bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1645: CEACAM1-blockade for T-cell activation and antitumor T-cell response
Authors: Eun So-Young 
Published: July 2017

Abstract
Immune checkpoint blockade became the most powerful way to control cancer without causing tremendous side effects, since anti-PD-1 blocking antibodies proved their superiority in clinical outcomes to those of traditional chemo- or targeted therapeutics. CEACAM1 (CCM1) is one of the several immune checkpoint receptors expressed on T cells that mediate suppression of inflammatory T cell response. CCM1 caught our attention for a cancer immune-therapeutic target, because of its inhibitory role in TCR proximal signaling complex. The anti-cancer therapeutic potential of CCM1-blockade has already been studied in mouse models, and one of the anti-human CCM1 antibody clones recently emerged in clinical Phase I studies. CCM1-targeting antibody candidates were screened out of our in-house synthetic libraries, among which a few of the clones stood out showing their significant blocking activities against CCM1-CCM1 homophilic interaction, enhancement of T cell activation, cytokine release, NFAT signaling, and tumor lysis. One of the clones (C25) showed its strongest efficacy equivalent to that of a reference Ab in CCM1-dependent T cell activation, proliferation, and IL-2 release, in parental Jurkat cells as well as in CCM1-overexpressing stable Jurkat cells. Moreover, C25 also enhanced tumor lysis by CCM1+ NK cells or CCM1+ cytotoxic T cells in a CCM1-dependent manner. In addition, C25 shows distinct characteristics in binding to CCM family from those of a reference Ab. Thus, C25 is thought to have a strong therapeutic potential on CCM1+ cancer.
Citation Format: So-Young Eun. CEACAM1-blockade for T-cell activation and antitumor T-cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1645. doi:10.1158/1538-7445.AM2017-1645
Abstract 1647: Characterization of MiXenoTM humanized mouse model for immuno-oncological therapy evaluation
Authors: Zhang Juan , Shi Qian , Zhang Lan 
Published: July 2017

Abstract
Backgrounds: Despite the unprecedented success of immune checkpoint antibody therapy in patients with various cancer types, lack of stable experimental immunotherapy models is still a big challenge in development of effective new immune-therapeutics. Different strategies of humanized mouse model system, including human hematopoietic stem cell (HSC) or human PBMC humanization in immune-deficient mice, or chimeric models harboring human immune checkpoint targets in immune-competent mice have been reported. CrownBio has successfully established a number of human PBMC-humanized xenograft models MiXenoTM for in vivo IO therapy evaluation, which has been shown to be a rapid and simple strategy of humanization. However, several outstanding questions, e.g. the optimal PBMC injection route and cell number, the donor dependence of the efficacy result and impact of donor HLA type on the efficacy, etc., need to be further addressed.
Results: PBMC number was titrated in one of our MiXenoTM model HCC827, and PBMC injection via i.p. vs. i.v. was compared. Tumor growth curve, graft versus host disease (GVHD), and blood immunophenotyping were followed under different settings. Furthermore, the antitumor activity of PD-1 antibody pembrolizumab in a panel of PBMC donor context that bears diversified HLA types was precisely analyzed. We found that the efficacy was highly donor dependent, and there was lack of correlation between efficacy and donor/tumor HLA match.
Conclusion: The MiXenoTM model provides an alternative to the full stem cell reconstitution approach. Better understanding on the characteristics of the model may allow a rational model selection and study design in the discovery IO therapeutics.
Citation Format: Juan Zhang, Qian Shi, Lan Zhang. Characterization of MiXenoTM humanized mouse model for immuno-oncological therapy evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1647. doi:10.1158/1538-7445.AM2017-1647
Abstract 1656: Comprehensive evaluation of human immune system reconstitution in NSGTM and NSGTM-SGM3 toward the development of a novel Onco-HuTM xenograft model
Authors: Middlebrook Aaron J. , Snowden Eileen , Porter Warren , Hahn Friedrich , Ferguson Mitchell , Soper Brian , Keck James , Malcolm Joan , Dillmore Shannon , Ghanekar Smita , Blaesius Rainer 
Published: July 2017

