bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4985: TLR agonists for anticancer immunotherapy
Authors: Zhang Wenqiu , Kim Hyunjoon , Khanna Vidhi , Ferguson David M. , Griffith Thomas , Panyam Jayanth 
Published: August 2019

Abstract
Introduction: Toll-like receptors (TLRs) are important pattern recognition receptors through which innate immune cells recognize invasive microorganisms. The immunostimulatory property of TLR agonists allows for activation of dendritic cells (DCs) and enables their use as anticancer vaccine adjuvants. Because TLR 7 and 8 can be activated by synthetic small molecules, they are of particular interest as a target in vaccine adjuvant discovery. However, a key drawback of these synthetic small molecules is that they also induce immunosuppressive cytokines, resulting in immunosuppression.
Methods: We have previously developed a suite of highly substituted imidazoquinolines, which potently activate TLR 7 and/or 8. In this study, we tested some selected TLR7, TLR8 and TLR7/8 dual agonists for their ability to activate DCs without inducing immune suppressive cytokines. Murine bone marrow-derived dendritic cells (BMDCs) were generated from C57BL/6 mice. BMDCs were treated with one of seven TLR agonists for 72 hrs. Cells were collected and stained for flow cytometry analysis, and the culture supernatants were examined for secretion of pro-inflammatory cytokines, IL-12p70 and IFN-γ, and an immunosuppressive cytokine, IL-10, by ELISA. We also investigated activation of T cells by these agonists. Human peripheral blood mononuclear cells (hPBMCs) from healthy donors were incubated with one of seven TLR agonists overnight and cells were analyzed by flow cytometry for the expression of T cell activation marker CD69 and production of IFN-γ.
Results: All the TLR agonists investigated activated BMDCs, as evidenced by the upregulation of costimulatory markers CD40, CD80 and CD86 on DCs. In addition, all the agonists examined induced the secretion of IL-12p70 and IFN-γ. TLR 8 agonists showed the least induction of IL-10 secretion. All the TLR agonists activated both CD4 and CD8 T cells. TLR 8 agonists induced higher production of IFN-γ in both type of T cells than other candidates.
Conclusion: Both TLR 8 and TLR 7/8 agonists activated BMDCs and stimulated strong pro-inflammatory cytokine production. However, TLR8 activation was associated with less immunosuppression. These results suggest that these new imidazoquinoline esters are promising candidates for use as anti-cancer vaccine adjuvants.
Citation Format: Wenqiu Zhang, Hyunjoon Kim, Vidhi Khanna, David M. Ferguson, Thomas Griffith, Jayanth Panyam. TLR agonists for anticancer immunotherapy [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 4985.
Abstract 4987: Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and reduce response to immuno-oncology treatments
Authors: Sitnikova Suzanne I. , Morrow Michelle , Valge-Archer Viia , Wilkinson Robert W. , Dovedi Simon J. , Robinson Matthew J. 
Published: August 2019

Abstract
Immuno-oncology research relies heavily on murine syngeneic tumor models. However, whilst the median age for a cancer diagnosis is 65 years or older, for practical purposes the majority of preclinical studies are conducted in young mice, despite the fact that aging has been shown to have a significant impact on the immune response. Using aged mice bearing CT26 tumors, we analysed how aging impacts the immune composition of the tumor, spleen and tumor-draining lymph nodes by flow cytometry. We found many age-related changes between aged (60-72 weeks old) and young (6-8 weeks old) mice, such as a reduction in the naïve T cell population and a decreased CD8/Treg ratio in aged animals. Profiling of co-inhibitory and co-stimulatory receptor expression levels on immune cells in aged versus young mice also identified altered expression profiles in both the periphery and tumor. We hypothesised that these differences may contribute to impaired anti-cancer immune responses in aged mice. To investigate this, we compared the anti-tumor efficacy of immune checkpoint blockade (PD-L1 and CTLA-4) and T-cell costimulation (OX-40) in aged versus young mice. Our data demonstrate that aged mice retained their capacity to generate effective anti-tumor immune responses, albeit often attenuated when compared to the responses observed in young mice. These differences highlight the potential importance of age-related immunological changes in assessing and refining the translational insights gained from preclinical mouse models.
Citation Format: Suzanne I. Sitnikova, Michelle Morrow, Viia Valge-Archer, Robert W. Wilkinson, Simon J. Dovedi, Matthew J. Robinson. Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and reduce response to immuno-oncology treatments [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 4987.
Abstract 4992: The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis
Authors: Yang Xu , Wang Dongxu , Lin Jianzhen , Xiong Jianping , Long Junyu , Bai Yi , Bian Jin , Huang Hanchun , Yang Xiaobo , Mao Yilei , Sang Xinting , Zhao Haitao 
Published: August 2019

