bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B093: Development of prediction software PrDx, trained on peptide-MHC stability assays, shows new important positions in the binding patterns of the peptides-MHC I and II complexes
Authors: Thorgrimsen Stephan , Justesen Sune , Rapin Nicolas 
Published: February 2019

Abstract
Mutations in cancer cells may lead to the formation of neo-epitopes potentially presented by both major histocompatibility complex (MHC) class I or II. These neo-epitopes may be recognized by CD8+ or CD4+ T-cells, and trigger an immune response. Only a small fraction of the neoepitopes will be displayed by the MHC class I or II. One of the challenges of cancer immunotherapy is therefore to predict which neoepitopes are susceptible to elicit a T-cell response. Software tools such as netMHC, MHC Flury and many others are over-predictive as the bulk part of the data used to train these methods are based on affinity assays. Several publications have indicated that stability assays may provide data that better correlate with epitope presentation by MHC. Prediction tools trained on stability assays may therefore be better at selecting neoepitopes resulting in more effective cancer vaccine design. We performed stability assay measurements for 10 MHC class I and 10 MHC class II alleles using a peptide scan library approach. In brief, random 9-mers where one position is known were used to measure stability of the peptide MHC complex. Next, the data were used to train a prediction tool, PrDx, that relies on a combination of different machine learning methods (random forest, feed forward neural networks and recurrent neural networks), of which the outputs are gathered in an assemble model. The model was then further trained with peptides predicted to bind with high stability, to the MHC alleles, until satisfactory performances were attained. To our surprise, PrDx showed new binding patterns for the alleles we trained. Although mostly similar to the binding patterns seen with affinity data trained method, the stability trained method is able to show new important positions in the binding patterns of the peptide-MHC complexes. Through retrospective analysis, our method seems able to select more accurately peptides susceptible to elicit a T-cell response, compared to state-of-the-art epitope prediction methods. Our results suggest that PrDx may be an attractive prediction tool for neo-epitopes discovery.
Citation Format: Stephan Thorgrimsen, Sune Justesen, Nicolas Rapin. Development of prediction software PrDx, trained on peptide-MHC stability assays, shows new important positions in the binding patterns of the peptides-MHC I and II complexes [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 B093.
Abstract B116: Nano-neo-mRNA vaccine: A novel platform technology for cancer-immunotherapy
Authors: Koyakutty Manzoor , Ramesh Navyashree A. , Nambiar Ashwathy , Anna Najuma Nujum Ambili , Abraham Manju C. , Anoop Minu , Ramkumar Anjana , Shanti Nair , Harish Vijay Harish , Ashokan Anusha 
Published: February 2019

Abstract
Nanoparticle-based immunotherapeutic platforms are emerging as radically different, biocompatible alternatives for viral-vectors. Liposomal nanoplexes already showed potential for clinical translation of mutanome specific personalized cancer-vaccines in human. Here, we report a novel nanoparticle platform technology for neoantigen specific mRNA (neo-mRNA) vaccine delivery and demonstrated its potential for evoking T-cell mediated immune response against drug/radiation resistant glioma cells. Glioblastoma multiforme (GBM) is one of the most aggressive type primary brain tumors with high rate of recurrence and poor prognosis. Temozolomide (TMZ) chemotherapy in concurrence with radiation is less effective for patients with over-expression of DNA repair protein, O6-methyl guanine-DNA methyltransferase (MGMT) or epidermal growth factor receptor variant III (EGFRvIII) mutation. Here, we developed a unique pathogen mimicking nanoparticle platform that can effectively encapsulate and transfect dendritic cells with mRNA vaccine specific to MGMT or EGFRvIII. MGMT/EGFRvIII mRNA was synthesized by in vitro transcription (IVT) from respective cDNA plasmid and 100-150nm sized nanoplex was formed with mRNA at the core with &gt;90% encapsulation efficiency. This Nano-neo-mRNA vaccineTM platform was successfully delivered to human monocyte derived DCs with a transfection efficiency of 35-50% compared to 3-5% in the case of naked mRNA. The transfected DCs showed significant phenotypic expression of MGMT-GFP with MHC I/II and CD80/86 co-activation compared to the naked mRNA or vehicle control. The efficiency of vaccinated DCs to prime cytotoxic T-cells was demonstrated in co-cultures where the nanoplex showed efficient activation of T-cell-mediated cytotoxicity on MGMT or EGFRvIII expressing, TMZ/radiation resistant glioblastoma cells . Biocompatibility of the nano-carrier was demonstrated in primary human cells and animal models. Thus, we present a new, biocompatible nanoparticle platform technology for IVT-mRNA based cancer-immunotherapy.
Citation Format: Manzoor Koyakutty, Navyashree A. Ramesh, Ashwathy Nambiar, Najuma Nujum Ambili Anna, Manju C. Abraham, Minu Anoop, Anjana Ramkumar, Nair Shanti, Vijay Harish Harish, Anusha Ashokan. Nano-neo-mRNA vaccine: A novel platform technology for cancer-immunotherapy [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 B116.
Abstract B119: DC-recruiting biomaterial vaccine to enhance antitumor immunity
Authors: Li Aileen W. , Dellacherie Maxence O. , Sobral Miguel , Ali Omr O. , Kim Jaeyun , Mooney David J. 
Published: February 2019

