bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 537: Antibody drug conjugate to treat triple negative breast cancer
Authors: Si Yingnan , Dang Nghi , Kim Seulhee , Zhou Lufang , Han Xiaosi , Liu Runhua , Liu Xiaoguang (Margaret) 
Published: August 2019

Abstract
Triple negative breast cancer (TNBC) is characterized by rapid growth, metastasis, and high recurrence. The severe adverse effects and drug resistance associated with standard cytotoxic chemotherapies minimize their clinical benefits. The anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) had been developed and tested to treat TNBC, but no significant efficiency was demonstrated in clinical trials. The goal of this study was to develop a novel antibody-drug conjugate (ADC) to treat TNBC. Specifically, we established a platform to conjugate anti EGFR mAb with mertansine, which inhibits cell division by blocking tubulin polymerization, and also improved the conjugation efficiency by optimizing the linker and drug-to-antibody ratio. Flow cytometry and live cell confocal laser scanning microscopy analysis confirmed that the anti-EGFR ADC can specifically bind to multiple TNBC subtypes, is effectively internalized, and release potent drug intracellularly within 1 hour after mixing. The IC50 study showed that the anti-EGFR ADC killed &gt;90% TNBC cells with dose of 5 nM. The TNBC xenograft mouse model also showed that the constructed ADC had high anticancer efficacy and successfully inhibited tumor growth. Moreover, the live-animal imaging using In Vivo Imaging System and the tissue microarray samples with immunohistochemical analysis of TNBC and organs indicated that our ADC specifically target TNBC in vivo. Further evaluations, such as maximal tolerated dose (MTD), pharmacokinetics (PK), and biodistribution, are needed. To summarize, we developed an EGFR-targeted ADC, which could provide an effective targeted therapy to treat TNBC and improve the life quality and survival rate of patients with TNBC.
Note: This abstract was not presented at the meeting.
Citation Format: Yingnan Si, Nghi Dang, Seulhee Kim, Lufang Zhou, Xiaosi Han, Runhua Liu, Xiaoguang (Margaret) Liu. Antibody drug conjugate to treat triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 537.
Abstract 54: Characterization of patient-derived organoids cultured on a gas-rich, liquid-liquid interface
Authors: Shoemaker James T. , Richardson Katherine R. , Arnst Jamie , Marcus Adam , Vukasinovic Jelena 
Published: August 2019

Abstract
Modeling tissues in vitro has long consisted of two-dimensional (2D) monolayer cultures grown in a dish, flask, or multi-well plate. While these methods remain adequate for some applications, the advent of personalized cancer therapies has necessitated the development of more complex models that more accurately represent the in vivo environment. Attempting to characterize tumor cell biology and response to candidate pharmaceuticals in 2D cultures has led to results that fail to translate to clinical therapies. A key source of this failure is the loss of cell diversity due to selective pressure resulting in cell populations that favor adhering to a rigid substrate. Three-dimensional (3D) cell culture methods have produced models that capture many of the dynamics of the in vivo tissue environment. Patient-derived organoids (PDOs) are quickly becoming the most attractive solution for creating predictive, patient-specific tumor models in vitro. Typically grown as spheroids, these models still present limitations in terms of cell survival and recapitulation of tumor development.
Lena Biosciences has previously developed complex, vascularized tissue models using patented 3D scaffolds and a perfusion system. Hepatocytes grown in this system demonstrated increased cell viability and recovery of cytochrome P450 enzyme activity compared to 2D controls. Integral to the perfusion system is a pure, synthetic liquid that is twice as dense as and immiscible with cell culture medium and reagents. It is permissive to atmospheric gases, providing a gas-rich, liquid-liquid interface below 3D cultures maintained in the system. We hypothesized that PDOs could be cultured without a 3D scaffold, directly at the interface between the cell culture medium and this synthetic liquid. A specific preparation of this interface resulted in lung-derived PDOs that spontaneously formed dense, 3D, tissue-like structures that showed increased viability (as measured by a 50% reduction in LDH release) and cellular respiration (three-fold increase as measured by an alamarBlue assay). Ongoing studies are focused on characterizing PDOs from other patients and other tissues as they develop in long-term in vitro studies. Should this PDO model prove to be a faithful representation of in vivo tumor development, this system would be ideal for applications such as testing drug efficacy and studying mechanisms of tumor metastasis.
Citation Format: James T. Shoemaker, Katherine R. Richardson, Jamie Arnst, Adam Marcus, Jelena Vukasinovic. Characterization of patient-derived organoids cultured on a gas-rich, liquid-liquid interface [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 54.
Abstract 550: Tumor-conditional anti-CTLA-4 uncouples anti-tumor efficacy from immunotherapy-related toxicity
Authors: Pai Steven C. , Simons Donald M. , Lu Xiaoqing , Ritacco Wendy , Evans Michael , Kingsbury Gillian , Fong Lawrence 
Published: August 2019