Abstract
The recent successes of immunotherapeutic approaches to the treatment of melanoma and the promise of similar treatments in a variety of other cancers underscore the importance of the immune system in cancer. Indeed, effective therapeutic design and evaluation require a comprehensive understanding of the interplay between the immune compartment and the proliferating tumor cells that comprise the tumor microenvironment. A humanized mouse strain engrafted with cancerous tissue from a patient derived xenograft (PDX) tumor provides researchers with a highly sophisticated tool, ideally suited to facilitate the design of treatment strategies that prevent tumor evasion of immune cells and that improve cytotoxic responses. Severely combined immunodeficient mice such as NOD scid gamma (NSGTM) and triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSGTM-SGM3) are proven hosts for the engraftment of human tumors and establishment of human immune system components following hematopoietic stem cell (CD34+) transplantation. The endogenous expression of cytokines that support the development of myeloid lineages and regulatory T cells potentially represents a substantial improvement over standard NSG mice. Here we employ four 14-color flow cytometry panels to perform a comprehensive and detailed analysis of the entire immune system. The four panels are designed to fully characterize specific branches of the immune system: 1) T cells 2) NK cells/dendritic cells/B cells 3) myeloid lineages, and 4) immune checkpoint markers. Blood, spleen, and bone marrow tissue from both NSG and NSG-SGM3 mice were evaluated at 9, 16, 21, and 31 weeks of age using each of the four phenotyping panels. Our results indicate that the triple transgenic NSG-SGM3 mice exhibit a more completely humanized immune system compared to NSG mice, with specific improvements in the distribution of T-cell subsets and overall representation of the myeloid lineage. NSG mice engrafted with allogeneic human tumors represent a valuable preclinical testing platform for immuno-oncology.
Citation Format: Aaron J. Middlebrook, Eileen Snowden, Warren Porter, Friedrich Hahn, Mitchell Ferguson, Brian Soper, James Keck, Joan Malcolm, Shannon Dillmore, Smita Ghanekar, Rainer Blaesius. Comprehensive evaluation of human immune system reconstitution in NSGTM and NSGTM-SGM3 toward the development of a novel Onco-HuTM xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1656. doi:10.1158/1538-7445.AM2017-1656
Abstract 1670: Identification and characterization of novel mediators of tumor-induced T-cell dysfunction
Authors: Markowitz Geoffrey J. , Philip Mary , Schietinger Andrea , Mittal Vivek 
Published: July 2017

Abstract
Immunotherapies targeting T-cell functionality have been shown to have efficacy in numerous cancers, including non-small cell lung cancer (NSCLC). However, treatment with currently available therapeutics, such as anti-PD-1 and anti-CTLA-4, induce responses only in a subset of patients. This raises the possibility that numerous other effectors of T-cell dysfunction remain to be elucidated. To evaluate possible novel mediators of T-cell dysfunction, we isolated CD8+ T-cells from orthotopic KrasG12D/p53-/- murine lung adenocarcinomas (HKP-1) that exhibited either stable or progressive disease as a function of tumor growth. RNAseq analysis revealed increased expression of several genes including Tim3, PD-1, Lag3, 2B4, and CISH, and decreased expression of GzmB and Eomes in CD8+ T-cells isolated from progressive tumors indicative of a dysfunctional state, as well as multiple novel genes not previously associated with T-cell dysfunction. To explore the functional role of the novel candidate genes, we have developed in vitro and in vivo assays leveraging Ova and GFP overexpression in our HKP-1 cell line (KP1-Ova-GFP). We have begun to target these unique set of candidate genes in tumor-specific T-cells associated with dysfunction through innovative RNAi/shRNA and adoptive transfer approaches to facilitate therapeutic reprogramming and enhanced T-cell-mediated immunity in lung cancer. We expect to provide novel strategies for designing rational immunotherapies targeting dysfunctional tumor-specific CD8+ T-cells to generate durable anti-tumor immune responses for the treatment of lung adenocarcinoma.
Citation Format: Geoffrey J. Markowitz, Mary Philip, Andrea Schietinger, Vivek Mittal. Identification and characterization of novel mediators of tumor-induced T-cell dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1670. doi:10.1158/1538-7445.AM2017-1670
Abstract 1673: Mass spectrometric characterization of peptides associated with molecules of the major histocompatibility complex
Authors: Ford Michael , Jones Richard , Allen David , Amunugama Ravi , Rizzo Paul Del , Pisano Michael , Mobley James , Domanski Paul , Ho Bill , Bochar Daniel 
Published: July 2017