Abstract
Biomaterials have shown substantial potential to integrate synergistically with current cancer vaccine strategies and enhance their effectiveness. We recently developed an injectable biomaterial vaccine via spontaneous assembly of mesoporous silica (MPS) microparticles into a 3D scaffold in vivo. When formulated with GM-CSF and the TLR-9 agonist CpG, the MPS vaccine modulates host dendritic cell (DC) activation and trafficking. Here we demonstrate that a single injection of the MPS vaccine induced persistent germinal center B cell activity for over 30 days. Consequently, when immunized with a small linear Her2/neu peptide within the Trastuzumab binding domain, the MPS vaccine elicited over 2 orders of magnitude higher IgG1 and IgG2a antibody titer compared to a traditional bolus vaccine, and the antibody exhibited immunoreactivity on the native Her2 structure on breast cancer cells. To further enhance CTL responses against tumor antigens, we co-presented the antigen with polyethylenimine (PEI) in the MPS vaccine. PEI increased antigen cross-presentation in murine DCs, and TNF-a and IL-6 production in both murine and human DCs in vitro. Compared to the MPS vaccine, the MPS-PEI vaccine enhanced activated and antigen+ DCs in the vaccine and the vaccine draining lymph node by ~2 fold. Systemically, using both OVA and a HPV-E7 peptide as antigens, the MPS-PEI vaccine induced ~2.5 fold higher IFN-y producing antigen specific circulating CD8+ T-cells compared to the MPS vaccine. Impressively, using a HPV-E7 expressing tumor model, we demonstrated that a single injection of the MPS-PEI vaccine completely eradicated large established tumors in over 80% of mice. Finally, when immunized with a pool of recently sequenced B16 melanoma neoantigen peptides, the MPS-PEI vaccine induced potent therapeutic tumor growth control and synergy with anti-CTLA4 checkpoint blockade therapy. These findings suggest that the MPS vaccine may serve as a facile multifunctional and multi-epitope platform to modulate host immune cell function and augment personalized antitumor immunity.
Citation Format: Aileen W. Li, Maxence O. Dellacherie, Miguel Sobral, Omr O. Ali, Jaeyun Kim, David J. Mooney. DC-recruiting biomaterial vaccine to enhance antitumor immunity [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 B119.
Abstract B120: TIPE2 regulates apoptosis and autophagy to inhibit tumorigenesis in colon cancer
Authors: Li Jun , Xia Xiaoli 
Published: February 2019

