bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A015: Cellular immunomonitoring for personalized adoptive cellular therapy trial ACTolog® (IMA101-101)
Authors: Mendrzyk Regina , Ulges Alexander , Demberg Thorsten , Stephens Geoffrey , Reinhardt Carsten , Walter Steffen , Maurer Dominik 
Published: February 2019

Abstract
Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g., only one target is addressed), or iii) off-target toxicities (e.g., expression of targets on normal tissues). ACTolog® concept, utilizing antigen specific T-cells (IMA101), identified by the Immatics’ proprietary XPRESIDENT® technology, is intended to overcome these limitations by introducing multiple novel tumor targets. ACTolog® is a personalized ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Target positive tumors are identified by qPCR. Expression levels predictive for antigen presentation are determined by mass spectrometry. Autologous T-cells against ACTolog targets are in vitro primed in the presence of IL-21 followed by HLA tetramer-guided cell sorting and expansion prior to infusion. IMA101-101 is a first-in-human clinical trial in HLA-A*02:01 positive patients with relapsed or refractory solid tumors using the multitargeted ACTolog® approach in which up to four products with different tumor target-specificities are manufactured and infused for each patient. We developed two flow cytometric phenotyping assays that allow us to determine the frequency of target-specific cells in the final product and persisting cells in the blood as well as to deeply characterize the memory marker expression (CD45RA, CCR7, CD27, CD28, CD45RO, CD62L, CD57, CD127) and immune checkpoint expression (CD137, LAG-3, PD-1, TIGIT, TIM-3) of target-specific cells. Product characterization and initial persistence data of the three first treated patients revealed a high prevalence of persisting target-specific cells in the blood until 2 months after infusion as well as a favorable phenotype of target-specific cells. At the conference 6 months’ data for one patient will be available and presented.
Citation Format: Regina Mendrzyk, Alexander Ulges, Thorsten Demberg, Geoffrey Stephens, Carsten Reinhardt, Steffen Walter, Dominik Maurer. Cellular immunomonitoring for personalized adoptive cellular therapy trial ACTolog® (IMA101-101) [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 A015.
Abstract A026: Novel electroporation method for quick CAR-T-cell manufacture
Authors: Chen Jian , Xia Xiaofeng 
Published: February 2019

Abstract
CAR-T-cells are currently manufactured for clinical use by infection of human T-cells with viral vectors containing the CAR gene. T lymphocytes have to be stimulated and expanded ex vivo because the viral vectors infect fresh natural lymphocytes very poorly. The viral vector approach is extremely expensive due to the high cost of virus production and the high cost of long-term cell expansion that could take 10-14 days in a GMP facility. The viral vector approach also has a huge biologic downside: ex vivo expanded T-cells become bulky and lose efficacy against tumor cells. The use of electroporation technology in CAR-T-cell manufacturing has attracted increasing interests for its low cost and the wide range of applications, including transposon based stable CAR expression, transient expression and genome editing. However, actual clinical use of electroporation technology in CAR-T has been difficult and several clinical trials have met significant problems due to the poor transfection efficiency and decreased T-cell survival with traditional electroporation methods. Through theoretical analysis of the other existing electroporation technologies, we found that they all have problems in electrophysical design. The problems include physical design of devices, electrical pulse selection, and buffer composition. With a redesigned electroporation system, we can now achieve very high transfection efficiency for T-cells while maintaining cell survival. For Sleeping Beauty transposon-based CAR expression, we found that over a period of two to three weeks the efficiency can get to 60% to 90% with fasT-cell proliferation. The protein expression time after electroporation is very short. For simple GFP plasmids we can observe GFP expression after only 30 minutes. Unlike viral vectors, electroporation works well on fresh natural T-cells, thereby eliminating the need for expensive cell expansion and virus production altogether and cutting the huge economic burden of CAR-T therapy. By reinfusion of more natural T-cells, the antitumor efficacy of CAR-T-cells could be improved while the side effects of cytokine release syndrome could be minimized.
Citation Format: Jian Chen, Xiaofeng Xia. Novel electroporation method for quick CAR-T-cell manufacture [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 A026.
Abstract A048: Targeting the tumor microenvironment to enhance immunotherapy against cancer
Authors: Slaney Clare Y. , Oliver Amanda J. , Kershaw Michael H. 
Published: February 2019

