bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 180: Identifying signatures of vulnerability through machine learning in an umbrella trial for glioblastoma
Authors: Lee Matthew Eric , Tang Nanyun , Ahluwalia Manmeet , Fonkem Ekokobe , Fink Karen , Dhurv Harshil , Dhurv Harshil , Berens Michael E. , Peng Sen 
Published: July 2021

Abstract
Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. An umbrella trial tests multiple investigational treatment arms depending on corresponding biomarker signatures. A contingency of an efficient umbrella trial is a suite of preferably orthogonal molecular biomarkers to classify patients into the likely-most-beneficial arm. Assigning thresholds of molecular signatures to classify a patient as a “most-likely responder” for one specific treatment arm is a crucial task. Gene Set Variation Analysis (GSVA) of specimens from a GBM clinical trial of methoxyamine associated differential enrichment in DNA repair pathways activities with patient response. However, the large number of DNA-repair related pathways confound confident “high” enrichment of responder, as well as obscuring to what degree each feature contributes to the likelihood of a patient's response. Here, we utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression (ERLR) to predict vulnerability classification. By first training all available data using semi-supervised algorithms we transformed unclassified TCGA GBM samples with highest certainty of predicted response into a self-labeled dataset. In this case, we developed a predictive model which has a larger sample size and potential better performance. Our umbrella trial design currently includes three treatment arms for GBM patients: arsenic trioxide, methoxyamine, and pevonedistat. Each treatment arm manifests its own signature developed by the above (or similar) machine learning pipeline based on selected gene mutation status and whole transcriptome data. In order to increase the robustness and scalability (with future more treatment arms), we also developed a multi-label classification ensemble model that's capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. By expansion to three, independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models placed 4 out of 6 models into a “high likelihood of response” regimen. Our utilization of multiple vulnerability signatures in an umbrella trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.
Citation Format: Matthew Eric Lee, Nanyun Tang, Manmeet Ahluwalia, Ekokobe Fonkem, Karen Fink, Harshil Dhurv, Harshil Dhurv, Michael E. Berens, Sen Peng. Identifying signatures of vulnerability through machine learning in an umbrella trial for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 180.
Abstract 1801: Development of a comprehensive biomarker strategy to support phase 1 clinical trial of SRK-181 the latent TGFβ1 inhibitor
Authors: Brueckner Christopher , Faucette Ryan , Caldwell Charles , Reitsma Sofia , Wawersik Stefan , Kalra Ashish , Gan Lu , Lee-Hoeflich Si Tuen 
Published: July 2021

Abstract
TGFβ signaling appears to be a key mediator of primary resistance to programmed cell death protein (PD-1) pathway blockade. SRK-181 is an investigational stage, high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. Preclinical data demonstrate that combining SRK-181 with a PD-1 inhibitor modulates tumor microenvironment (TME), including an influx of CD8 positive T cells that correlates with anti-tumor responses. The ongoing DRAGON trial is a multi-center, open-label, Phase 1, first in-human (FIH), dose-escalation, and dose-expansion study. The goal of the trial is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered alone and in combination with an anti-PD-(L)-1 in adult patients with locally advanced or metastatic solid tumors. To support this ongoing DRAGON clinical trial and further explore the mechanism of action of SRK-181, a comprehensive biomarker strategy is being developed to assess the alternation of immune profile in TME and potential predictors of therapeutic response to SRK-181. Here we describe the development and refinement of several biomarker assays. First, an image analysis-based algorithm for CD8 immunohistochemistry (IHC) is established utilizing human cancer tissue in a pre-clinical study. This novel digital pathology analysis enables identification of CD8 positive T cells in discrete compartments, including the tumor nests, stroma and tumor/stromal margins, to better capture the heterogeneity of the CD8 signal within tissues. Second, we describe methods to evaluate the TGFβ pathway including quantitative analysis of tumor tissue phospho-Smad2 and circulatory levels of TGFβ1 ligand. A companion assay to exclude blood samples with nonspecific background signals has been characterized and will be performed in parallel when evaluating circulatory TGFβ1 in clinic. In summary, we present several novel, tailored biomarker readouts that are part of a broader biomarker strategy aimed at maximizing detection of relevant clinical data to both support the ongoing clinical trial and provide further insight into the mechanism of action of SRK-181.
Citation Format: Christopher Brueckner, Ryan Faucette, Charles Caldwell, Jr., Sofia Reitsma, Stefan Wawersik, Ashish Kalra, Lu Gan, Si Tuen Lee-Hoeflich. Development of a comprehensive biomarker strategy to support phase 1 clinical trial of SRK-181 the latent TGFβ1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1801.
Abstract 1803: Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors
Authors: Sugiyama Daisuke , Muramatsu Tomoaki , Noguchi Takuro , Akatsuka Yoshiki , Nishikawa Hiroyoshi 
Published: July 2021