Abstract
TIPE2 is an important immune negative regulator which regulates innate immunity and adaptive immunity to maintain immune homeostasis. Abnormal expression of TIPE2 is related to many acute and chronic inflammatory diseases, as well as the tumorigenesis. Here, we identified that overexpression of TIPE2 in colon cancer cell line inhibited cell growth. Recombinant adenovirus-expression TIPE2 effectively inhibited the proliferation of several kinds of cancer cell. Using protein biochip ananlysis, we found that in the TIPE2-overexpressing colon cancer cell, the expression levels of phosphorylated p38-MAPK/JNK, pro-apoptotic survivin were downregulated. These results suggest TIPE2 regulates tumor cell growth though p38-MAPK/JNK pathway. Western blot analysis showed that the proliferation level of AKT and the expression level of Bad were also changed in the TIPE2-overexpressing colon cancer cell, suggesting that TIPE2 may inhibit tumor cell proliferation through inducing cell death. Using flow cytometry analysis, we found that the overexpression of TIPE2 could promote apoptosis of tumor cell while knockdown of TIPE2 expression by shRNA could inhibit apoptosis. Previous studies have demonstrated that p38-MAPK/JNK and Akt pathway play important roles in autophagy. In this study, with the accumulation of LC3-II by stimulating TIPE2, tumor autophagy was increased in vitro. Thus, the function of TIPE2 in the inhibition of tumorigenesis may have broad implications in cancer gene therapy.
Citation Format: Jun Li, Xiaoli Xia. TIPE2 regulates apoptosis and autophagy to inhibit tumorigenesis in colon 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 B120.
Abstract B132: A new concept of cancer immunotherapy by targeting pancreatic ductal adenocarcinoma through a childhood recall antigen
Authors: Selvanesan Benson C. , Chandra Dinesh , Quispe Wilber , Patel Ankur , Meena Kiran , Libutti Steven K. , Yuan Ziqiang , Chuy Jennifer , Gravekamp Claudia 
Published: February 2019

Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) have a five-year survival of only 6%. Cancer immunotherapy has shown promising results for metastatic cancer but only in 20% of the patients. Our lab has developed a new concept of immunotherapy using an attenuated non-pathogenic bacterium Listeria monocytogenes for the selective delivery of a highly immunogenic recall antigen tetanus toxoid (TT) into tumor cells of pancreatic tumors and metastases. Most individuals have been exposed to TT during childhood vaccinations and memory T-cells to TT circulate in blood for live. These memory T-cells to TT can be reactivated by Listeria-TT at any time in life and will now destroy the infected tumor cells. Low doses of gemcitabine (GEM) were added to further improve T-cell responses. Panc-02 and KPC mice were immunized with the “human TT vaccine” to generate memory T-cells before development of the pancreatic cancer. After cancer development, mice were treated with Listeria-TT and GEM, and tumors (weight) and metastases (number) were analyzed by eye in the Panc-02 mice, and by SUVmax (measurement of tumor growth) in the KPC mice. T-cell responses in the spleen were analyzed by flow cytometry and ELISPOT, and KPC tumors were analyzed by RNAseq. Listeria-TT and GEM nearly completely eliminated both early and advanced pancreatic cancer in Panc-02 and KPC mice, in correlation with abundant CD4 and CD8 T-cell responses producing perforin, granzyme B, or IFNγ, in vivo or in vitro, respectively. RNAseq analysis of “treated” KPC tumors showed a strong influx of CD4 and CD8 T-cells, upregulation of multiple granzymes, perforin, co-stimulatory molecules, and cell death pathways. These results suggest the multiple synergistic effects of Listeria-TT and GEM on pancreatic cancer. This novel treatment modality of Listeria-TT and GEM warrants further investigation in a clinical setting.
Citation Format: Benson C. Selvanesan, Dinesh Chandra, Wilber Quispe, Ankur Patel, Kiran Meena, Steven K. Libutti, Ziqiang Yuan, Jennifer Chuy, Claudia Gravekamp. A new concept of cancer immunotherapy by targeting pancreatic ductal adenocarcinoma through a childhood recall antigen [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 B132.
Abstract B149: Real-time analysis of cell membrane protein and virus internalization using site-specific conjugation of protease-sensitive probes
Authors: Cheloha Ross W. , Li Zeyang , Bousbaine Djenet , Woodham Andrew , Perrin Priscillia , Volaric Jana , Ploegh Hidde L. 
Published: February 2019