Abstract
The major histocompatibility complex (MHC) is a region of highly polymorphic genes encoding for glycoproteins (MHC molecules) that form part of the cell-mediated branch of the acquired immune system. In the cytosol, cellular self and foreign (non-self) proteins are constantly being degraded; it is the peptides generated that are presented, non-covalently bound to MHC molecules, on the surface of cells for inspection by cytotoxic T-lymphocytes (CTLs). Non recognition of the presented peptide ultimately leads to cell destruction.
Characterizing the factors associated with Non recognition is an attractive proposition for anyone interested in generating tools for targeted cell destruction. In the field of oncology the obvious application then is the targeted destruction of cancerous cells. To enable the molecular level characterization of peptides associated with molecules of the major histocompatibility complex requires a targeted protein complex enrichment, an unbiased peptide elution and finally a peptide analysis method. Most frequently an immunoprecipitation is used to isolate the target complex. The peptide elution is performed under conditions minimizing protein contamination and finally peptide analysis is accomplished by mass spectrometry.
Here we present a case study of our recent work optimizing and performing a workflow for the analysis of peptides associated with Class I MHC molecules. The goal of the assay optimization was to minimize the amount of antibody required for the assay, to minimize the amount of biological material needed from which the complex is isolated and to achieve the optimum sensitivity towards the hitherto unknown target peptides.
Citation Format: Michael Ford, Richard Jones, David Allen, Ravi Amunugama, Paul Del Rizzo, Michael Pisano, James Mobley, Paul Domanski, Bill Ho, Daniel Bochar. Mass spectrometric characterization of peptides associated with molecules of the major histocompatibility complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1673. doi:10.1158/1538-7445.AM2017-1673
Abstract 1674: Quantifying tumor-infiltrating leukocytes in hematoxylin stained NSCLC tissue samples using morphometric features
Authors: Ergon Elliott , Harney Allison S. , Martin Nathan , Paces Will , Aeffner Famke , Wilson Kristin , Patterson-Kane Janet , Ryall Karen , Rudmann Daniel G. , Hirsch Brooke , Krueger Joseph 
Published: July 2017

