bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3211: MTL-CEBPA combined with radiofrequency ablation and immunotherapy enhances immunological anti-tumour response in an HCC mouse model
Authors: Sodergren Mikael H. , Huang Kai-Wen , Reebye Vikash , Chee Cheng-Ean , Zacharoulis Dimitris , Habib Robert , Blakey David , Rossi John , Habib Nagy 
Published: August 2019

Abstract
The transcription factor CEBPA (CCAAT/enhancer-binding protein alpha) is recognised for its antiproliferative effects. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA and amongst other effects causes and immunomodulatory effect on peripheral granulocytes. Radiofrequency ablation (RFA) is standard treatment for some tumour types such as liver cancer and induces modulation of both innate and adaptive immune systems. To investigate any synergistic effect of MTL-CEBPA with RFA and immune checkpoint inhibition we initiated a reverse translation experiment, where syngeneic BNL hepatocellular carcinoma tumour cells were injected in the two opposite flanks of immunocompetent BALB/c mice (n=8 in each group). Treatments for hepatoma bearing mice included: 1) RFA on one flank (day 0), 2) Anti-PD-1 inhibition immunotherapy (RMP1-14 antibody, BioXCell, West Lebanon, NH, USA at 200 μg IV/mouse/dose on days 0, 2 & 5) and 3) MTL-CEBPA (3mg/kg IV/mouse/dose on days 0, 2 & 5) as well as combinations of all 3 interventions. We found that tumour control on the opposite flank was augmented by addition of RFA and most significant in the triple combination group (RFA + anti-PD1 + MTL-CEBPA) in which 2/8 animals showed a complete response and 5/8 a partial response. This was also the only group that showed a statistically significant increase in CD8+ (Cytotoxic) as well as CD49b+/CD45+ (Natural Killer) tumour infiltrating lymphocytes. These data suggest a clinical role for combination treatment with checkpoint blockade, RFA and MTL-CEBPA through synergistic priming of the immune tumour response, enabling RFA to have a pronounced anti-tumour abscopal effect.
Citation Format: Mikael H. Sodergren, Kai-Wen Huang, Vikash Reebye, Cheng-Ean Chee, Dimitris Zacharoulis, Robert Habib, David Blakey, John Rossi, Nagy Habib. MTL-CEBPA combined with radiofrequency ablation and immunotherapy enhances immunological anti-tumour response in an HCC mouse model [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 3211.
Abstract 3216: CKD-516, a novel vascular disrupting agent, enhances anticancer activity of anti-PD-1 antibody in SMAD4-deficient colon cancer model
Authors: Kim Soo Jin , Kim Hark Kyun , Ryu Keun Ho , Hong Chung Il 
Published: August 2019

Abstract
CKD-516 is a potent vascular disrupting agent (VDA), selectively acting on tumor vessels. A clinical study of CKD-516 combined with irinotecan is undergoing in colorectal cancer. There have been exponential gains in immune-oncology (I-O) in recent times through the development of immune checkpoint inhibitors (ICIs). ICIs demonstrated durable response and some patients achieved disease control for several years. However, there are still critical unmet medical needs for the combination therapies due to limited response rate of ICIs. The first step of the cancer-immunity cycle is dendritic cells (DCs) maturation which is necessary for the anticancer immunity. It is well known that mature DCs play critical roles in priming immune responses in cancer patients. We found that CKD-516 is able to induce DC maturation through Rho signaling pathway in DCs. A tumor suppressor gene, SMAD4 is associated with several cancers including stomach cancer, colorectal cancer, and pancreas cancer. The loss of SMAD4 is a poor prognostic biomarker in these cancer types and its mutation is related to poor clinical outcome on immunotherapies. A SMAD4-deficient mouse colorectal cancer cell line (3349LM) was primary cultured from a spontaneous intestinal adenocarcinoma formed in a Villin-Cre;Smad4(F/F);Trp53(F/F) mouse. CKD-516 showed a synergistic effect with anti-PD-1 antibody in 3349LM syngeneic model. In addition, 3349LM is also a MSS type cancer. Thus, CKD-516 displayed a therapeutic potential for several cancer patients who do not respond to immunotherapy. In summary, CKD-516 is a novel VDA with immune boosting effect. In SMAD4 deficient cancer model, CKD-516 has shown synergistic effects in combination with PD-1 antibody. Therefore, these data suggest that CKD-516 potentiates the anticancer activity of immunotherapy.
Citation Format: Soo Jin Kim, Hark Kyun Kim, Keun Ho Ryu, Chung Il Hong. CKD-516, a novel vascular disrupting agent, enhances anticancer activity of anti-PD-1 antibody in SMAD4-deficient colon cancer model [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 3216.
Abstract 322: Discovery of synergistic PI3K inhibitor combination therapies using high throughput approaches in HNSCC
Authors: Michmerhuizen Nicole Lynn , Leonard Elizabeth , Heenan Caitlin , Nair Vivek , Matovina Chloe , Harris Micah , Herbst Gabrielle , Kim Daniel , Bachand Amanda , Zhai Jingyi , Foltin Susan K. , Kulkarni Aditi , Carey Thomas E. , Bradford Carol R. , Jiang Hui , Brenner John C. 
Published: August 2019

