bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA14: PDX models in head and neck cancers: Present status and future application for immune-oriented biology and therapy development
Authors: Jimeno Antonio 
Published: March 2017

Abstract
Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is dramatically increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from over 100 HNSCC patients, both HPV+ and HPV-, have been implanted on mice, giving rise to over 50 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. The genetic makeup of these tumors was consistent with the frequencies of TP53, PI3KCA, NOTCH1, and NOTCH2 mutations found in landmark genomic characterization of large HNSCC patient cohorts. Tumors maintained their original morphology, genetic profiles, and drug susceptibilities through serial passaging. Cancer cells deceive the host to create an advantageous microenvironment and evade immune surveillance. A limitation to studying human cancer is the limited availability of in vivo models with appropriate human stroma and immunity. To address this unmet need, we generated an allogeneic humanized mouse (aHM) model where HNSCC were implanted on NOD/SCID/IL2rg-/- (NSG) mice reconstituted with human hematopoietic stem cells (HSCs) and other precursors from an unrelated donor. In aHM, bone marrow-derived human immune and mesenchymal cells homed into the growing tumor and interacted with human cancer cells as they would in a patient, partially reversing the gene expression drift that occurs after tumor passage on immune compromised mice. Further work is aimed at improving upon this platform. In summary, we have developed a HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. Then, we have generated an aHM model to enable immune biology and therapy exploration in HNSCC. These models will enable prospectively testing therapeutic-oriented hypotheses leading to enhanced precision medicine, especially in the field of immune therapy.
Citation Format: Antonio Jimeno. PDX models in head and neck cancers: Present status and future application for immune-oriented biology and therapy development. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA14.
Abstract IA19: Phase II human clinical trials in mice-modeling inter-patient response heterogeneity in PDXs
Authors: Gao Hui 
Published: March 2017

Abstract
The current strategy of profiling candidate therapeutics using a limited set of cancer models during pre-clinical development rarely enables accurate predictions of clinical efficacy, or the identification of factors underlying heterogeneous patient responses that inform clinical patient selection strategies. Novartis established ~1000 patient-derived tumor xenograft models (PDXs), where mutation and copy number based genomic landscape analyses revealed a relatively broad conservation of driver mutations found in human cancers. Using this panel of PDXs, we performed population-based in vivo compound screens using a 1x1x1 experimental design (PDX clinical trial or PCT). We demonstrate both the reproducibility and translatability of this approach by identifying associations between genotype and drug response, and clinically established mechanisms of resistance. We therefore propose a new experimental paradigm that can potentially revolutionize preclinical evaluation of novel treatment modalities and improve our ability to predict clinical trial response.
Citation Format: Hui Gao. Phase II human clinical trials in mice-modeling inter-patient response heterogeneity in PDXs. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA19.
Abstract IA27: Small cell lung cancer circulating tumor cell-derived explants: A new preclinical platform for examining drug response
Authors: Frese Kristopher K. , Morrow Christopher , Miller Crispin , Blackhall Fiona , Dive Caroline 
Published: March 2017

Abstract
Small cell lung cancer (SCLC) is a highly aggressive disease with a 5 year survival of 5% that has remained relatively unchanged for the past several decades. Despite a robust response the first line chemotherapy, 95% of patients relapse within a few months. Due in part to the paucity of SCLC tissue samples available for preclinical studies, the molecular mechanisms unpinning disease relapse and acquired drug resistance are poorly understood. Non-invasive collection of liquid biopsies have proven useful in for tumor diagnosis and monitoring, however they have traditionally provided limited utility in mechanistically interrogating drug sensitivity. We have recently demonstrated that SCLC circulating tumor cells (CTCs) are tumorigenic in mice and the resulting patient CTC-derived explants (CDX) mirror patients' disease. We have developed a library CDX where CTCs were enriched either at baseline or upon progression from chemosensitive or chemorefractory SCLC patients. Strikingly, these CDX faithfully recapitulate the histological, genomic, and chemoresistance aspects of patient tumors, suggesting they may be a suitable platform for identifying new drug targets, testing novel drugs, and exploring drug resistance mechanisms. Studies underway are aimed at providing mRNA and genomic DNA analysis from the same CTC or CDX sample to establish direct linkage between mutational changes and emergent mRNA profiles to gain insights into mechanisms underpinning treatment responses.
Citation Format: Kristopher K. Frese, Christopher Morrow, Crispin Miller, Fiona Blackhall, Caroline Dive. Small cell lung cancer circulating tumor cell-derived explants: A new preclinical platform for examining drug response. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA27.
Abstract A09: A bioinformatics workflow to identify neoantigens using next-generation sequencing
Authors: Zhang Shile , So Alex , Kaplan Shannon , Kruglyak Kristina 
Published: March 2017