Abstract
While immune checkpoint blockade leads to potent anti-tumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in multi-organ inflammation including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA-4 antibody (anti-CTLA-4 DVD) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA-4 binding domain. Upon reaching the tumor, the outer domain is cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA-4 blockade. Anti-CTLA-4 DVD significantly reduced multi-organ immune toxicity by preserving tissue-resident regulatory T cells (Tregs) in Rag 1-/- mice that received naïve donor CD4+ T cells from wild-type C57BL/6j mice. Moreover, anti-CTLA-4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2 bearing C57BL/6j mice. Tregs depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA-4 without the FcγR binding portion (anti-CTLA-4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrated a new approach to anti-CTLA-4 blockade that depletes tumor-infiltrating, but not tissue-resident Tregs, preserving anti-tumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA-4 DVD provides an avenue to uncouple anti-tumor efficacy from immunotherapy-induced toxicities.
Citation Format: Steven C. Pai, Donald M. Simons, Xiaoqing Lu, Wendy Ritacco, Michael Evans, Gillian Kingsbury, Lawrence Fong. Tumor-conditional anti-CTLA-4 uncouples anti-tumor efficacy from immunotherapy-related toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 550.
Abstract 565: A novel T-cell costimulatory Humabody® VH therapeutic for PSMA-positive tumors
Authors: Legg James W. , McGuinness Brian , Archer Sophie , Bland-Ward Phil , Brucklacher Verena , Craigen Jenny , Edwards Carolyn , Hames Emma , Majithiya Jay , Pisa pavel , Revi Bhindu , Royale Nikki , Sette Angelica , Teng Yumin , Thompson Lorraine , Wang Wembin , Wilson Chris , Wyre Chris , Rossant Chris 
Published: August 2019

Abstract
Agonistic monoclonal antibodies targeting CD137/4-1BB have shown much preclinical promise but their clinical development has been slowed due to a poor therapeutic index, in particular liver toxicity. CB307 is a novel half-life extended bispecific Humabody VH targeting CD137 (4-1BB) and prostate specific membrane antigen (PSMA). The design of CB307 enables agonism of CD137 selectively in the presence of PSMA positive tumour cells and in this way enable tumour selective T cell activation whilst minimising systemic activation. The molecular weight of CB307 is less than 50 kDa (around a third of the size of a standard IgG) and it does not contain an Fc domain, thereby avoiding interaction with Fc receptors. Half life extension is achieved through the inclusion of a VH domain with specificity for human serum albumin (HSA). The identification of CB307 using the Crescendo Mouse™ which develops fully human VH domains in a background devoid of light chains will be described along with characterisation of the key properties of the molecule in in vitro and in vivo models. In dual target binding assays CB307 shows potent co-binding to both PSMA and CD137 targets and mediates CD137 signalling in an NFKB cell reporter assay in the presence of PSMA positive cells but not PSMA negative cells. Co-incubation of primary human T-cells from healthy individuals or cancer patients together with PSMA positive tumour cells and CD3 stimulation induces T-cell activation and cytokine release. In an in vivo model using NSG mice engrafted with human PBMCs the growth of PSMA positive DU145 prostate tumour cells is inhibited by a surrogate bispecific. Together these data support progression of CB307 into clinical development.
Citation Format: James W. Legg, Brian McGuinness, Sophie Archer, Phil Bland-Ward, Verena Brucklacher, Jenny Craigen, Carolyn Edwards, Emma Hames, Jay Majithiya, pavel Pisa, Bhindu Revi, Nikki Royale, Angelica Sette, Yumin Teng, Lorraine Thompson, Wembin Wang, Chris Wilson, Chris Wyre, Chris Rossant. A novel T-cell costimulatory Humabody® VH therapeutic for PSMA-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 565.
Abstract 573: Mutations found by targeted next generation sequencing is associated with intra-tumor immune profile and may predict response to anti-PD1 therapy in lung adenocarcinoma
Authors: Lupo Audrey , Biton Jerome , Alifano Marco , Damotte Diane , Arrondeau Jennifer , Boudou Pascaline , Goldwasser François , Leroy Karen , Wislez Marie , Laurent-Puig Pierre , Cremer Isabelle , Blons Helène , Herbst Ronald 
Published: August 2019