Abstract
Recent head and neck squamous cell carcinoma (HNSCC) sequencing studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite frequent activating mutation or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K), targeted PI3K inhibitors have shown limited clinical efficacy as monotherapies. To identify factors that might predict sensitivity and resistance to PI3K inhibitors, we tested a panel of more than 40 patient-derived HNSCC cell lines and observed varying sensitivity to PI3K inhibitors. While all cell lines were much more sensitive than fibroblasts to these drugs, responses varied widely; for pan-PI3K inhibitor BKM120, IC50 values ranged from 0.2 to 4.2 μM across the OSCC cell line panel. Responses to BKM120 do not correlate with PIK3CA mutation status copy number, RNA expression, p110α protein levels, and AKT phosphorylation at baseline and after inhibitor treatment, among other genetic or phenotypic features.
In order to characterize potential mechanisms of PI3K inhibitor resistance in HNSCC, we have also developed and optimized an unbiased, high-throughput screening approach. We have used this assay to test ~1400 inhibitors as monotherapies and in combination with PI3K inhibitors HS-173 and BKM120 in ten HNSCC models. Our initial screening data suggested that combinations of PI3K inhibitors and ALK inhibitors are among the most synergistic in a subset of cell lines. We have evaluated the effects of these drug combinations on apoptosis, cell cycle, and downstream signaling in several in vitro HNSCC models, observing synergy in response to FDA-approved agents PI3K inhibitor pictilisib and ALK inhibitor brigatinib in various systems using a range of techniques. We next plan to expand these analyses to organoid and xenograft models to evaluate their effects in more clinically relevant settings.
Future studies will also examine additional factors that may predict PI3K inhibitor responses and will seek to better understand promising combination treatments and advance them for effective use in HNSCC patients.
Citation Format: Nicole Lynn Michmerhuizen, Elizabeth Leonard, Caitlin Heenan, Vivek Nair, Chloe Matovina, Micah Harris, Gabrielle Herbst, Daniel Kim, Amanda Bachand, Jingyi Zhai, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Hui Jiang, John C. Brenner. Discovery of synergistic PI3K inhibitor combination therapies using high throughput approaches in HNSCC [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 322.
Abstract 3223: Overcome LKB1 mutated cancer resistance to anti-PD1 treatment
Authors: Deng Jiehui , Thennavan Aatish , Pan Yuanwang , Dolgalev Igor , Chen Ting , Silver Heather , Harris Matthew , Pyon Val , Li Fei , Lee Chelsea , Tsirigos Aristotelis , Rothenberg Eli , Perou Charles M. , Wong Kwok-Kin 
Published: August 2019

Abstract
KRAS/STK11 (LKB1) mutant lung cancers are a subtype of cancer that respond poorly in the clinic to immunotherapies with shorter progression-free survival and overall survival comparing with other KRAS mutant lung cancer patients. Interestingly, this group of patients have high tumor mutational burden (TMB) comparable with other KRAS mutant lung cancers, which usually is an indicator for better response to anti-PD1 treatment. By using genetically engineered mouse model (GEMMs), we found that LKB1 loss of function can cause high level of nonsynonymous mutations, as a consequence of both replication dependent and independent DNA repair machinery dysfunctions. This LKB1 mutant dependent increased mutational load might further synergize with smoking mutagen exposures. When LKB1 function is defective, the neoantigens are not properly presented to T cells, which is required for proper T cell activation and effector T cells expansion. This will lead to insensitivity to anti-PD1 antibodies in high TMB tumors and tolerance to neoantigens produced by cancer cells. We further demonstrated that using a small molecule drug that impacts on the LKB1 downstream effector pathway, we can reverse this process through activating innate immunity in tumors, which will restore the antigen presentation functions. Combinational treatment of this small molecule with anti-PD1 can reverse the tumor progression in vivo, through releasing the suppressive tumor infiltrating lymphocytes (TILs) in LKB1 mutant lung cancers. Our study not only helps to further our understanding of the mechanism that contributes to immune evasion in high TMB tumors, but also provides a potential solution for LKB1 mutant cancers to overcome resistance to anti-PD1 treatment in the clinic.
Citation Format: Jiehui Deng, Aatish Thennavan, Yuanwang Pan, Igor Dolgalev, Ting Chen, Heather Silver, Matthew Harris, Val Pyon, Fei Li, Chelsea Lee, Aristotelis Tsirigos, Eli Rothenberg, Charles M. Perou, Kwok-Kin Wong. Overcome LKB1 mutated cancer resistance to anti-PD1 treatment [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 3223.
Abstract 3236: T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade
Authors: Moogk Duane , Wang Lin , Li Kaitao , Yuan Zhou , Weber Jeffrey , Osman Iman , Zhu Cheng , Krogsgaard Michelle 
Published: August 2019