Abstract
Immune checkpoint inhibitors (ICIs) and other cancer immunotherapies resurge T cell responses that target tumor antigens expressed by cancer cells, particularly tumor neoantigens derived from genetic alterations. However, tumors establish immune escape mechanisms during tumor development and progression, including the loss of pre-existing tumor antigens and impaired T cell responses. In the last decade, various strategies to overcome the immune escape mechanisms have been investigated in the clinic to achieve a cure for cancer. Here, we show that a newly emerged immunogenic neoantigen changes the tumor environment and inhibits tumor growth. To develop animal models, we employed a Tet-on gene expression system, in which immunogenic neoantigens including chicken ovalbumin (OVA) and human cancer-testis antigen NY-ESO-1 were newly emerged upon doxycycline (Dox) treatment. MC-38 (colorectal cancer) inducing OVA, CT26 (colorectal cancer) inducing NY-ESO-1 and B16 (melanoma) inducing NY-ESO-1 were developed, and these cell lines were administered into mice. Induction of these model neoantigens by Dox treatment after tumor establishment (approximately 8~10 mm) significantly inhibited tumor growth. The antitumor effects were not observed in nude mice lacking T cells or CD8+ T-cell depleted mice, indicating an important role of CD8+ T cells. Furthermore, PD-1/PD-L1 blockade further enhanced CD8+ T cell responses against the newly emerged immunogenic neoantigens, resulting in a far stronger tumor growth inhibition. We then propose that newly-emerged immunogenic neoantigens are sufficient to induce antitumor effects that can overcome immune escape mechanisms in the tumor microenvironment, thereby inhibiting tumor growth and that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to ICI therapy.
Citation Format: Daisuke Sugiyama, Tomoaki Muramatsu, Takuro Noguchi, Yoshiki Akatsuka, Hiroyoshi Nishikawa. Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1803.
Abstract 1804: Modulation of Nr2f2 reprograms tumor blood vessels to enhance anti-tumor immunity and immunotherapy
Authors: Zhu Yu , Lazarus Nicole , Brulois Kevin , Salazar Nicole , Dinh Theresa , Pan Junliang , Butcher Eugene 
Published: July 2021

Abstract
A critical limitation to cancer immunotherapy is posed by the paucity of anti-tumor T cells in tumor tissues, even after therapeutic intervention. Development of effective strategies to enhance T cell recruitment remains challenging. As a critical regulator of immune cell trafficking, the tumor vasculature is a promising target that can be utilized to enhance anti-tumor immunity. Functional vasculature requires specialization of endothelial cells (ECs): capillary ECs transport oxygen and nutrients to promote tumor growth, while venular ECs regulate the recruitment and extravasation of immune cells. The majority of the current vessel-targeting therapies are designed to deplete endothelial cells indiscriminately with the goal of starving tumor cells. Loss of venules as a consequence could further block sustained recruitment of anti-tumor T cells. An alternative strategy that instead promotes capillary-to-venule “reprogramming” could simultaneously inhibit the tumor-promoting activities of capillaries and preserve the T cell-recruiting functions of tumor vessels, and thus better augment anti-tumor immunity and benefit immunotherapies. Through single cell transcriptomic profiling of tumor ECs, we found the nuclear receptor Nr2f2 to be specifically expressed in tumor-associated venules but not in capillaries. Upon ectopic expression of Nr2f2 in tumor ECs, capillary vessels undergo fate switch and adopt the venular phenotype and functions, as confirmed by immune profiling and single cell transcriptomic analyses. Nr2f2-driven capillary-to-venule reprogramming enhanced the recruitment of cytotoxic T cells into the tumor tissue, and led to a significant reduction of tumor burden in mouse breast and pancreatic tumor models. Interestingly, Nr2f2-driven EC fate switch enhanced the anti-tumor efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy by transferring T cells specific for a surrogate tumor cell antigen. Collectively, these data suggest that strategies that reprogram tumor vessels from capillaries into venules can be exploited to enhance anti-tumor immune responses and sensitize tumors to immunotherapy, especially in immunologically cold tumors.
Citation Format: Yu Zhu, Nicole Lazarus, Kevin Brulois, Nicole Salazar, Theresa Dinh, Junliang Pan, Eugene Butcher. Modulation of Nr2f2 reprograms tumor blood vessels to enhance anti-tumor immunity and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1804.
Abstract 1811: A novel OX40 humanized mouse model for efficacy assessment of OX40-targeting therapies
Authors: Sônego Fabiane , Martin Gaëlle , Beringer Audrey , Beuraud Chloé , Cherifi Yacine , Fraichard Alexandre , Petit Patricia Isnard , Thiam Kader 
Published: July 2021

