, Amanda L. Huff, Jill Thompson, Amy Molan, Reuben S. Harris, Jose S. Pulido, Phonphimon Wongthida. Cancer immunotherapy with APOBEC3B-induced heteroclitic library tumor cell vaccines and immune checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B138.
Abstract B141: Anti-tumor immune responses elicited by mesothelin virus-like particles vaccine effectively controls pancreatic cancer in animal models
Authors: Yao Qizhi Cathy , Poteet Ethen , Liang Zhengdong , Lewis Phoebe , Yu Zhiyin , Chen Changyi 
Published: February 2019

Abstract
Pancreatic cancer is the 12th most common cancer, but is the 3rd leading cause of cancer death in America. This disparity is directly related to three factors: the difficulty in early detection of the disease, pancreatic cancer’s resistance to chemotherapy, and a tendency for the cancer to metastasize early and quickly. Here, we propose a novel immunotherapy to bypass pancreatic cancer’s resistance to standard chemotherapy. We have developed a virus-like particle (VLP) based on an HIV backbone Gag and pancreatic cancer-associated protein mesothelin (MSLN). Vaccination of C57BL/6 mice with MSLN VLP can efficiently activate the immune system and reduce and in some cases eliminate the host’s pancreatic cancer. Our results show that MSLN VLPs induce both humoral and cytotoxic specific response against MSLN in mouse pancreatic cancer models. Specifically, after vaccination with MSLN VLPs, significant increases in CD8+ MSLN specific T-cells and increases in serum anti-MSLN IgG were detected. Furthermore, we observed an increase in the serum of pro-inflammatory cytokine IFN-γ and B cell stimulator IL-5. Consistent with the increased IL-5, we observed a significant increase in tumor infiltrating B cells in the MSLN VLP immunized groups, but neither Gag VLP control nor unimmunized mice. Furthermore, while all tumor-bearing mice generated some antibodies towards MSLN, our MSLN VLP immunized mice had significantly higher serum titers of IgG1, IgG2B, and IgG3. Both Gag VLP and MSLN VLP immunized mice had a decreased tumor volume compared to control, but passive transfer of sera only from MSLN VLP immunized mice decreased tumor volume and increased survival of unimmunized tumor bearing mice, while Gag VLP immunized mice had much less effect. Overall, we have developed a promising vaccine for pancreatic cancer warranting additional studies with adjuvants and combination treatments with standard-of-care chemotherapy.
Citation Format: Qizhi Cathy Yao, Ethen Poteet, Zhengdong Liang, Phoebe Lewis, Zhiyin Yu, Changyi Chen. Anti-tumor immune responses elicited by mesothelin virus-like particles vaccine effectively controls pancreatic cancer in animal models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B141.
Abstract B179: The regulation of silent apoptotic cell-clearance in tissue-resident macrophages
Authors: Pestal Kathleen , Barton Gregory M. 
Published: February 2019

Abstract
When normal, healthy cells die by apoptosis, they must be cleared to ensure tissue homeostasis. Failure to clear apoptotic cells (ACs) efficiently enables the release of inflammatory stimuli, such as nucleic acids, leading to tissue injury and, ultimately, autoimmunity. Clearance of ACs is largely performed by tissue-resident macrophages. Despite expressing many innate immune receptors, these cells do not respond to the potentially stimulatory ligands within ACs. Recently, the Barton Lab has identified several populations of AC-engulfing macrophages with many common features. These features include the expression of AC-recognition receptors and reduced TLR responsiveness to nucleic acids. The transcription factors KLF2 and KLF4 appear to contribute to this expression program both in vitro and in vivo in distinct AC-clearing macrophage populations. Macrophages that are removed from their environments lose this program and the program can be adopted by transferring TLR responsive macrophages into environments where endogenous silent residents are maintained. This coordinated silent immune program allows tissue-resident macrophages to maintain homeostasis while efficiently clearing ACs.
Citation Format: Kathleen Pestal, Gregory M. Barton. The regulation of silent apoptotic cell-clearance in tissue-resident macrophages [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B179.
Abstract B187: Origins of neoantigens for the major histocompatibility complex class I pathway
Authors: Sroka Ewa Maria , Martins Rodrigo Prado , Daskalogianni Chrysoula , Apcher Sebastien , Fahraeus Robin 
Published: February 2019

Abstract
Neoantigens are antigens generated by somatic mutations that can be recognized by the host immune system, firstl described as differentiating or tumor antigens back in 80s and 90s in research related to mice melanoma and breast cancers carried out by Houghton’s and Cheever’s teams, respectively. Now, during the era of potent immunotherapies, cancer vaccines and checkpoint inhibitors (CTLA-4, PD-1), neoantigens again attract much of scientists’ attention. With the use of cutting-edge technologies like next-generation sequencing, mass spectrometry, and predictive algorithms, more is known about antigen presentation and the links between occurrence of somatic mutations in cancer cells and antigen recognition by CD8+T-cells. Interestingly, discoveries of alternative sources of antigenic peptides (e.g., DRIPs and PTPs) challenged the notion about full-length proteins being the main supplier of material for MHC class I pathway and shifted focus of search for new sources to ribosomal scanning during pioneer round of translation. Despite the fact that pathways involved in processing and presentation of peptides have been thoroughly studied, there is still more to be learned about the sources of peptide material for the endogenous and exogenous MHC class I pathways. Based on works related to Epstein-Bar virus, it has been shown that MHC class I immune surveillance is directly correlated with the mechanism that regulates protein synthesis. Together with other results, it highlights the importance of pre-mRNA and mRNA processing in providing antigenic peptides for MHC class I surveillance. Here we revise some significant research related to the production of alternative antigenic peptides, their importance in cancer research, immunosurveillance and generation of tolerance. The lack of animal models to study the origin of alternative antigenic peptides hinders research in the field of neoantigens. I will describe results of the presentation of intron-derived antigenic peptides in mice model developed by our team.
Citation Format: Ewa Maria Sroka, Rodrigo Prado Martins, Chrysoula Daskalogianni, Sebastien Apcher, Robin Fahraeus. Origins of neoantigens for the major histocompatibility complex class I pathway [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B187.
Abstract B197: Translational control in macrophages during inflammatory response
Authors: Xiang Kehui , Bartel David P. 
Published: February 2019

Abstract
Translational control has been increasingly appreciated as a critical gene-regulatory mechanism during immune responses. Previous studies suggested that translation of select cytokines could be regulated by mRNA poly(A)-tail lengths in memory T-cells and macrophages. We carried out transcriptome-wide analysis with mRNA sequencing, ribosome-footprinting profiling as well as poly(A)-tail length profiling in both RAW264.7 cells and mouse thioglycollate-elicited peritoneal macrophages. No coupling between poly(A)-tail length and translational efficiency (TE) was observed in either cell type, arguing against a global translational-regulatory regime mediated by poly(A)-tail lengths. Immune activation with the treatment of lipopolysaccharides (LPS) to these cells did not change the uncoupled regime. Moreover, gene expression landscape in LPS-treated macrophages was dominated by mRNA level changes, with little contribution from TE changes. The up- or down-regulation of TE was not accompanied by concerted lengthening or shortening of poly(A) tails, implying existence of yet unclear translational control mechanisms in these immune cells. Finally, our studies in other biologic systems, including HeLa cells, Xenopus oocytes and yeast suggest that saturating levels of poly(A)-binding proteins might suppress poly(A) tail length-mediated translational control in various uncoupled systems, including immune cells.
Citation Format: Kehui Xiang, David P. Bartel. Translational control in macrophages during inflammatory response [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B197.