bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract TMIM-078: USING A DYNAMIC, LOW-SHEAR ENVIRONMENT TO MIMIC PHYSIOLOGICAL FLUID SHEAR STRESS IN OVARIAN CANCER IN VITRO MODELING
Authors: Masiello Timothy J. , Hemachandra L.P. Madhubhani , Castracane James 
Published: June 2021

Abstract
Ovarian cancer is the most lethal gynecological cancer with a five-year survival rate as low as 30%. Early diagnosis could offer high chances of survival as most ovarian cancer cases are diagnosed only after metastasis has taken place. Some of the challenges in diagnosis and treatment are due to ovarian cancer's preference for the transcoelomic metastatic pathway over the more well-known hematogenic pathway, where spheroids suspended in the peritoneal cavity invade through the mesothelial layer that lines it. Spheroids for in vitro experiments have been generated for decades using common methods such as hanging drops and liquid overlay, but these models typically do not account for the fluid shear stress present in vivo, especially following the formation of ascites. One method to mimic this in vitro is to use dynamic cell culture to generate shear stress. Fluid movement parameters (rotation, shaking, etc.) can be tuned to achieve physiologically-relevant shear stress while facilitating the formation of spheroids. Dynamic culture improves the roundness and size consistency of spheroids, facilitating functional assays such as spheroid migration and mesothelial clearance. The addition of shear stress is expected to increase the metastatic behavior of spheroids as it better recreates the in vivo environment. This model also provides a platform for incorporating other in vivo elements such as co-culture, use of ascites samples, etc. This work is ultimately aimed at improving our fundamental understanding of peritoneal metastasis with new insights for determining optimal therapeutic approaches.
Citation Format: Timothy J. Masiello, L.P. Madhubhani Hemachandra, and James Castracane. USING A DYNAMIC, LOW-SHEAR ENVIRONMENT TO MIMIC PHYSIOLOGICAL FLUID SHEAR STRESS IN OVARIAN CANCER IN VITRO MODELING [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-078.
Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
Authors: Horak Peter , Heining Christoph , Kreutzfeldt Simon , Hutter Barbara , Mock Andreas , Hüllein Jennifer , Fröhlich Martina , Uhrig Sebastian , Jahn Arne , Rump Andreas , Gieldon Laura , Möhrmann Lino , Hanf Dorothea , Teleanu Veronica , Heilig Christoph E. , Lipka Daniel B. , Allgäuer Michael , Ruhnke Leo , Laßmann Andreas , Endris Volker , Neumann Olaf , Penzel Roland , Beck Katja , Richter Daniela , Winter Ulrike , Wolf Stephan , Pfütze Katrin , Geörg Christina , Meißburger Bettina , Buchhalter Ivo , Augustin Marinela , Aulitzky Walter E. , Hohenberger Peter , Kroiss Matthias , Schirmacher Peter , Schlenk Richard F. , Keilholz Ulrich , Klauschen Frederick , Folprecht Gunnar , Bauer Sebastian , Siveke Jens Thomas , Brandts Christian H. , Kindler Thomas , Boerries Melanie , Illert Anna L. , von Bubnoff Nikolas , Jost Philipp J. , Spiekermann Karsten , Bitzer Michael , Schulze-Osthoff Klaus , von Kalle Christof , Klink Barbara , Brors Benedikt , Stenzinger Albrecht , Schröck Evelin , Hübschmann Daniel , Weichert Wilko , Glimm Hanno , Fröhling Stefan 
Published: June 2021

AbstractThe clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio &gt;1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population.Significance:Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659
Abstract A19: Metronomic chemotherapy enhances immunotherapy by preventing stroma-induced immunosuppression
Authors: Tsai Kelvin K. , Chan Tze-sian 
Published: June 2021