Abstract
Immunotherapies through targeting of activating and inhibitory immune checkpoints (ICP) has revolutionized the treatment of cancers. To facilitate the translation of basic research into clinical application of these immunotherapies, we developed a pipeline of immunocompetent mouse models expressing humanized ICP instead of their mouse counterparts, thus compounds can be tested in the absence of endogenous cross-reacting mouse targets. The humanization strategy is target-dependent but ensures that the biology of the target, its physiological regulation and interacting partners are preserved. Herein, we describe a novel OX40 humanized mouse model (hOX40 model), designed to assess the efficacy and mechanism of action of compounds targeting human OX40 (hOX40). The expression of the fully human OX40 protein (human extracellular, transmembrane and intracellular domains) did not alter the distribution of immune cells in spleen, blood and bone marrow. hOX40 was expressed on CD4 and CD8 T cells upon activation and the kinetic of expression mirrored the expression of mouse OX40 in WT cells activated under the same conditions. Treg cells isolated from hOX40 mice expressed hOX40 and this expression was upregulated upon activation, also recapitulating the expression of mouse OX40 in WT cells, and suggesting that the regulation of OX40 expression was kept in the hOX40 mice. hOX40 was also found to be functional on CD4 T cells, as evidenced by the increased proliferation and cytokine production upon stimulation with human OX40 ligand. Importantly, hOX40 mice bearing MC38 tumors showed a tumor growth inhibition upon treatment with an anti-human OX40 therapy with agonist activity. This model should also enable the investigation of mechanism of action as well as tumor immunological memory, as a similar design of the hOX40 model was used for the assessment of a bispecific therapy targeting OX40 and CTLA-4 (Kvarnhammar et.al, 2019). The hOX40 mouse model is currently being crossed with other models expressing humanized immune checkpoint to enable the assessment of bispecifics and combo therapies.
Citation Format: Fabiane Sônego, Gaëlle Martin, Audrey Beringer, Chloé Beuraud, Yacine Cherifi, Alexandre Fraichard, Patricia Isnard Petit, Kader Thiam. A novel OX40 humanized mouse model for efficacy assessment of OX40-targeting therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1811.
Abstract 1815: Defining cell population diversity and T cell dysfunction in a mouse model of obesity
Authors: Baracho Gisele V. , Widmann Stephanie , Tyznik Aaron 
Published: July 2021

Abstract
Obesity creates a chronic inflammatory environment that can lead to an exhausted phenotype among T cells. Since exhausted T cells gradually lose their effector functions, obese patients may be at higher risk of developing different disorders, including infectious diseases and cancer. Using the BD FACSymphonyTM A5 Cell Analyzer, we applied a 21-color high-parameter flow cytometry panel to assess various immune cell types in a mouse model of obesity. Also, a flow-based functional assay provided insights into obesity-associated T cell dysfunction. To address progressive changes that might have been caused by a high-fat diet over time, C57BL/6 mice were fed with a high-fat diet for a period of 4 or 16 weeks. Cell populations were examined in blood, spleen and epididymal fat tissue with the latter being known as a location that harbors local inflammation in obese mice. Computational tools for high-dimensional data analysis allowed a thorough characterization of tissue-specific cell phenotypes and their relationship with obesity. Notably, the frequency of effector/memory CD8 T cells and TCRγδ T cells were increased in the fat of obese mice. However, assessment of T cell effector functions in vitro revealed an impairment in cell proliferation, suggesting that fat CD8 T cells from obese mice may not effectively respond to stimulation. Though further studies are required, these results support previous published evidence that low-grade chronic inflammation associated with obesity may impact T cell responses. The data also represent an efficient stepwise approach for staining of surface and intracellular markers and for evaluation of T cell function in vitro and demonstrates the utility of computational tools available in FlowJo™ v10 Software.
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Citation Format: Gisele V. Baracho, Stephanie Widmann, Aaron Tyznik. Defining cell population diversity and T cell dysfunction in a mouse model of obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1815.
Abstract 1822: Novel DNA encoded tumor attacking bridges (dTABs) targeting IL13Rα2 display potent tumor control in an animal model of glioblastoma multiforme
Authors: Bhojnagarwala Pratik Sanjivkumar , O'Connell Ryan , Park Daniel , Gary Ebony , Zhu Xizhou , Weiner David 
Published: July 2021