Abstract
Immunotherapies that harness the immune system against cancer are an attractive proposition for cancer treatment. While there have been some promising successes, only a small fraction of patients obtain clinical benefit. It has become clear that the immunosuppressive tumor microenvironment (TME) is a major obstacle for immunotherapies, because the TME suppresses immune responses, leading to reduced efficacy. We previously demonstrated that the site of tumor growth is a major determinant in sculpting the organ-specific TME, and thus predisposes treatment efficacy (1). In this project, we hypothesize that the TME of visceral tumors is more immunosuppressive than those of the tumors growing elsewhere. We investigated in murine models the difference in the TME in breast cancer growing orthotopically and the same breast cancer growing in the common metastatic sites, such as the lungs. Our findings showed that the breast cancer growing in the lungs was resistant to immunotherapies such as anti-PD1 and anti-CTLA-4, whereas the breast cancer growing orthotopically could be completely eradicated even when the cancer burden was greater. Through an institutional prospective community-based rapid autopsy program (CASCADE), we obtained genetically matched metastases and surrounding tissues from several sites in the same breast cancer patients and investigated the TME from these tumors using novel technologies such as RNAseq and multiplex immunohistochemistry. Strikingly, the TMEs from the same organs in different patients have similar immune gene expression profiles and in contrast, TMEs from the same patient differ greatly in different organs. Together, our research demonstrates an organ-specific difference between TMEs that leads to different responses to therapies. We anticipate that further study of how cancer cells sculpt the TME at different sites will greatly enhance our understanding of the TME and provide promising targets to enhance current immunotherapies, especially for patients who do not respond to existing therapies. Reference: 1. Devaud C., et al. Molecular Therapy 2014;22:18-27.
Citation Format: Clare Y. Slaney, Amanda J. Oliver, Michael H. Kershaw. Targeting the tumor microenvironment to enhance immunotherapy against 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 A048.
Abstract A055: Lineage–tracing reveals a unique contribution of embryonic macrophages to NSCLC progression
Authors: Casanova Maria 
Published: February 2019

Abstract
Macrophages are the professional phagocytes of the innate immune system required to remove cellular debris and maintain tissue homeostasis. However, they can also play a role in the pathophysiology of many diseases. In non-small-cell lung carcinoma (NSCLC), macrophages constitute one of the major leukocyte subsets founds in tumors and contribute to immunosuppression by releasing growth factors, inhibiting immune T-cell surveillance, and enhancing angiogenesis, among other mechanisms. Importantly, macrophages in the lung can arise from embryonic or from adult hematopoietic precursors derived from the bone marrow (BM). This dual source of phagocytes has long been ignored and their contribution to tumor progression and response to immunotherapy has remained largely unexplored. Here we propose to analyze the role of macrophages during early and late stages of NSCLC. Using lineage-tracing murine models, tumor spheroids, and high-dimensional techniques to capture macrophage heterogeneity within the lesions (scRNAseq), we found that embryonic macrophages are progressively excluded from the tumor mass, whereas BM-derived ones are evenly distributed. Depletion of embryonic macrophages in a pretumor implantation setting diminishes tumor size and metastasis and leads to an increase in T-cell infiltration and antitumor activity, whereas elimination of tissue-resident macrophages post-tumor implantation does not impact tumor burden or immunity. Importantly, early human NSCLC lesions (stage I) show reduced macrophage infiltrates within the tumor microenvironment, which correlate with poor T-cell infiltration. Our findings suggest that macrophage ontogeny plays a pivotal role in tumor immunity. In this context, we aim to develop novel immunotherapies that harness embryonic macrophages to prevent tumor progression during early phases of lung cancer.
Citation Format: Maria Casanova. Lineage–tracing reveals a unique contribution of embryonic macrophages to NSCLC progression [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 A055.
Abstract A060: Targeting glioma-macrophage interplay via LOX in PTEN-deficient glioblastoma
Authors: Chen Peiwen , Wang Alan , DePinho Ronald 
Published: February 2019