Abstract
Introduction: Immune-related adverse events (irAEs) were mostly induced by immune checkpoint blockade (ICB) and were associated with the immune response. Whether irAEs are associated with clinical benefits during ICB treatment in cancer patients remains unclear. This systematic review and meta-analysis aimed to investigate the relationship between irAEs and clinical efficacy.
Methods: We systemically searched and selected irAEs and clinical outcome data from cancer patients treated with ICB in the PubMed, Embase, and Cochrane Central Trial databases up to July 26, 2018. Keywords used for the search included PD-1, PD-L1, CTLA-4, immune checkpoint and immune-related adverse events. The relationships between the occurrence of irAEs and the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed using relative risk (RR) or hazard ratio (HR) values and 95% confidence intervals (CIs) in random-effect models.
Results: Nineteen eligible observational articles were included in this systematic review and fourteen studies including 3022 participants (1264 with irAEs and 1758 with non-irAE) were included in our meta-analysis. The occurrence of irAEs was significantly associated with higher ORR (RR = 2.36, 95% CI: 1.85-3.02; P &lt; 0.001), better PFS (HR
= 0.48, 95% CI: 0.26-0.70; P &lt; 0.001), and longer OS (HR = 0.42; 95% CI = 0.18-0.67; P = 0.001) than those in the non-irAE group. Subgroup analysis showed that the effect size of ORR in anti-PD-1 therapy (RR = 2.68, 95% CI, 2.21-3.26) was inferior to that of the anti-CTLA-4 therapy (RR = 1.91, 95% CI, 0.44-8.32). The meta-regression models also found that ICB type (anti-CTLA-4 or anti-PD-1) were associated with significant heterogeneity (P = 0.005).
Conclusion: In conclusion, irAEs indicate greater ORR, PFS and OS than non-irAEs in ICB treatment, and the relationship in anti-PD-1 therapy was stronger than in anti-CTLA-4 therapy. With appropriate management of irAEs, the clinical predictor, continued treatment may be possible to maximize its potential ICB benefits.
Note: This abstract was not presented at the meeting.
Citation Format: Xu Yang, Dongxu Wang, Jianzhen Lin, Jianping Xiong, Junyu Long, Yi Bai, Jin Bian, Hanchun Huang, Xiaobo Yang, Yilei Mao, Xinting Sang, Haitao Zhao. The occurrence of immune-related adverse events indicates better efficacy of immune checkpoint blockade in solid tumors: A systematic review and meta-analysis [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 4992.
Abstract 5: Pre-clinical development of CDK9 inhibitor - LS007 for the treatment of acute myeloid leukemia
Authors: Hui Wang , Shudong Wang 
Published: August 2019