Abstract
Quantification of tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancers (NSCLC) is valuable for understanding patient prognosis and survival. TILs comprise a subset of tumor-infiltrating leukocytes that modulate immune evasion and response to therapy. Understanding the composition of TIL subsets, especially relative to the total tumor leukocyte population, may provide additional context for understanding NSCLC pathogenesis and patient response to treatment. However, availability of tissues and use of chromogenic assays can limit the number of TIL and leukocyte subset markers assayed in a tissue section. Therefore, this study evaluated the identification of total leukocyte component in NSCLC using morphometric parameters and routine TIL marker monoplex immunohistochemistry (IHC) assays to further identify the composition of TIL subsets. Computational Tissue Analysis (cTA™) tools were used to determine the morphometric parameters which could identify immune cells in the absence of biomarker stain. The morphometric features which characterized immune infiltrates were used to quantify the total immune cell population frequency in the tumor nests and surrounding stroma in hematoxylin-stained tissues. The leukocyte population identified with morphometric parameters was correlated with CD45+ cell frequencies identified by cTA based on biomarker staining in CD45-stained serial sections. This morphometric ruleset was then applied to CD3- and CD8-stained tissues to evaluate the frequency of CD3+ and CD8+ TILs in the context of total infiltrating leukocytes. The relative populations of CD3+ and CD8+ TILs were consistent with available literature demonstrating that the morphometric ruleset could be utilized to enable evaluation of TIL sub-types relative to total leukocyte population without the need for additional IHC stains. The approach could, therefore, provide an added dimension of analysis for tissues stained by IHC for identifying the total immune cell infiltrating component without requiring additional biomarker staining.
Citation Format: Elliott Ergon, Allison S. Harney, Nathan Martin, Will Paces, Famke Aeffner, Kristin Wilson, Janet Patterson-Kane, Karen Ryall, Daniel G. Rudmann, Brooke Hirsch, Joseph Krueger. Quantifying tumor-infiltrating leukocytes in hematoxylin stained NSCLC tissue samples using morphometric features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2017-1674
Abstract 1690: Epitope-minigenes for optimal induction of the immune response against tumor associated antigens and neoantigens
Authors: Bandini Silvio , Luberto Laura , Palombo Fabio , Roscilli Giuseppe , Marra Emanuele , Ciliberto Gennaro , Aurisicchio Luigi 
Published: July 2017

Abstract
We have recently established a workflow that allows the identification of T cell epitopes within Tumor Associated Antigens (TAAs) and the construction of genetic cancer vaccine based on the use of minigenes. The T-cell epitope in silico prediction approach is based on three criteria: 1) binding to MHC Class I alleles; 2) uniqueness to the antigen of interest; 3) increased likelihood of natural processing. The combination of in silico prediction and a biochemical binding/stability assay resulted in an accurate identification of novel TAA-derived epitopes. Predicted T cell epitopes were connected by furin sensitive linkers and linked to human tissue plasminogen activator (TPA) signal and E. Coli enterotoxin B subunit, to construct an optimal minigene scaffold used as vaccine candidate. The present study was aimed at evaluating HER2/neu and hTERT (telomerase) minigenes with the same technology platform. First of all, minigenes delivered via Electro Gene Transfer (DNA-EGT) were more immunogenic than genetic vectors encoding the full-length protein or peptides injected subcutaneously and they were able to break immune tolerance in wild type and HLA-A0201 transgenic mice. Moreover, this technology applied to epitopes selected within Mutated Tumor Antigens results in strong immunogenicity and significant antitumor effects in mouse models. In conclusion, we show that minigenes delivered via DNA-EGT and based on predicted and/or experimentally identified epitopes are powerful tools to induce immune responses and combat cancer. Combination studies of minigenes with peptide vaccination, chemotherapy and immune checkpoint blockade may define new therapeutic opportunities for cancer patients.
Citation Format: Silvio Bandini, Laura Luberto, Fabio Palombo, Giuseppe Roscilli, Emanuele Marra, Gennaro Ciliberto, Luigi Aurisicchio. Epitope-minigenes for optimal induction of the immune response against tumor associated antigens and neoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1690. doi:10.1158/1538-7445.AM2017-1690
Abstract 1692: KRAS-mediated therapeutic resistance abrogates immunogenic cell death in colorectal cancer cells
Authors: Wang Yi-Jun , Chen Dongshi , Tong Jingshan , Yu Jian , Bardelli Alberto , Zhang Lin 
Published: July 2017