Abstract
Reagents that label specific subsets of cells are broadly useful for the treatment of cancer and modulation of cells of the immune system. Labeling is often achieved through the identification and characterization of proteins specifically expressed on selected cells but not others. Knowledge of cell membrane protein routing dynamics can be leveraged to efficiently deliver cytotoxic or immune stimulating payloads. The most common method for monitoring internalization relies on labeling proteins with antibodies modified with a fluorophore or other tag that can also be used to report on whether the protein of interest has been internalized. This approach requires indirect methods, such as multiple rounds of cell staining, to differentiate extracellular protein from protein that has been internalized and recycled to the cell surface. Here we report a method for the characterization of protein internalization in real time through the sortase-mediated, site-specific labeling of single domain antibodies or viral proteins with a newly developed, cathepsin-sensitive quenched-fluorophore probe. This approach allows quantitative measurement of the movement of proteins into protease-containing endosomes in real time in live cells. This method revealed variation in the rate of internalization for different cell surface receptors and allowed for kinetic characterization of influenza virus internalization. These findings help to explain the utility of certain single domain antibody-antigen conjugates for inducing humoral immune responses. The tools and methods described here should be useful for the identification of proteins expressed on target cells that are ideal for antibody-mediated drug delivery or for promotion of specific types of immune responses.
Citation Format: Ross W. Cheloha, Zeyang Li, Djenet Bousbaine, Andrew Woodham, Priscillia Perrin, Jana Volaric, Hidde L. Ploegh. Real-time analysis of cell membrane protein and virus internalization using site-specific conjugation of protease-sensitive probes [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 B149.
Abstract B156: Characterization and role of CCR8+ regulatory T-cells in mouse models of malignant melanoma
Authors: Edwards Andrew K. , Skobe Mihaela , Rogic Anita , Bosenberg Marcus 
Published: February 2019

Abstract
Melanoma cells disseminate through lymphatic vasculature into the regional lymph nodes early in disease progression. We found that a large subset of metastatic melanomas express chemokine receptor CCR8. Its principal ligand, CCL1, is constitutively expressed by lymphatic endothelial cells in the lymph node and is further upregulated by inflammation. The CCL1-CCR8 axis is an important checkpoint for melanoma lymph node metastasis, as an inhibition of CCR8 leads to arrest of melanoma cells in collecting lymphatic vessels and prevents lymph node metastasis. Among immune cells, CCR8 is predominantly expressed by regulatory T-cells (Treg) and by activated Th2 cells, and has been implicated mainly in allergic inflammation. Here we characterized CCR8+ immune cells and examined the role of CCR8 in mouse models of melanoma. Using inducible, genetically engineered (Tyr::CreER;BrafCAPtenloxPCtnnb1loxex3) and syngeneic mouse models of melanoma (B16F10) we characterized CCR8 expression on different immune cell subsets in primary tumors and in sentinel lymph nodes by flow cytometry. In primary tumors, CCR8 was exclusively expressed by CD4+ T-cells, with the highest percentage being FOXP3+CCR8+ Tregs. Increased numbers of CD4+FOXP3+CCR8+ Tregs were found in sentinel lymph nodes with metastases, compared to non-tumor-draining lymph nodes and lymph nodes from tumor-naïve mice. This also corresponded with an increase in the total number of FOXP3+ T-regs in sentinel lymph nodes, compared to non-tumor draining lymph nodes. We then evaluated the role of CCR8 on B16F10 tumor growth. Tumor growth was significantly reduced in CCR8-/- mice compared to WT mice when anti-tumor immunity was stimulated with Poly(I:C). However, B16F10 tumor growth did not differ between untreated wild-type (WT) and CCR8 -/- mice. These results suggest that targeting CCR8+ Tregs may increase antitumor immune response. Further studies are required to determine the mechanism by which CCR8+ immune cells facilitate melanoma growth and to explore CCR8 as a therapeutic target in melanoma immunotherapy.
Citation Format: Andrew K. Edwards, Mihaela Skobe, Anita Rogic, Marcus Bosenberg. Characterization and role of CCR8+ regulatory T-cells in mouse models of malignant melanoma [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 B156.
Abstract B160: Comparative analysis of pharmacokinetics and antitumor effect between anti-PD-1 and anti-PD-L1 in mice models
Authors: Hatakeyama Hiroto , Kurino Taiki , Suzuki Hiroyuki , Terui Ayu , Uehara Tomoya , Arano Yasushi , Hisaka Akihiro 
Published: February 2019