Abstract
Chemotherapy (C/T) drugs are usually administered to cancer patients every few weeks at a high, “maximum tolerated” dose (MTD). Though this approach kills the majority of tumor cells, it often spares a small number of stem-like cancer cells (CSCs) that subsequently give rise to new tumors. Moreover, these recurring tumors are often more aggressive and able to metastasize to other tissues, in part because high doses of C/T drugs also affect cells in the stromal tissue that surrounds tumors, including carcinoma-associated fibroblasts (CAFs) and immune cells. Many human solid tumors are characterized by a pronounced stromal reaction characterized by a desmoplastic response produced by CAFs as well as an extensive infiltration by immunosuppressive cell populations such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Importantly, both the tumor epithelium and adjacent stroma respond to systemic C/T and a therapy-modified stroma can deleteriously influence treatment efficacy. Recently, we have demonstrated in assorted mouse tumor models that traditional C/T using the MTD regimens of C/T agents such as cyclophosphamide, doxorubicin, gemcitabine, and paclitaxel could paradoxically render CAFs oncogenic through the stromal-epithelial ELR+-chemokine/CXCR-2 signaling axis, which expands CSCs, enhances tumor neovascularization, and induces immunosuppressive M2 subtype TAM infiltration, together leading to tumor recurrence and treatment refractoriness (Chan et al., J. Exp. Med 2016). By contrast, the same total accumulated dose of the C/T agents administered as a low-dose metronomic (LDM) regimen could largely prevent the therapy-induced stromal alterations and CSC expansion and thereby substantially enhance the treatment response. We subsequently showed that LDM C/T not only obviated the MTD-C/T-elicited CSC expansion but also attenuated the influx of the highly immunosuppressive granulocytic MDSCs, thereby potentiating immunotherapy such as anti-PD-1. We thus anticipate that, while pharmacologic inhibition of CXCR-2 has enhanced the antitumor efficacy of immune checkpoint blockade, LDM C/T may provide a clinically applicable alternative of enhancing immune surveillance in stroma-rich and T-cell inflamed tumors. Collectively, our studies provide compelling evidence and novel mechanistic insights into the unique benefit of LDM C/T on the tumor stroma. Given that MTD C/T exerts favorable influences on tumor stemness and immunity, it may better synergize with emerging CSC-targeted or immunotherapeutics than traditional MTD C/T to further enhance the therapeutic outcome of human solid tumors.
Citation Format: Kelvin K. Tsai, Tze-sian Chan. Metronomic chemotherapy enhances immunotherapy by preventing stroma-induced immunosuppression [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A19.
Abstract A24: Antigen-targeted soluble bispecific T-cell receptor (ImmTACTM) molecules in immunotherapy
Authors: Vuidepot Annelise 
Published: June 2021

Abstract
Cancer immunotherapies function to harness the body’s own immune system to eradicate cancer cells. Critical to this process is the T cell, capable of directing potent and antigen-specific immune responses. T-cell receptor (TCR) antigens are short intracellularly processed peptides presented on the cell surface. As the majority of the proteome is processed and presented on the surface of cells and hence can be targeted by a TCR, TCR-based therapies offer distinct advantages over antibody-based therapies that are limited to targeting only secreted or cell surface proteins. In this study, we describe our approach to address the limitations and utilize the natural advantages of the human TCR to target a diverse range of tumor indications. Immune mobilizing monoclonal TCRs Against Cancer (ImmTAC) molecules are a novel class of bispecific biologic formed from an affinity-engineered, soluble, targeted TCR fused to a T cell redirecting anti-CD3 scFv. We describe our process to engineer high-affinity ImmTAC molecules towards novel cancer antigens that have been identified and validated in house. Additionally, we discuss the challenges and opportunities in the preclinical testing of an exquisitely human-specific biologic that led to the development of an entirely in vitro preclinical package that is proven to support the clinical development of ImmTAC molecules to clinical development. In summary, we present a novel approach to cancer immunotherapy, detailing the engineering, optimization, preclinical testing and clinical development of ImmTAC molecules, a new bispecific biologic.
Note: This abstract was not presented at the conference.
Citation Format: Annelise Vuidepot. Antigen-targeted soluble bispecific T-cell receptor (ImmTACTM) molecules in immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A24.
Abstract A31: Comparing IL-12 and IL-18 secreting CAR T-cell efficacy
Authors: Bebernitz Christina E. , Brentjens Renier J. 
Published: June 2021