Abstract
Immuno-oncology is an emerging field of research that represents tremendous promise for cancer patients. Accumulating evidence suggests that tumor-specific neoantigens can persistently stimulate cytotoxic T lymphocytes, which may eradicate cancer cells in a favorable immune microenvironment. Next-generation sequencing (NGS) is a key technology enabling advances in this field. Here we present a complete bioinformatics workflow using tumor/normal whole-exome sequencing (WES) and tumor-only whole-transcriptome sequencing (WTS) to predict neoantigens presented by cancer cells. We evaluate existing WES probe designs for MHC class I genes and show that accurate four-digit HLA typing can be achieved using standard WES solutions, thus allowing for a simplified experimental workflow by removing the need for targeted HLA assays. Final neoantigen candidates are prioritized based on in silico peptide-HLA binding predictions, variant allele frequencies for clonal somatic mutations, tumor RNA expression, and self-similarities between mutant peptide to wildtype peptide. This workflow will be available through BaseSpace® Sequence Hub, which can be accessed via an intuitive web-based interface or Linux-based command line tool, providing any researcher with rapid analysis of NGS data and neoantigen predictions.
Citation Format: Shile Zhang, Alex So, Shannon Kaplan, Kristina Kruglyak. A bioinformatics workflow to identify neoantigens using next-generation sequencing. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A09.
Abstract A37: CBP501 induces tumor immunogenic cell death and CD8 T cell infiltration into tumor in combination with platinum, thereby increasing the efficacy of immune checkpoint inhibitors against tumors in mice
Authors: Sakakibara Keiichi , Sato Takuji , Kufe Donald W. , VonHoff Daniel D. , Kawabe Takumi 
Published: March 2017

Abstract
Introduction: CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate that has completed two Phase II clinical trials for patients with malignant pleural mesothelioma and non-small cell lung carcinoma (NSCLC). CBP501 enhances the uptake of platinum agents by cancer cells specifically and induces immunogenic cell death within the clinically achievable dose levels of both CBP501 and cisplatin (CDDP) (EORTC 2015 abstract#C106). Here we treated tumor bearing mice with the combination of CBP501, platinum agents (CDDP and carboplatin), and immune checkpoint inhibitors and analyzed the tumor growth and behaviors of immune cells.
Methods: Immuno-competent BALB/c mice were subcutaneously inoculated with CT26WT (5 x105 cells/mouse). A week later, mice were apportioned into 8 groups (6 mice/group) and treated with 2 dosing cycles for 3 anti-cancer agents, alone or in different combinations [CDDP: 4 mg/kg x 1/week, CBP501: 6.0 mg/kg x 1/week, anti-mPD1 mAb (RMP1-14) or anti-PD-L1 mAb (10F.9G2): 200 ug/mice x 2/week].
Results: In BALB/c mice bearing CT26WT tumor, CDDP- or immune checkpoint inhibitor-treated mice showed a minimal anti-tumor effect compared to the vehicle-treated mice. CDDP/immune checkpoint inhibitor-treated mice showed an additive anti-tumor effect. CBP501 significantly enhanced the anti-tumor effect of CDDP/immune checkpoint inhibitor combination. Flow cytometry analysis of single suspension cells from the tumor tissue showed that treatment of CDDP/CBP501 or CDDP/CBP501/anti-mPD1 mAb but not CDDP or anti-mPD1 mAb increased the percentage of tumor-infiltrating CD8+ T cell.
Conclusion: An increase of tumor-infiltrating CD8+ T cells in CDDP/CBP501-treated mice supported the conclusion that CDDP/CBP501 treatment induced immunogenic cell death not only in vitro but also in vivo. It also supported the notion that CBP501 would not increase cytotoxicity of platinum agents to non-tumor cells. The fact that CBP501 enhanced anti-tumor activity of immune checkpoint inhibitors in combination with platinum agents (CDDP and carboplatin) would support further clinical development of CBP501.
Citation Format: Keiichi Sakakibara, Takuji Sato, Donald W. Kufe, Daniel D. VonHoff, Takumi Kawabe. CBP501 induces tumor immunogenic cell death and CD8 T cell infiltration into tumor in combination with platinum, thereby increasing the efficacy of immune checkpoint inhibitors against tumors in mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A37.
Abstract B32: Loss of MK2 in tumor stroma promotes aggressive tumor development in an advanced stage lung cancer model
Authors: Sriram Ganapathy , Suarez-Lopez Lucia , Yaffe Michael B. 
Published: March 2017