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor clinical prognosis and there is significant need for new, improved therapies. Immunotherapy is a growing therapeutic research area for patients with advanced brain cancers. DNA encoded Tumor Attacking Bridges (dTABs) are bispecific antibodies that redirect T cell activity against Tumor Associated Antigens (TAAs) of interest. Here, we describe the design and development of in vivo generated dTABs targeting IL13Rα2, which is expressed in tumors of approximately 75% of GBM patients. Four dTABs targeting 2 different epitopes of IL13Rα2 were designed to compare alternate orientations of heavy and light chains in the dTABs. All dTABs bound to U87 cells expressing target as well as CD3 on T cells. The dTABs induced T cell activation, cytokine production, and tumor killing in the presence of target expressing tumor cells in a dose dependent manner. An important issue in the field of antibody guided therapies is on target - off tumor T cell activity which can cause serious side effects in patients. In order to minimize such toxicities, we identified one arrangement of dTAB which induced high T cell activation with potent tumor killing in the presence of target expressing tumor cells, but not when co-cultured with tumors that do not express IL13Rα2. We were able to detect expression of this lead dTAB for up to 19 days in the serum of NSG mice after a single DNA injection followed by electroporation. Serum from mice injected with this dTAB activated T cells which potently killed target expressing U87 GBM cells. In a subcutaneous xenograft mouse model of human GBM, this in vivo produced dTAB demonstrated significant tumor control and improved survival of mice. This study illustrates the potential of dTABs targeting IL13Rα2 as a novel approach for immunotherapy of this difficult to treat brain cancer.
Citation Format: Pratik Sanjivkumar Bhojnagarwala, Ryan O'Connell, Daniel Park, Ebony Gary, Xizhou Zhu, David Weiner. Novel DNA encoded tumor attacking bridges (dTABs) targeting IL13Rα2 display potent tumor control in an animal model of glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1822.
Abstract 1833: Development of anti-CLDN18.2-anti-CD3 bispecific antibody as cancer therapeutics
Authors: Lin Haishan , Li Huey , Drobenaire Hunter , Pizzarella Veronica , Zhang Richard 
Published: July 2021

Abstract
Claudin-18 (CLDN18) is a member of the large Claudin family of four-span transmembrane proteins, which are essential components of the mammalian tight junctions (TJs) in the epithelial cells. Claudin-18 has two splice variants, CLDN18.1 and CLDN18.2. While CLDN18.1 is specifically expressed in the lung tissue, CLDN18.2 expression in normal tissue is more restricted and is only detected in small patches of stomach mucosal. CLDN18.2 expression is elevated in many types of epithelial cancers including stomach, esophagus, pancreatic and ovarian cancers. Anti-CLDN18.2 monoclonal antibody Claudiximab (IMAB362) demonstrated promising results in clinical trials for gastric cancers. Using a combination of DNA, protein, and transfected cells as immunogens, we have generated a panel of mouse monoclonal antibodies which are highly specific for CLDN18.2 but do not cross-react to CLDN18.1. The lead antibody E9 had higher binding affinity for CLDN18.2, compared to the IMAB362. The humanized anti-CLDN18.2 antibody showed a strong antibody dependent cytotoxicity (ADCC) activity against Mia PaCa-2 cells overexpressing CLDN18.2. To redirect T-cell-mediated lysis toward CLDN18.2-overexpressed tumor cells, we generated an anti-CLDN18.2/anti-CD3 bispecific antibody. We demonstrated that the bispecific antibody binds to both human T cells and CLDN18.2-expressing tumor cells. Furthermore, the anti-CLDN18.2/anti-CD3 bispecific antibody had robust activity in killing Mia PaCa-2 cells overexpressing CLDN18.2 in the in vitro T cell-dependent cellular cytotoxicity (TDCC) assay. In addition, the bispecific antibody retained the in vitro ADCC activity against Mia PaCa-2 cells overexpressing CLDN18.2. Taken together, our data suggest that the anti-CLDN18.2/anti-CD3 bispecific antibody is a promising cancer therapeutic candidate utilizing multiple anti-tumor mechanisms of action, including ADCC and TDCC.
Citation Format: Haishan Lin, Huey Li, Hunter Drobenaire, Veronica Pizzarella, Richard Zhang. Development of anti-CLDN18.2-anti-CD3 bispecific antibody as cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1833.