Abstract
MUC16, a subunit of CA125 that is overexpressed on epithelial ovarian cancers, can be targeted by T cells via the incorporation of the 4h11m28m chimeric antigen receptor (CAR) into the T-cell surface. However, the microenvironment of ovarian cancers consists of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages that act to immunosuppress CAR T-cell function, thus abrogating CAR T-cell efficacy. To overcome this immunosuppression, our lab has developed IL-12 and IL-18 secreting CAR T cells, which have shown enhanced efficacy in a syngeneic ovarian cancer model when compared to second-generation CAR T cells. While IL-18 secreting CAR T cells have proven to be superior to IL-12 secreting CAR T cells in various leukemia and lymphoma mouse models, this observation does not translate to the ovarian cancer model. Mechanistic studies into the effects of IL-18 and IL-12 in a syngeneic ovarian cancer model are currently under way in order to better understand what each cytokine is doing to the tumor microenvironment as well as to the CAR T cell. With better understanding of the effects of IL-18 and IL-12, we can contribute to the immunobiology of these cytokines as well as harness their efficacy to apply to other tumor models.
Citation Format: Christina E. Bebernitz, Renier J. Brentjens. Comparing IL-12 and IL-18 secreting CAR T-cell efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A31.
Abstract A61: The positive effect of SKD plus IOT and HBO2T in the treatment of cancer
Authors: Niknamian Sorush 
Published: June 2021

Abstract
Background: The aim of this research is to figure out the effectiveness of the Sorush Cancer Treatment Protocol (SCTP), which is based on the Evolutionary Metabolic Hypothesis of Cancer (EMHC) and introducing the Specific Ketogenic Diet (SKD) plus Intravenous Ozone Therapy (IOT) in phase (1) on 54 cancer patients, and combination of hyperbaric oxygen therapy with vitamin/mineral and herbal supplementation beside the SKD and IOT in phase (2) of this research on the remaining 31 cancer patients.
Introduction: Cancer based on the introduction of EMHC by Dr. Somayeh Zaminpira and Dr. Sorush Niknamian in 2017 is an evolutionary metabolic disease and through the incline of the reactive oxygen species (ROS) and the Butterfly Effect in normal eukaryotic cells, the mitochondria become damaged or shut down. Cancer cells are primitive eukaryotic cells that have existed since around 1.5 billion years ago before the entrance of mitochondrion as endosymbiont.
Materials and Methods: Based on the researches from 1928-2016 and the experimentation of cancer treatments and protocols on cancer patients, we have reached a treatment and decided to test it on 54 voluntary cancer patients in the first stage of their disease. In this treatment we used a 5-day water fasting state, the Specific Ketogenic Diet (SKD) designed by ourselves and Intravenous Ozone Therapy (IOT) in the duration of 90 days (phase 1) and another 90 days (phase 2) with the entrance of hyperbaric oxygen therapy (HBO2T) and several supplements that have been effective in previous studies on cancer patients. We have used the measurement of saliva PH, the MRI device and statistical methods to test the shrinkage of the tumors.
Results: After phase (1) of this research on 54 patients, the average percentage decrease in the tumors was 58%, and after phase (2) on 31 remaining cancer patients the average percentage decrease in the tumors was 98.8%. The average saliva PH in the fasting state of the cancer patients improved from acidic to alkaline as well.
Conclusion: We have reached an effective cancer treatment based on SCTP by the usage of SKD, IOT, HBO2T and several supplements. There was an obvious improvement of cancer tumor decrease, lifestyle, and saliva PH, and we did not observe any side effects or cachexia in any of the patients.
Citation Format: Sorush Niknamian. The positive effect of SKD plus IOT and HBO2T in the treatment of cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A61.
Abstract A62: Directly visualizing interactions between lung microbiota, tissue-resident immune cells and tumor cells in a genetically engineered lung adenocarcinoma mouse model
Authors: Zhao Chen , Li Weizhe , Jin Chengcheng , Germain Ronald N. 
Published: June 2021