Abstract
MAPKAP Kinase-2 (MK2) is a serine/threonine protein kinase that is activated by p38MAPK in response to a variety of stresses including DNA damage, osmotic shock, thermal injury, and inflammation/innate immune signaling downstream of TLR4 activation. MK2 controls the synthesis of many pro-inflammatory cytokines, modulates the actin cytoskeleton in stressed cells, and is responsible for maintaining both the G1/S and G2/M cell cycle checkpoints in p53-defective tumor cells after genotoxic damage. We recently created a “Cre-reversible" MK2 knock-out mouse model that allows the function of MK2 within either the tumor cells or within the tumor microenvironment to be studied independently. We found that MK2-deficient tumor cells in an MK2 wild-type stroma were dramatically sensitized to the anti-tumor effects of cisplatinum and doxorubicin (Morandell et al., Cell Reports, 2013). Here, we report that loss of MK2 in the tumor stroma with preservation of MK2 in tumor cells results in an aggressive tumor-promoting phenotype in an immuno-competent transplant K-RasG12D/p53-/- model of NSCLC. A similar tumor aggressive phenotype was observed in Tie2-Cre-driven endothelial and bone marrow-specific MK2-knockout mice compared to wild-type controls. Tumor-bearing mice with MK2-null stroma display increased total levels of MIP-1α, G-CSF, GM-CSF and IL-6 in the lung. Myeloperoxidase immunohistochemistry reveals enhanced tumor infiltration by neutrophils in these stromal MK2-deficient animals, consistent with the cytokine profile. In contrast with loss of MK2 in the stroma, direct activation of the p38MAPK/MK2 pathway in the tumor microenvironment by weekly intra-tracheal LPS exposure dramatically reduces tumor formation in an autochthonous K-RasG12D/p53-/- murine NSCLC model. Collectively, these results suggest that MK2 signaling in the endothelium and/or immune cells suppresses NSCLC tumor progression and modulates the inflammatory milieu in the tumor microenvironment.
Citation Format: Ganapathy Sriram, Lucia Suarez-Lopez, Michael B. Yaffe. Loss of MK2 in tumor stroma promotes aggressive tumor development in an advanced stage lung cancer model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B32.
Abstract B45: Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: Rationale for combination therapies
Authors: Dominguez Charli , Tsang Kwong-Yok , Palena Claudia 
Published: March 2017

Abstract
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been approved for years as a first-line therapy for patients harboring EGFR sensitizing mutations. With the promising implementation of immunotherapeutic strategies for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize immune approaches in the context of conventional or targeted therapies. Tumor cells are known to evade immune attack by multiple strategies, including undergoing phenotypic plasticity via a process designated as the epithelial-mesenchymal transition (EMT). As signaling through EGFR is a major inducer of EMT in epithelial cells, we have investigated the effect of EGFR inhibition with erlotinib on tumor phenotype and susceptibility to immune attack. Utilizing a panel of lung carcinoma cell lines with mutated EGFR, we have evaluated the ability of erlotinib to modulate tumor phenotype and to modulate cytotoxic responses to effector NK cells and T cells specific for brachyury and MUC-1. The effect of erlotinib treatment was also evaluated with single cell clonal populations of lung cancer cells isolated based on their expression of epithelial and mesenchymal markers. Our data shows that short-term exposure of tumor cells to low dose erlotinib leads to a remarkable enhancement of tumor lysis mediated by innate NK cells and antigen-specific T cells. This effect positively correlated with the ability of short-term EGFR blockade to modulate tumor phenotype towards a more epithelial one, as well as altered apoptotic signaling through enhanced caspase cleavage. The effect, however, was lost when erlotinib was utilized for long periods of time in vitro or in vivo, which resulted in gain of mesenchymal features and decreased (rather than increased) tumor lysis in response to immune effector mechanisms. Additionally, with the utilization of single cell clones, it was evident that there was a selection of mesenchymal populations during erlotinib treatment, which could explain the acquired resistance to immune attack seen at longer time points. Our data provides rationale for potential combinations of erlotinib and immunotherapies for the treatment of lung carcinomas in the early setting, prior to the establishment of tumor relapse with long-term EGFR inhibition.
Citation Format: Charli Dominguez, Kwong-Yok Tsang, Claudia Palena. Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: Rationale for combination therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B45.
Abstract B47: Stabilization of programmed death ligand-1 by epidermal growth factor enhances cancer cell immune escape
Authors: Lim Seung-Oe , Li Chia-Wei , Hung Mien-Chie 
Published: March 2017