Abstract
Purpose: the immune environment of cancer is the target of immunotherapies with programmed cell death 1 (PD-1) therapeutic antibodies. However, factors that can robustly predict long-lasting responses are still needed. Previous studies showed a role of cancer cells on immune response setting, but the impact of somatic mutations on the composition of the immune stroma is not fully characterized.
Experimental Design: We characterized the immune profile of 221 lung adenocarcinomas using immunohistochemistry (CD8 T cells, Macrophages, neutrophils, PD-L1) and compare to tumor mutational status using targeted next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort of 31 lung carcinomas according to tumor mutational profiles and to tumor cell PD-L1 expression.
Results: We report that distinct combinations of STK11, EGFR and TP53 mutations, allows the identification of immune cells combination and prediction of PD-L1 expression on tumor cells. Lung adenocarcinomas with the highest CD8 T cell density and PD-L1 expression were those with TP53 mutations without co-occurring STK11or EGFR alterations (TP53-mut/STK11-EGFR-WT), and independently of KRAS status. Interestingly in TP53-mut/STK11-EGFR-WT tumors, pathways related to T cell chemotaxis, immune cell cytotoxicity, and antigen processing were up-regulated. In accordance with these results we found a prolonged progression-free survival (PFS: HR=0.32; 95% CI, 0.16-0.63, p&lt;0.001) in anti-PD-1 treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.
Conclusions: Our study reveals that mutations in lung adenocarcinoma impact intra-tumor immune profile and predict response to PD-1 blockade.
Citation Format: Audrey Lupo, Jerome Biton, Marco Alifano, Diane Damotte, Jennifer Arrondeau, Pascaline Boudou, François Goldwasser, Karen Leroy, Marie Wislez, Pierre Laurent-Puig, Isabelle Cremer, Helène Blons, Ronald Herbst. Mutations found by targeted next generation sequencing is associated with intra-tumor immune profile and may predict response to anti-PD1 therapy in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 573.
Abstract 575: Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer
Authors: Laheurte Caroline , Dosset Magalie , Vernerey Dewi , Joseph Elodie Lauret Marie , Boullerot Laura , Kaulec Vincent , Jacquin Marion , Cuche Laurie , Eberst Guillaume , Jacoulet Pascale , Westeel Virginie , Adotevi Olivier 
Published: August 2019

Abstract
Despite the critical roles played by IFN-γ+ CD4 Th1 response in tumor immunity, the translation of their potential in clinic remains challenging. Here, we evaluate the clinical significance of circulating anti-tumor CD4 Th1 response in non-small cell lung cancer (NSCLC) patients. 170 naïve-treatment patients were enrolled in this immune monitoring study. The antitumor adaptive Th1 response was assessed by IFN-γ ELISPOT assay in blood lymphocytes using a mixture of eight highly promiscuous and Th1-polarized HLA class II-restricted epitopes from telomerase (TERT). The presence of anti-TERT Th1 response was detected in 59/170 patients (35%). We found an opposite link between anti-TERT Th1 and hyper exhausted T cells co-expressing PD-1+ and TIM-3+ in NSCLC patients. In contrast to hyper exhausted CD8 T cells, the presence of anti-TERT Th1 response was associated with a low rate of hyper exhausted CD4 T cells. We showed that NSCLC stage dissemination is associated with a decrease of anti-TERT Th1 response but an increase of circulating hyper exhausted PD-1+/TIM-3+ CD4 T cells. Notably, anti-telomerase Th1 response and hyper exhausted CD4 T-cells displayed opposite prognosis value in NSCLC. While high level of anti-TERT Th1 cells play a protective role, hyper-exhausted PD-1+TIM-3+ CD4 T cells negatively affect patients’ survival. By using these two circulating immune factors, we stratified patients in distinct prognostic group. Patients with anti-TERT Th1high/CD4 PD-1 TIM-3low immune profile had better overall survival than anti-TERT Th1low/CD4 PD-1 TIM-3high group (median OS : not reached versus 4 months respectively p&lt;0.0001). In conclusion, high circulating anti-TERT Th1 response plays a strong protective role in NSCLC by counteracting the deleterious effect associated with hyper exhausted T cells in blood. Our study provides a dynamic blood-based immunomonitoring tool allow patients stratification.
Citation Format: Caroline Laheurte, Magalie Dosset, Dewi Vernerey, Elodie Lauret Marie Joseph, Laura Boullerot, Vincent Kaulec, Marion Jacquin, Laurie Cuche, Guillaume Eberst, Pascale Jacoulet, Virginie Westeel, Olivier Adotevi. Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 575.
Abstract 578: Investigation of the effect of hypoxia on presentation of HPV16-derived antigens - implications for therapeutic vaccine design
Authors: Mohan Nitya , Bonsack Maria , Förster Jonas , Steinbach Alina , Blatnik Renata , Salek Mogjiborahman , Riemer Angelika B. 
Published: August 2019