Abstract
Lung adenocarcinoma is closely associated with chronic inflammation, but the underlying mechanism has not been fully elucidated yet. As a mucosal organ, lung was thought to be sterile in the past due to the limitation of bacteria culture techniques, but recent 16s RNA sequencing analysis has proved that lung is colonized by a diverse bacterial community. Recent studies suggest that the dysbiosis of lung microbiota plays a critical role in lung cancer tumorigenesis. However, there is no direct evidence addressing the complex interactions between local microbiota, immune cells and tumor cells due to the limitation of traditional imaging methods. Here we developed an advanced imaging technique combining RNA fluorescent in situ hybridization, immunostaining and Clearing-enhanced 3D (Ce3D), and applied it in a genetically engineered mouse model harboring the most common mutations (activation of Kras and p53 loss of function) in patients with lung adenocarcinoma. It revealed a strong spatial-temporal correlation between lung microbiota and tissue-resident immune cells during lung adenocarcinoma development. This research was supported by the Intramural Research Programs of NIAID and NHLBI, NIH.
Citation Format: Chen Zhao, Weizhe Li, Chengcheng Jin, Ronald N. Germain. Directly visualizing interactions between lung microbiota, tissue-resident immune cells and tumor cells in a genetically engineered lung adenocarcinoma mouse model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A62.
Abstract A64: Commensal dysbiosis alters the tumor microenvironment in breast cancer and diminishes efficacy of PD-L1 blockade
Authors: Rosean Claire Buchta , Bostic Raegan , Feng Tzu Yu , Rutkowski Melanie R. 
Published: June 2021

Abstract
Hormone receptor-positive (HR+) breast cancer is largely nonresponsive to checkpoint blockade therapy. Alterations in the composition of commensal microbes influence the systemic immune environment and can diminish responses to checkpoint blockade. Reduced diversity of commensal microbes, known as dysbiosis, has been demonstrated in women with advanced breast cancer and is associated with increases of systemic immunosuppressive mediators that are detrimental in the context of breast cancer, including prostaglandin E2 (PGE2). This bioactive lipid promotes the differentiation of myeloid cells that can exert immunosuppressive effects in the tumor microenvironment. In a novel, clinically relevant model of HR+ breast cancer, PD-L1 blockade was effective when combined with meloxicam, a drug that targets PGE2 synthesis through inhibition of COX-2. However, this combination therapy was ineffective in mice that were previously treated with antibiotics to induce dysbiosis, despite elevated levels of PGE2 in these animals. Commensal dysbiosis altered the cellular composition within the tumor microenvironment, promoting the recruitment of suppressive myeloid populations and driving significant and irreversible T-cell dysfunction. Importantly, COX-1 also regulates PGE2 synthesis, and mammary glands from dysbiotic mice showed significantly enhanced COX-1 activity, suggesting a previously unknown mechanism by which dysbiosis can affect breast tumor progression and resistance to therapy. Targeting COX-1-mediated PGE2 synthesis resulted in decreased tumor burden only in dysbiotic mice, suggesting that dysbiosis-induced COX-1-mediated tissue inflammation is sufficient to drive immune suppression in advanced breast cancer. This work provides important insights on the premalignant environment in the breast, enhances our understanding of the mechanisms driving failure of PD-1/PD-L1 blockade, and identifies novel targets that may provide clinical benefit for women with breast cancer.
Citation Format: Claire Buchta Rosean, Raegan Bostic, Tzu Yu Feng, Melanie R. Rutkowski. Commensal dysbiosis alters the tumor microenvironment in breast cancer and diminishes efficacy of PD-L1 blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A64.
Abstract A70: IFN-III is selectively produced by cDC1 and predicts good clinical outcome in human breast cancer
Authors: Hubert Margaux , Couillault Coline , Manh Thien Phong Vu , Ollion Vincent , Lopez-Mestre Helene , Rahmouni Nabil , KIielbassa Janice , Rodriguez Celine , Sajous Christophe , Dumont Benoit , Doffin Anne-Claire , Treilleux Isabelle , Tredan Olivier , Dalod Marc , BendrissS-Vermare Nathalie , Caux Christophe , Valladeau-Guilemomd Jenny 
Published: June 2021