Abstract
Acute myeloid leukemia (AML) is the most common form of acute leukaemia with an increasing incidence and dismal long-term prognosis with age. The most aggressive subtype, MLL-AML, is characterized by translocations of the mixed-lineage leukaemia gene (MLL) in chromosome band 11q23 and resistance to conventional chemotherapy with a short overall survival of only 9 months. Cyclin-dependent 9 (CDK9) activity is required for MLL-driven oncogenic transcription. Inhibition of CDK9 directly targets the transcriptional machinery required for MLL-fusion proteins (e.g. MLL-AF4, MLL-AF9 and MLL-ENL), thereby leading to apoptosis.
We have developed a highly effective drug candidate - LS007 that inhibited CDK9 with a Ki = 4 nM. It suppressed proliferation and induced apoptosis in a range of AML cell lines and patient samples. LS007 was highly efficacious against several AML cell line xenografts and patient-derived xenografts, and well tolerated in mice after oral administration. In a Molm-13 xenograft model, after 21 days of orally daily dosing at 25 mg/kg and 50 mg/kg LS007
inhibited tumor growth (p &lt; 0.001) with T/C = 44 % and 18 %, respectively. Similarly, in a HL-60 xenograft model, LS007 exhibited a significant tumor growth inhibition at 45 mg/kg and 60 mg/kg daily by oral administration with T/C = 40 % and 20 %, respectively.
The pharmacokinetic profiles of LS007 was further assessed in the cynomolgus monkeys. After oral doses at the dose of 2, 4 and 8 mg/kg, LS007 was detected in the plasma with the maximum concentration (Cmax) from 55.9 to 279.5 ng/mL and the area under the plasma drug concentration-time graph (AUC) up to 1862.7 h·ng/mL. The mean terminal half-life (T 1/2) was around 3 h. LS007 possessed the favorable pharmacokinetic profiles with oral bioavailability F = 56% in the cynomolgus monkey (at dose 4 mg/kg), suggesting its therapeutic potential as an orally bioavailable anti-AML agent. The GLP- toxicological studies of LS007 in the cynomolgus monkey were completed, and the maximum tolerated doses were identified, which were used to estimate the safe starting dose for the Phase I clinical trials.
With its excellent anti-cancer efficacy along with appreciable absorption and safety profiles, LS007 offers a very exciting prospect as a clinical development candidate. The application of Investigational New Drug (IND) has been approved allowing the commencement of clinical trials of LS007 in patients with AML.
Citation Format: Wang Hui, Wang Shudong. Pre-clinical development of CDK9 inhibitor - LS007 for the treatment of acute myeloid leukemia [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 5.
Abstract 500: Predicting patient response to immuno-oncology agents in vitro using 3D cultures
Authors: Appleton Kathryn M. , Guo Qi , Elrod Ashley , Lotstein Alina , Holmes Lillia , DesRochers Teresa M. 
Published: August 2019

Abstract
Immuno-oncology (I/O) based therapeutics, including cellular therapies and checkpoint inhibitors have surged in the last 2 years, but the technology to accurately test them in a pre-clinical setting is significantly lacking. While animal models have tried to provide accurate testing platforms, the ultimate goal of a matched patient tumor and immune system is not achievable in mice. To overcome this issue, we have developed two 3D tissue systems for in vitro testing that combine a patient’s tumor cells and autologous immune cells for accurate testing and prediction. We hypothesize that our 3D cell culture systems can recapitulate the patient’s tumor microenvironment to detect I/O response. Our spheroid-based system allows us to monitor how primary T-cells are affected by paired tumor cells and/or the PD-1 inhibitor pembrolizumab using flow cytometry. We have successfully detected pembrolizumab binding to T-cells in a dose dependent manner, clonal expansion of lymphocyte populations, as well as increased expression of activation markers on CD3+ cells following combination with tumor cells and exposure to pembrolizumab. This model also accurately detects CD3+CD8+ T-cell mediated tumor cell death and can be used to track changes in secreted cytokines and chemokines such as Granzyme B and IFN gamma. Our second model, a 3D microtumor platform, allows us to detect immune cell migration and infiltration and therapy related cell death. Our results show pembrolizumab can increase lymphocyte infiltration while simultaneously decreasing microtumor growth in matched patient samples whose tumor cells express PD-L1 and whose lymphocytes are CD8+. Cytokine secretion detected by multiplex technology from our microtumor model supports our observed enhanced T-cell activation in the presence of pembrolizumab. The data generated from our two complex 3D in vitro models can recapitulate in vivo biology in order to derive correlations to I/O drug response. These models can be utilized for preclinical testing of new I/O agents as well as for patient response predictions to I/O therapies.
Citation Format: Kathryn M. Appleton, Qi Guo, Ashley Elrod, Alina Lotstein, Lillia Holmes, Teresa M. DesRochers. Predicting patient response to immuno-oncology agents in vitro using 3D cultures [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 500.
Abstract 502: Aldo-keto reductase 1B8 (AKR1B8) deficiency causes intestinal immune deficiency
Authors: Wang Xin , Cao Deliang 
Published: August 2019