Abstract
Glioblastoma multiforme (GBM) is the most lethal form of brain cancer in adults. The median survival of GBM patients is only about one year after initial diagnosis. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways, including RTK/RAS/PI3K/PTEN, P53/ARF/MDM2 and RB/CDKN2A pathways. However, targeted therapies, such as therapy against EGFR, have failed in the clinic, and no effective therapeutic drugs are available to target tumor suppressors. A key reason for therapeutic failure is inter- and intra-tumoral cancer cell genetic instability and heterogeneity, resulting in aberrant activation of multiple signaling pathways within and across tumors. Stromal/immune cells in the tumor microenvironment (TME) are genetically stable, which not only play a pivotal role in GBM progression by affecting multiple cancer hallmarks, but can also be educated by cancer cells. However, whether and how the behavior and function of specific stromal/immune cells in the TME are regulated by cancer cell with specific genetic alterations in GBM remain relatively undefined. Utilizing a large scale of bioinformatic analysis in TCGA GBM patients, we revealed that genetic alteration (deletion/mutation) of PTEN in GBM patients specifically triggers immune response by promoting macrophage recruitment, without affecting macroglia and other immune cells. Using unbiased transcriptome profiling following functional validation, we identified that lysyl oxidase (LOX) is preferentially secreted by PTEN-deficient cancer cells. In vitro transwell migration assay and in vivo Matrigel Plug assay demonstrated that LOX is a potent macrophage chemoattractant. Transcriptome profiling following Gene Set Enrichment Analysis (GSEA) and functional validation demonstrated that activation of SRC and AKT signaling pathways drives LOX upregulation in PTEN-deficient cancer cells. Genetic and pharmacologic inhibition of LOX in PTEN-deficient cancer cells does not affect tumor cell proliferation in vitro, but markedly inhibits macrophage density and tumor growth in vivo. Using the bioinformatics analysis in clinical GBM samples, we demonstrated that LOX is enriched in GBM patients with higher macrophage density, and that these patients show lower survival. Together, our findings highlight the significance of PTEN-LOX axis in macrophage infiltration in GBM, and demonstrate a possibility of improving GBM treatment by targeting this axis-mediated macrophage recruitment.
Citation Format: Peiwen Chen, Alan Wang, Ronald DePinho. Targeting glioma-macrophage interplay via LOX in PTEN-deficient glioblastoma [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 A060.
Abstract A078: Dissecting the myeloid lineage in human gliomas
Authors: Han Claudia Z. , Duttke Sascha H. , Ouyang Zhengyu , Preissl Sebastian , Schlachetzki Johannes C.M. , Nott Alexander , Fitzpatrick Conor , O'Connor Carolyn , Coufal Nicole G. , Gupta Mihir , Gonda David D. , Levy Michael L. , Sharona Ben-Haim , David Barba , Ciacci Joseph D. , Khalessi Alexander A. , Chen Clark C. , Ren Bing , Glass Christopher K. 
Published: February 2019

Abstract
The immune cell composition of the tumor microenvironment can be a decisive factor for tumor pathogenesis. Gliomas are tumors that develop from the glial cells of the brain and spinal cord and make up to 30% of all brain tumors. In gliomas, microglia and infiltrating macrophages can comprise up to 30 to 50% of total tumor-associated cells. Increased CD68 staining, a marker of microglia/macrophages, in adult gliomas is positively associated with histologic tumor grade. Despite the accumulated evidence substantiating a critical role for microglia and infiltrating macrophages in gliomagenesis, little is known is about the molecular mechanisms driving microglial contribution to tumor growth and whether microglia/macrophages are therapeutic targets in both low- and high-grade gliomas. Despite microglia sharing common properties with other tissue-resident macrophages, they express hundreds of genes at higher levels compared to other tissue-resident macrophages, many of which are influenced by the brain micro-environment. Additionally, engraftment of bone-marrow derived cells into the central nervous system fails to produce microglia identical to yolk sac-derived microglia at the transcriptional level. Hence, in any inflammatory context, including cancer, an interesting question arises: how does each population contribute to the pathogenesis and/or resolution of inflammation? To elucidate the role(s) of microglia/macrophages in gliomas, we isolated the myeloid fraction from primary pediatric and adult low-grade and high-grade gliomas using flow cytometry. By integrating bulk and single-cell transcriptome analysis, we find significant inter- and intratumoral heterogeneity within the myeloid population. Additionally, we find evidence for tumor environment-dependent gene change. In combination with ongoing comparative analysis of the corresponding epigenetic landscapes of the myeloid populations, we seek to decipher how the tumor microenvironment reprograms the transcription factor network in microglia/macrophages to generate tumor-promoting cells.
Citation Format: Claudia Z. Han, Sascha H. Duttke, Zhengyu Ouyang, Sebastian Preissl, Johannes C.M. Schlachetzki, Alexander Nott, Conor Fitzpatrick, Carolyn O'Connor, Nicole G. Coufal, Mihir Gupta, David D. Gonda, Michael L. Levy, Ben-Haim Sharona, Barba David, Joseph D. Ciacci, Alexander A. Khalessi, Clark C. Chen, Bing Ren, Christopher K. Glass. Dissecting the myeloid lineage in human gliomas [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 A078.
Abstract A081: Tumors expressing ACKR1 exhibit a unique signature of tumor-infiltrating immune cells in women with breast cancer
Authors: Jenkins Brittany D. , Fleifel Talina , Martini Rachel , Ali Haythem , Newman Lisa , Davis Melissa 
Published: February 2019