Abstract
Dendritic cells (DCs) play a key role in the orchestration of antitumor immune responses. The cDC1 subset was demonstrated as essential for tumor control and response to immunotherapies in mice, but its precise role in human is largely unexplored. In our study, we combined the analysis of large cohorts of fresh breast and ovarian primary tumors and of public transcriptomic data sets to elucidate human cDC1 functions and clinical impact compared with other DC subsets. We identified a key role for intratumoral cDC1 in producing selectively type III interferon (IFN-III), strongly associated with cytokines and chemokines promoting cytotoxic immune cell recruitment and activation. Of utmost importance, we also revealed a positive impact of IFN-III and cDC1 on patient outcome in many human cancers and identified TLR3-triggering as a therapeutic strategy to trigger IFN-III production by tumor-associated cDC1. These data may pave the way for new IFN or cDC1-targeting antitumor therapies.
Citation Format: Margaux Hubert, Coline Couillault, Thien Phong Vu Manh, Vincent Ollion, Helene Lopez-Mestre, Nabil Rahmouni, Janice KIielbassa, Celine Rodriguez, Christophe Sajous, Benoit Dumont, Anne-Claire Doffin, Isabelle Treilleux, Olivier Tredan, Marc Dalod, Nathalie BendrissS-Vermare, Christophe Caux, Jenny Valladeau-Guilemomd. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in human breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A70.
Abstract A78: IFNg-activated lymphatic vessels express PD-L1 and suppress effector T-cell function in melanoma
Authors: Lane Ryan S. , Breazeale Alec P. , Lund Amanda W. 
Published: June 2021

Abstract
Peripheral tissues adopt mechanisms of immune suppression that counteract protective immunity to prevent immunopathology and are co-opted by tumors for immune escape. In tumors, cytotoxic, antigen-specific T cells produce IFNg and activate multiple mechanisms of adaptive immune resistance, including upregulation of the T-cell inhibitory molecule programed death ligand 1 (PD-L1). Tumor cell PD-L1 expression does not predict response to anti-PD-L1 immunotherapy, indicating, however, that other sources of PD-L1 in tumor microenvironments may contribute to PD-L1-dependent immune suppression. Lymphatic vessels facilitate antigen and dendritic cell transport to draining lymph nodes and are required for antitumor immunity. Interestingly, lymphatic endothelial cells in lymph nodes are tolerogenic at steady-state and constitutively express PD-L1 to delete self-reactive CD8+ T cells. However, whether lymphatic endothelial cells in tumor microenvironments are also directly immunosuppressive remains unclear. Here we test the hypothesis that peripheral, tumor-associated lymphatic vessels acquire immunosuppressive mechanisms, e.g., PD-L1 expression, that limit effector CD8+ T-cell accumulation and function in melanoma. We demonstrate that host nonhematopoietic, nontumor, PD-L1 limits CD8+ T-cell accumulation in murine melanoma. Further, we show that tumor-associated lymphatic endothelial cells upregulate PD-L1 in response to IFNg produced by tumor-infiltrating, antigen-specific CD8+ T cells. As such, loss of IFNgR by lymphatic endothelial cells improves CD8+ T-cell accumulation in murine melanomas, thereby enhancing tumor control and improved overall survival. Importantly, this robust lymphatic vessel-dependent tumor control was revealed in the context of murine melanomas with significant UVB-induced somatic mutation burden, consistent with a cytotoxic T cell-mediated negative feedback mechanism. Consequently, we present IFNg-mediated activation of tumor-associated lymphatic vessels as a new component of adaptive immune resistance, suggesting that context-dependent lymphatic vessel function may provide novel, targetable mechanisms of immune control in melanoma.
Citation Format: Ryan S. Lane, Alec P. Breazeale, Amanda W. Lund. IFNg-activated lymphatic vessels express PD-L1 and suppress effector T-cell function in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A78.