Abstract
Background: Intestinal epithelial cells (IECs) are crucial mediators of intestinal immunity. IECs defects may disrupt development and maturation of intestinal immunity. Aldo-keto reductase 1B10 (AKR1B10) is a regulator of de novo fatty acids synthesis and lipid synthesis by mediating acetyl-CoA carboxylase-α (ACCA) stability. Aldo-keto reductase 1B8 (AKR1B8) is an ortholog in mice of human AKR1B10, which has similar regulatory function in fatty acid/lipid synthesis. AKR1B8 deficiency causes IECs defects in proliferation and self-renewal, which may lead to dysregulation of intestinal immunity.
Methods: AKR1B8 -/- mice mouse stain was produced by homozygous recombination. Immune cells were isolated from colonic lamina propria (cLP) and mesenteric lymph nodes (MLN). Flow cytometry and immunofluorescence staining were applied for immune cell sorting and measurements. Microbiota composition were quantified by next generation sequencing.
Results: AKR1B8 deficiency causes infiltration of neutrophils, mast cells and basophils in the colon. Also, AKR1B8 deficiency causes impaired γδT cells and T helper cells (Th cells) immunity, such as IFNγ, IL17, IL4 or IL22 production, in colon and mesenteric lymph nodes, while enhances distinct arm of CD8 activity and Treg cells. These alterations may be due to the changes of MHCII+ DCs and CD103+ DCs in AKR1B8 deficient mice. Meanwhile, AKR1B8 inhibits the phosphorylation of p-AKT (T308 and S473) and p-ERK (1/2) in IECs, and suppresses the regulation IKKα/NF-κB signaling cascades. Furthermore, AKR1B8 deficiency induces gut microbiota shifts with higher ratio of Firmicutes/Bacteroidetes.
Conclusions: AKR1B8 is a critical mediators for IECs signaling and immune homeostasis. Loss of AKR1B8 in IECs induces Th cells immune deficiency. This study identified a new compensatory mechanism under IECs defects for maintaining intestinal immune homeostasis.
Citation Format: Xin Wang, Deliang Cao. Aldo-keto reductase 1B8 (AKR1B8) deficiency causes intestinal immune deficiency [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 502.
Abstract 5050: Testosterone supplementation in relation to prostate cancer in a US commercial insurance claims database
Authors: Cook Michael B. , Beachler Daniel C. , Parlett Lauren E. , Cochetti Philip T. , Finkle William D. , Lanes Stephan , Hoover Robert N. 
Published: August 2019

Abstract
Background: Testosterone supplementation (TS) has dramatically increased in the United States (US). We conducted a study of TS and prostate cancer risk using a large US commercial insurance research database.
Methods: From the HealthCore Integrated Research Database (HIRDSM), we selected men aged 30 years or greater who were new users of TS during 2007-2015. We selected two male comparison groups: 1) unexposed (matched 10:1); 2) new users of a phosphodiesterase type 5 inhibitor (PDE5i). Incident prostate cancer was defined as diagnosis of prostate cancer within four-weeks following prostate biopsy. Propensity scores and inverse probability of treatment weights were used in Poisson regression models to estimate adjusted incidence rates, incidence rate ratios (IRRs) and 95% confidence intervals (CI) using doubly robust estimation. Subgroup analyses included stratification by prostate cancer screening, hypogonadism, and follow-up time.
Results: The adjusted prostate cancer IRR was 0.77 (95%CI: 0.68, 0.86) when comparing TS with the unexposed group and 0.85 (95%CI: 0.79, 0.91) in comparison with the PDE5i group. Inverse associations between TS and prostate cancer were observed in a majority of subgroup analyses, although in both comparisons estimates generally attenuated with increasing time following initial exposure. Amongst TS users, duration of exposure was not associated with prostate cancer.
Conclusion: In this study, men who received TS did not have a higher rate of prostate cancer compared with the unexposed or PDE5i comparison groups. The inverse association between TS and prostate cancer could be the result of residual confounding, contraindication bias, or undefined biologic effect.
Citation Format: Michael B. Cook, Daniel C. Beachler, Lauren E. Parlett, Philip T. Cochetti, William D. Finkle, Stephan Lanes, Robert N. Hoover. Testosterone supplementation in relation to prostate cancer in a US commercial insurance claims database [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 5050.
Abstract 5057: Single cell RNA sequencing reveals altered natural killer-like, effector CD8+ T lymphocytes in smokers
Authors: Martos Suzanne N. , Campbell Michelle R. , Iannone Marie A. , Pittman Gary S. , Wan Ma , Bell Douglas A. 
Published: August 2019