Abstract
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumor-associated immune escape. Despite efforts to limit the interaction between cancer cells and immune cells, the molecular mechanism by which cancer cells initiate immune escape is less understood. Here, we show that the immunosuppression activity of PD-L1 is stringently modulated by the spatial competition between ubiquitination and N-glycosylation. We identified glycogen synthase kinase 3β (GSK3β) as a novel protein that interacts with PD-L1 and can induce phosphorylation-dependent proteasome degradation by β-TrCP. In depth analysis of PD-L1 N192, N200, and N219 glycosylation suggests glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer (BLBC). Inhibition of EGF signaling by gefitinib destabilizes PD-L1, enhances antitumor T cell immunity, and sensitizes BLBC cells to PD-1 blockade. Together, our results link ubiquitination and glycosylation pathways with stringent regulation of PD-L1, which could open new therapeutic strategies to enhance cancer immune therapy efficacy.
Citation Format: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung. Stabilization of programmed death ligand-1 by epidermal growth factor enhances cancer cell immune escape. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B47.
Abstract B49: Sustained IFNalpha treatment inhibits metastasis in 4T1 mammary carcinoma and correlates with decreasing myeloid-derived suppressor cells
Authors: Kochel Christina , Pande Kalyan , Ueda Roanna , Gorman Dan , Laface Drake 
Published: March 2017

Abstract
In order to model pharmacokinetics and pharmacodynamics of pegylated IFNalpha, we utilized hydrodynamic delivery technology using minicircle DNA vectors encoding universal IFNalpha as a rapid and cost-effective method to obtain sustained levels of serum IFNalpha2alpha1. This approach is particularly useful for delivering secreted molecules, such as cytokines, as transfected hepatocytes secrete the transgene product in a paracrine manner providing a serum exposure profile resembling that reported in PEG-intron-treated patients. We found that sustained exposure of IFNalpha2alpha1 induced inhibition of metastasis. Primary 4T1 tumor growth was partially inhibited, while significant decreases in pulmonary metastatic burden were consistently observed. Further evidence that the observed inhibition of metastasis was independent of potential effects on the primary tumor was tested by resecting the primary tumor prior to treatment, which did not alter the outcome. Importantly, sustained IFNalpha2alpha1 treatment correlated with a significant increase in the survival of tumor-bearing animals. IFNalpha effects are plieotropic resulting in potential activation of numerous immune cell types associated with both innate and adaptive immunity. However, the mechanisms associated with IFNalpha-induced inhibition of lung metastasis were largely engendered by innate immune cells since treatment in BALB/c mice deficient for T and B cells did not affect the capacity of IFNalpha to inhibit pulmonary metastasis when compared to wild-type animals. The importance of NK cells has recently been reported as an important innate component for IFNalpha induced reduction of metastatic burden. However, little is known about IFNalpha-regulation of other innate cell types that may contribute to the inhibition of tumor metastasis. Here we report IFNalpha2alpha1 treatment induced marked decreases in 4T1-induced expansion and activation of immature CD11b+ Gr-1+ myeloid cells (aka: MDSC), which have been reported to contribute to metastatic potential. These results correlated with similar decreases in metastatic burden in mice following chlodronate-liposome depletion of CD11b+ Gr-1+ myeloid cells.
Citation Format: Christina Kochel, Kalyan Pande, Roanna Ueda, Dan Gorman, Drake Laface. Sustained IFNalpha treatment inhibits metastasis in 4T1 mammary carcinoma and correlates with decreasing myeloid-derived suppressor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B49.