Abstract
Human papillomavirus type 16 (HPV16) is a causal factor of ~50% of cervical cancers, and of ~95% of extra-cervical (other anogenital and oropharyngeal) HPV-mediated cancers. The aim of our group is to develop a therapeutic vaccine against HPV16-induced malignancies. To find optimal vaccine antigens, it is important to assess the effect of the tumor microenvironment on viral antigen presentation. Hypoxia has been reported to regulate HLA class-I expression levels in the context of various tumors. Thus, the aim of the present study was to explore the effect of hypoxia on various components of the antigen processing machinery (APM) in HPV16-positive tumor cells and on the HPV16 E6- and E7-derived HLA class-I epitope repertoire. We are investigating the effect of hypoxia on cervical cancer cells transformed with HPV16 variant lineages (European, Asian-American and African) correlated with differences in oncogenic potential. This is achieved by comparing cells cultured under hypoxia (1.2% O2) or normoxia (21% O2). We investigate E6 protein levels by immunoblotting and HLA-A2 surface expression by flow cytometry. Subsequently, quantitative PCR and immunoblotting are used to assess whether components of the APM are affected by hypoxia. Cervical cancer cell lines transformed by sublineages of the HPV16 European variant (CaSki and SNU17) showed a decrease in E6 protein levels upon hypoxic treatment. HLA-A2 levels were increased in SNU17 cells (HPV16 European Asian prototype), but no change was observed in CaSki cells (European Prototype 2). First qPCR experiments of SNU17 cells showed changes in additional components of the APM at the mRNA level, which still have to be assessed at the protein level. Cell lines transformed by HPV16 variants other than European will be subjected to the same analysis. Potential changes in the HPV16 epitope repertoire will be investigated using a targeted mass spectrometry-based epitope detection strategy established in the lab. These investigations may yield novel insights into HPV16 immune evasion pathways. Furthermore, the identification of epitopes that are presented under both normoxic and hypoxic conditions will provide optimal candidates for therapeutic vaccine design against HPV-induced malignancies.
Citation Format: Nitya Mohan, Maria Bonsack, Jonas Förster, Alina Steinbach, Renata Blatnik, Mogjiborahman Salek, Angelika B. Riemer. Investigation of the effect of hypoxia on presentation of HPV16-derived antigens - implications for therapeutic vaccine design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 578.
Abstract 597: Occupational exposure to diesel engine exhaust and alternations in serum microRNAs
Authors: Hu Wei , Bassig Bryan A. , Dai Yufei , Ren Dianzhi , Duan Huawei , Niu Yong , Xu Jun , Fu Wei , Meliefste Kees , Zhou Baosen , Yang Jufang , Ye Meng , Jia Xiaowei , Meng Tao , Bin Ping , Wong Jason YY , Hosgood Dean H. , Rothman Nathaniel , Vermeulen Roel C. , Silverman Debra T. , Zheng Yuxin , Lan Qing 
Published: August 2019

Abstract
Diesel engine exhaust (DEE) is a known lung carcinogen and may be associated with other tumors, however, the mechanisms of action by which DEE causes cancer is not well understood. MicroRNAs (miRNAs), which are small non-coding RNA molecules that play a role in post-transcriptional regulation of gene expression, are altered in multiple tumors and have been observed to be differentially expressed in a variety of biospecimen types in smokers as well as in relation to short-term air pollution exposure. To evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE, we analyzed samples collected in a cross-sectional molecular epidemiology study of diesel engine truck testing facility workers and comparable unexposed controls in China. A panel of 44 miRNAs were measured in 46 workers exposed to relatively high air levels of DEE and 45 controls using the Fireplex circulating miRNA assay (Abcam, Inc.), which profiles miRNAs directly from biofluids. The exposure-response relationship between categorical EC levels and each miRNA was analyzed by linear regression adjusted for age, body mass index, smoking status, current alcohol use and recent infection. We identified two miRNAs that showed a monotonic inverse exposure-response association with DEE: miR-191-5p and miR-93-5p. Levels of miR-191-5p in arbitrary units (A.U.) of fluorescence were 400.7, 333.0, 322.6, and 260.0 in controls and across increasing tertiles of EC, respectively (p for trend = 0.001, FDR = 0.05). Levels of miR-93-5p were 747.1, 713.7, 720.5, and 625.4 A.U. in controls and increasing tertiles of EC, respectively (p for trend = 0.008, FDR = 0.18). Both miRNAs have been reported to influence several biological processes important in carcinogenesis. Our results suggest that occupational exposure to DEE may affect circulating miRNAs in healthy workers.
Citation Format: Wei Hu, Bryan A. Bassig, Yufei Dai, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, Jufang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Jason YY Wong, Dean H. Hosgood, Nathaniel Rothman, Roel C. Vermeulen, Debra T. Silverman, Yuxin Zheng, Qing Lan. Occupational exposure to diesel engine exhaust and alternations in serum microRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 597.