Abstract
A hallmark of cancer is compromised immune surveillance, which is characterized by failure of the immune system to recognize tumor-associated antigens and specifically eliminate malignant cells. A number of studies showed the tumor microenvironment in colorectal cancer (CRC) patients is highly immunosuppressive. Conventional chemotherapy and recent targeted therapy can restore anti-tumor immune response through induction of immunogenic cell death (ICD) in tumor cells. However, the mechanism and functional role of ICD in CRC treatment remains vague. In this study, we found FOLFIRI (Leucovorin/5-Fluorouracil/Irinotecan) combined with the anti-EGFR antibody cetuximab, a commonly used regimen for CRC treatment, induces death of CRC cells with characteristics of necroptosis, including ATP depletion, release of HMGB1, and phosphorylation of RIP3 and MLKL. Cells subjected to the combination treatment exhibited features of ICD including plasma membrane exposure of calreticulin and phagocytosis by dendritic cells. We identified the BH3-only Bcl-2 family protein PUMA as a key mediator of necroptosis induced by the combination treatment in vitro and in vivo. Furthermore, we found that CRC cells with acquired cetuximab resistance due to KRAS mutation or amplification are deficient in ICD. Collectively, our results suggest that oncogenic mutations cause resistance of CRC cells to anticancer therapies in part by suppressing ICD.
Citation Format: Yi-Jun Wang, Dongshi Chen, Jingshan Tong, Jian Yu, Alberto Bardelli, Lin Zhang. KRAS-mediated therapeutic resistance abrogates immunogenic cell death in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2017-1692
Abstract 1695: Exploiting the pancreatic cancer mutome for immune interception
Authors: Kinkead Heather , Lutz Eric , Dubensky Thomas W. , Jaffee Elizabeth 
Published: July 2017

Abstract
This study aims to translate tumor-specific mutations identified by next-generation sequencing techniques into an effective anti-tumor vaccine for a classically non-immunogenic tumor, pancreatic ductal adenocarcinoma (PDA). Pancreatic ductal adenocarcinomas develop an average of 63 mutations during tumorigenesis, collectively referred to as the “mutome.” Of these, approximately 45 are amino acid point mutations. These mutations are not present in normal cells and provide a source of tumor-specific neoepitopes for targeted immunotherapy. Next-generation sequencing technologies allow for rapid identification of mutations present in patient tumors; however, methods for rapid identification of immunogenic neoepitopes which can be effectively targeted for tumor clearance, and optimized vaccination strategies for targeting them, still need to be developed.
In this study, we are using a transplantable murine PDA model, Panc02, to develop vaccination strategies for inducing neoepitope-specific T cell antitumor responses, and to define parameters for selecting appropriate targets. Exome sequencing identified 878 nonsynonymous mutations in the Panc02 cell line. Three immunological epitope prediction servers identified 878 potentially immunogenic peptides in the Panc02 model, 29 of which were strong candidates (scores &lt;50) and another 240 candidate epitopes within the limits of prediction (scores &lt;1000). Panc02 neoepitope peptide vaccinations in mice confirmed 14% of the predicted epitopes to be immunogenic by IFNγ ELISPOT, which may include both CD8+ and CD4+ T cell responses. Tumor transplant experiments demonstrate that therapeutic vaccination against neoepitopes in combination with a human STING-activating cyclic dinucleotide adjuvant is capable of inducing a temporary regression of implanted tumors. After tumor escape and regrowth, flow cytometry reveals a large population of infiltrating lymphocytes, the majority of which are co-expressing the checkpoint molecules PD-1, Tim3, and Lag3, indicating that treatment of vaccinated animals with checkpoint blockade therapy may potentiate infiltrating lymphocytes and ultimately result in permanent tumor regression. Thus, a broad and unbiased approach for screening vaccine targets will allow for the evaluation of predictive algorithms and ultimately the development of more effective vaccination approaches for targeting the tumor mutome.
Citation Format: Heather Kinkead, Eric Lutz, Thomas W. Dubensky, Elizabeth Jaffee. Exploiting the pancreatic cancer mutome for immune interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1695. doi:10.1158/1538-7445.AM2017-1695