Abstract
Tobacco smoke exposure is a risk factor for many human diseases and the global disease burden attributed to smoking remains substantial. In addition to DNA damage, smoking-induced epigenetic changes may contribute to etiology of complex smoking-associated diseases. Smoking alters the epigenome and transcriptome of human blood leukocytes. However, interpretation of bulk genomic approaches is limited because changes could indicate altered distribution of cell (sub)populations or changes in expression within (sub)populations. To characterize smoking-related gene expression changes in primary immune cells, we performed single cell RNA sequencing on human peripheral blood mononuclear cells (PBMCs) from smokers (n=4) and nonsmokers (n=4). Transcriptomes of 45,965 cells (78,183 reads per cell) revealed an altered population of Natural Killer (NK)-like T lymphocytes in smokers. Compared to NK cells, the NK-like T cell cluster had elevated expression of CD8A, CD8B, CD3D, CD3E, CD3G, CD6, and CD2, indicative of CD8+ T lymphocytes. Relatively rare in nonsmokers (2.2%), the transcriptionally unique subset of CD8+ T cells comprised 8.7% of PBMCs in smokers. Among CD8+ T cell subtypes, the increase in NK-like CD8+ T cells (Mann-Whitney p = 0.03) corresponded with a decrease in Naïve CD8+ T cells (p = 0.03). We did not observe changes in the frequencies of two additional CD8+ T cell clusters or in the overall frequency of CD8+ T cells. Mass cytometry of a 26-antibody leukocyte panel confirmed no differences in the frequencies of total CD8+ T (CD3+/CD8+/CD56-), total NKT (CD3+/CD56+) or CD8+ NKT (CD3+/CD8+/CD56+) cells between smokers and nonsmokers. This suggests smoking is associated with an increased number of CD8+ T cells that share characteristics with NK cells, but are not NKT cells. Consistent with an NK-like phenotype, altered effector CD8+ T cells had elevated expression of genes reported to be upregulated in T cells reprogrammed to NK-like cells. Compared to other effector CD8+ T cells, altered effector CD8+ T cells had reduced IL7R and increased FCGR3A (CD16), IFNG (interferon gamma), GZMB (granzyme B), and PRF1 (perforin) expression. In mice, granzyme B and perforin expressing CD8+ T cells contribute to the development of atherosclerotic plaques. Our data highlights a potential link between smoking-induced functional changes in human CD8+ T cells and atherosclerosis and /or immune surveillance in cancer.
Citation Format: Suzanne N. Martos, Michelle R. Campbell, Marie A. Iannone, Gary S. Pittman, Ma Wan, Douglas A. Bell. Single cell RNA sequencing reveals altered natural killer-like, effector CD8+ T lymphocytes in smokers [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 5057.
Abstract 5068: Genomic regulation of the cell cycle as a function of ARID1A occupancy in breast epithelial cells
Authors: Jdeed Sham , Balint Balint L. , Uray Iván P. 
Published: August 2019

Abstract
The idea of chemoprevention introduced a new concept both in clinical practice and experimental approaches. While single agent ER-independent chemopreventive therapy based on RXR-selective retinoids and other agents has produced promising results, even minor toxicity remains an obstacle to their clinical use. We performed unbiased high throughput screening to identify synergistic growth suppressive combinations of agents in normal mammary epithelial cells. A RXR-selective agonist and a beta-adrenergic inhibitor, as a candidate combination, at low concentrations demonstrated marked cancer preventive activity in a mouse model of Her2-induced ER-negative breast cancer. To elucidate the molecular mechanisms of this chemopreventive activity proteomic analyses of the candidate drug combination ensued. These revealed increased levels and phosphorylation of the DNA damage sensor ATM, along with elevated levels of the ARID1A subunit of the SWI/SNF chromatin remodeler in normal breast epithelial cells, but not in in situ breast carcinoma cells. Thus, we hypothesized that the maintenance of genomic integrity through ARID1A is a critical factor in the effectiveness of cancer preventive agents and helps reduce the odds of transformation. Genomic regions of increased accessibility are mapped by high throughput sequencing enabling multidimensional assays of the regulatory chromatin regions. Enhancers identified through chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) for H3K27 acetyl complemented with histones H3K4 will be discussed. We propose that ARID1A may mediate antiproliferative effects through genome-wide pausing of transcription of cell cycle regulatory genes. These results will help establish a role for the crosstalk of rexinoid and adrenergic signaling in the maintenance of a conserved chromatin remodeling mechanism and thus, premalignancy in breast epithelial cells.
Citation Format: Sham Jdeed, Balint L. Balint, Iván P. Uray. Genomic regulation of the cell cycle as a function of ARID1A occupancy in breast epithelial cells [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 5068.