Abstract
Although much clinical progress has been made in harnessing the immune system to recognize and target cancer, there is still a significant lack of an understanding of how tumors evade immune recognition and the mechanisms that drive tumor resistance to both T cell and checkpoint blockade immunotherapy. Our objective is to understand how tumor-mediated signaling through inhibitory receptors, including PD-1, combine to affect the process of T cell recognition of tumor antigen and signal activation in melanoma patients. The broader goal of the project is to understand the basis of resistance to PD-1 blockade and potentially identify new molecular targets to enable T cells to overcome dysfunction mediated by multiple inhibitory receptors (IR). Our biophysical measurements have shown that that the activities of TCR-proximal signaling components affect T cell antigen recognition and sensitivity at the earliest stages of T cell stimulation. We have shown that T cell antigen recognition is influenced by PD-1 and other inhibitory receptors via Shp-1/2 by targeting CD28 and Lckby directly suppressing TCR-pMHC-CD8 binding. Phospho-proteomics and flow cytometry-based analysis of melanoma patient-derived T cells from PD-1 blockade responders and non-responders identified additional mediators, signaling components and pathways associated with blockade resistance. CRISPR/Cas9 mediated genome editing was utilized to determine if resistance is mediated by the continued signaling of multiple IRs by perturbing IR signaling in mouse models of PD-1 blockade.Targeting these interactions and understanding the basis of resistance to PD-1 blockade would potentially allow identification of novel biomarkers of resistance or new molecular targets to enable T cells to overcome dysfunction during PD-1 checkpoint blockade.
Citation Format: Duane Moogk, Lin Wang, Kaitao Li, Zhou Yuan, Jeffrey Weber, Iman Osman, Cheng Zhu, Michelle Krogsgaard. T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade [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 3236.
Abstract 3251: Fibroblast activation protein (FAP)-selective delivery of CD40 agonistic DARPin®molecule for tumor-localized immune activation
Authors: Rigamonti Nicolo , Schlegel Anja , Barsin Sophie , Schwestermann Jonas , Mangold Susanne , Kaufmann Yvonne , Zitt Christof , Veitonmäki Niina , Levitsky Victor , Metz Clara 
Published: August 2019