Abstract
Introduction: Anti-PD-1 antibodies (αPD-1 Abs) are currently used in cancer immunotherapy that block the interaction between PD-1 and PD-L1. In addition to anti-PD-1 Abs, anti-PD-L1 (αPD-L1) Abs have also been approved to inhibit the PD-1/PD-L1 axis. However, the difference between both Abs in pharmacokinetics and anti-tumor effects have not been fully understood. In this study, we analyzed the difference between both Abs in blood concentration, biodistribution and degradation in tumor-bearing mice by using αPD-1/PD-L1 Abs labeled with radioisotopes (111In/125I) and evaluated the relationship between PK and therapeutic effects. Methods: Abs were labeled with 111In via chelate agents, and labeled with 125I through covalent bond. Tumor bearing mice were prepared by s.c. inoculation with mouse colon cancer MC38 cells or mouse breast cancer MM48 cells. The labeled Abs were intraperitoneally injected into tumor-bearing mice. Tumors and organs were harvested at several time points after the injection, and radioactivities in organs were measured by a gamma counter. The accumulation of Abs was expressed as % of injected dose/g organs. Because 111In tends to be accumulated in organs due to poor permeability and 125I was eliminated from organs rapidly due to high permeability, the ratio of 125I and 111In could reflect the degradation of Abs after cellular uptake. In pharmacologic studies, Abs were intraperitoneally injected into tumor-bearing mice at day 5, 8, and 12 after tumor-inoculation. Tumor volume was evaluated to evaluate tumor progression. Results and Discussion: It was observed that αPD-L1 Ab was largely accumulated in normal tissues, especially in the spleen and liver and degraded rapidly compared with αPD-1 Ab, resulting that the blood concentration and distribution in tumors of αPD-L1 Ab tended to be low in both tumor-bearing mice models. Moreover, αPD-L1 Ab showed lower antitumor effect due to less delivered aPD-L1 Ab to tumors than aPD-1 Ab. Collectively, the PK of αPD-1/PD-L1 Abs that target the same axis were not equivalent and the selectivity of expression of target molecules in both normal tissues and tumors should be considered to optimize their therapeutic efficacy.
Citation Format: Hiroto Hatakeyama, Taiki Kurino, Hiroyuki Suzuki, Ayu Terui, Tomoya Uehara, Yasushi Arano, Akihiro Hisaka. Comparative analysis of pharmacokinetics and antitumor effect between anti-PD-1 and anti-PD-L1 in mice 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 B160.
Abstract B164: Inhibiting glycolysis enhances imiquimod-induced immunogenic cell death and the antitumor immune response
Authors: Hunag Shi-Wei , Shieh Jeng-Jer , Wang Sin-Ting , Cho Der-Yang , Chiu Shao-Chih 
Published: February 2019

Abstract
Immunogenic cell death (ICD) characterized as cells undergo with ICD could elicit a specific immune response to against a subsequent challenge with the same type living cells. Imiquimod (IMQ), a synthetic Toll-like receptor 7 ligand, is a imidazoquinoline family member and contains both antitumor and antiviral activity. IMQ is currently clinical used in topical, noninvasive treatment for various skin malignances. IMQ exerts its anti-tumoral activity through stimulating TLR7/8 in dendritic cells and activate cell-mediated immune responses, and directly induces tumor cell death. Recently, we had demonstrated IMQ directly induced autophagic cell death and apoptosis to against tumor cells that independent of TLR7/8. Thus, IMQ may induce tumor undergo ICD to trigger specific antitumor immune response. We found that IMQ induced expression of ICD-associated features in various cancer cell lines. We demonstrated that vaccination of IMQ-induced ICD cell lysate provided significant antitumor immunity with increased CD4 and CD8 T lymphocytes proliferation, tumor-specific cytotoxic lysis and infiltration of CD4, CD8, CD11c and IL-17A-producing cells in tumor lesion. Pharmacologic inhibition and genetic manipulation of ICD-associated features repressed IMQ-treated cell lysate-mediated specific anti-tumor immunity. We also found that IMQ-induced ICD-associated features is mediated by ROS production and ER stress through PERK/eIF2α pathway. In addition, inhibition of glycolysis significantly enhanced IMQ-induced ICD cell lysate-mediated antitumor immunity and ICD-associated features. Taken together, these results provided solid evidence to support that IMQ is an authentic ICD inducer and independent of TLR7/8 expression, and targeting aerobic glycolysis could be a desirable strategy to enhance IMQ-induced ICD and antitumor immunity.
Citation Format: Shi-Wei Hunag, Jeng-Jer Shieh, Sin-Ting Wang, Der-Yang Cho, Shao-Chih Chiu. Inhibiting glycolysis enhances imiquimod-induced immunogenic cell death and the antitumor immune 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 B164.