Abstract
Tumor-associated immune cells, stroma and several other cell types make up the complex tumor microenvironment (TME) that contributes to a broad spectrum of potential clinical outcomes for breast cancer (BC) patients. Part of this delicate interplay is the interaction between pro-inflammatory chemokines and their receptors, which direct the migration of immune cells to areas of tumor-associated inflammation. Our focus in this complex process is on the role of the Atypical Chemokine Receptor 1 (ACKR1/DARC). In general immune response, its expression on erythrocytes helps to maintain chemokine homeostasis by sequestering chemokines in circulation while its expression on endothelial tissue transcytoses the chemokines from tissue into circulation, which ultimately affects which immune cells are brought to the TME. Its role in epithelial tissue expression is less understood. The purpose of this study is to investigate differential gene expression of ACKR1 in breast epithelial tumor tissue through IHC methods, and to determine how that expression correlates with both circulating and infiltrating proinflammatory chemokines. In addition, we will show this role to be associated with specific classes of tumor-infiltrating lymphocytes (TIL) in BC. Circulating chemokine levels for a variety of ACKR1-associated proinflammatory chemokines were determined using Luminex multiplexing assays. Results from our study cohort indicate differential expression of ACKR1 on epithelial tumor tissue, which correlated with a unique signature of immune cell infiltrates and associated proinflammatory chemokines. Tumors positive for AKCR1 expressed higher levels of circulating and infiltrating CCL2 (MCP-1) and lower levels of CXCL8 (IL-8). Tumor-expressing ACKR1 was also found to be associated with T-cells, B-cells, macrophages, and monocytes, where positive tumors tended to express a more robust profile of TILs. Our preliminary data suggest the presence or absence of ACKR1 on breast epithelial tumor tissue can influence the chemokine and immune cell profile within the TME, which can ultimately influence tumor aggressiveness, proliferation, and response to treatments, such as immunotherapies.
Citation Format: Brittany D. Jenkins, Talina Fleifel, Rachel Martini, Haythem Ali, Lisa Newman, Melissa Davis. Tumors expressing ACKR1 exhibit a unique signature of tumor-infiltrating immune cells in women with breast 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 A081.
Abstract A086: Omental fat in ovarian cancer induces lymphangiogenesis
Authors: Lenoir Bénédicte M.A. , Ferber Dyke , Starrach Victor , Suarez-Carmona Meggy , Schott Sarah , Zoernig Inka , Jäger Dirk , Halama Niels 
Published: February 2019

Abstract
Ovarian cancer metastasis occurs by direct multifocal seeding into the peritoneum as well as by migration through the lymphatic system. High-grade ovarian carcinoma patients often present with distant metastases. Significant risk factors for the development of those are stage, grade, and lymph node involvement. The increase of the number of lymphatic vessels seems to be implicated in ovarian tumor progression. While the tropism of ovarian cancer cells for fat is well described, the potential impact of an adipose-rich microenvironment on the dissemination of metastasis via lymphatic vessels has never been investigated. So far, in this study, we examined the effect of omental fat on lymphangiogenesis in ovarian carcinoma. For that we used a cohort of 80 ovarian cancer specimens. We observed a higher number of tumor-associated vessels and principally lymphatic vessels in ovarian cancer in contact with the omentum. These lymphatic vessels are predominantly localized along the fat tissue. A higher secretion of VEGF-C is observed in ovarian tissues containing fat compared to the ones without fat, giving a potential explanation to the observed increase of lymphatic vessels in fatty tissues. We also developed a healthy fat tissue explant culture model and treated whole tissue explants with ascites. Herein, we saw an increase of the number of adipose-derived stem cells (ADSCs). These ADSCs express lymphatic markers such as D2-40 and Lyve-1. We also observed an impact of fat supernatant on the proliferation, migration and tube formation of lymphatic endothelial cells in vitro. In conclusion, we can say that omental fat in ovarian cancer seems to have an impact on lymphangiogenesis. The close contact of ascites with fat tissue seems to lead to a differentiation of adipose-derived stem cells into lymphatic endothelial cells. Further investigations must be performed to understand the exact mechanisms underlying this phenomenon.
Citation Format: Bénédicte M.A. Lenoir, Dyke Ferber, Victor Starrach, Meggy Suarez-Carmona, Sarah Schott, Inka Zoernig, Dirk Jäger, Niels Halama. Omental fat in ovarian cancer induces lymphangiogenesis [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 A086.