Abstract
CD40 is a co-stimulatory molecule belonging to the tumor necrosis factor receptor superfamily which can activate both innate and adaptive immune system, making it an interesting target for tumor immunotherapy. Systemic administration of agonistic CD40 antibodies (Ab) has shown signs of activity in cancer patients, but dose-limiting toxicity impaired the clinical efficacy. New approaches are therefore needed to increase the therapeutic index of CD40-targeting molecules and achieve better clinical outcomes. Here, we report an alternative approach designed to activate CD40 specifically in the tumor microenvironment (TME), and not systemically, in order to increase efficacy and reduce systemic toxicity. This novel approach is based on a bispecific DARPin® molecule, targeting CD40 and fibroblast activation protein (FAP) alpha, intended to induce immune activation only when clustered by binding to FAP-expressing cells in the TME. The bispecific FAP x CD40 DARPin®molecule was tested in a reporter assay and in additional cell assays using primary human 1) B cells, 2) macrophages and 3) dendritic cells. These studies demonstrated CD40 activation only in the presence of FAP-positive, but not with FAP-negative cells, confirming a mechanism of action strictly dependent on FAP-mediated cross-linking. A surrogate mouse-specific FAP x CD40 DARPin® molecule (mFAP x CD40) was generated and tested in similar in vitro assays and showed FAP-dependent activation of CD40 and comparable results as the human construct. In vivo experiments, performed in tumor-free mice, showed a comparable half-life between mFAP x CD40 and an anti-mouse CD40 Ab (clone FGK45). However, mFAP x CD40, in contrast to the FGK45 Ab, did not increase the serum level of IL-6, supporting a mode of action that is dependent on FAP-mediated crosslinking of CD40 receptor. In additional studies mFAP x CD40 was active and inhibited the growth of FAP+ tumors. There were no signs of toxicity with mFAP x CD40 in contrast to the FGK45 Ab which resulted in body weight loss. In conclusion, we have generated bispecific agonist FAP x CD40 DARPin® molecules able to activate the CD40 pathway with a targeting (FAP)-dependent mechanism of action.
Citation Format: Nicolo Rigamonti, Anja Schlegel, Sophie Barsin, Jonas Schwestermann, Susanne Mangold, Yvonne Kaufmann, Christof Zitt, Niina Veitonmäki, Victor Levitsky, Clara Metz. Fibroblast activation protein (FAP)-selective delivery of CD40 agonistic DARPin®molecule for tumor-localized immune activation [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 3251.
Abstract 3254: A novel TGFβRI inhibitor suppresses tumor progression by increasing T-cell infiltration into tumor
Authors: Zusheng Xu , Lou Yangtong , Zhao Qiang , Wang Wei 
Published: August 2019

Abstract
TGF-beta (TGF-β) pathways, despite serving as tumor suppressor in early stage of carcinogenesis, have shown to be one of the key tumor-promoting factors in later-stage tumor progression. TGF-β receptor type 1 (TGFβRI) inhibitors have shown great potentials in their anti-tumor and anti-metastasis efficacy in preclinical studies and some of them are being tested in the clinical settings. A specific TGFβRI inhibitor YL-13027 was developed at Yingli Pharmaceutical. Our previous data have shown that YL-13027 significantly inhibited the T cell differentiation into Treg and the secretion of IL-10 in vitro, as well as tumor growth in immune-competent mice with CT26 tumors. Our further studies indicated that the anti-tumor efficacy of YL-13027 was largely mediated by T cells. More importantly, YL-13027 synergistically enhanced the anti-tumor efficacy of anti-PD-L1 antibody in CT26 model. YL-13027 displayed significant anti-tumor efficacy in other syngeneic mouse tumor models tested including orthotopic murine breast carcinoma 4T1 model in BALB/c mice and murine hepatocellular carcinoma Hepa1-6 model in C57BL/6 mice. YL-13027 is well tolerated by the animals with no treatment-related toxicity observed in these efficacy studies. Analyses of tumors treated with YL-13027 revealed that YL-13027 significantly increased the number of tumor-infiltrating lymphocytes in tumors. These data suggest that YL-13027, a novel TGFβRI inhibitor, represents a promising and safe immune modulator and shows great potential as a cancer immuno-therapeutics.
Citation Format: Xu Zusheng, Yangtong Lou, Qiang Zhao, Wei Wang. A novel TGFβRI inhibitor suppresses tumor progression by increasing T-cell infiltration into tumor [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 3254.
Abstract 3282: BMI and other factors in relation to overall survival of female breast cancer in China
Authors: Dong Yunqiu , Duijnhoven Franzel J. B. van , Wang Lu , Wu Ming , Qian Yun , Kampman Ellen 
Published: August 2019

Abstract
The aim of this study is to determine the relationship between body mass index(BMI) at diagnosis and various factors including the epidemiologic and clinical factors on survival of female breast cancers. We analysed the data of 653 patients in any stage from the Wuxi Breast Cancer Cohort. Cox Proportional Hazard regression models were conducted to compare the overall survival(OS) outcomes among BMI groups, and adjusted by covariates which yielded a &gt;10% change in the hazard ratios(HRs) estimate, including age, stage, menopause status, physical activity in work. There were significant differences among BMI groups in age(P=0.000), WHR(P =0.000), physical activity in work(P =0.019),red meat intake(P =0.029), oil intake(P =0.000),tumor stage(P =0.021),menopause status(P =0.001). Overweight(OW,BMI=24 to 27.9kg/m2) and obesity(OB, BMI≥28kg/m2) showed better OS comparing with normal weight(NW, BMI=18.5 to 23.9kg/m2)(respectively, adjusted HRs=0.45, 95%CI=0.15 to 1.34, adjusted HRs=0.59,95%CI=0.21 to 1.69), meanwhile underweight(UW, BMI&lt;18.5kg/m2) showed a poorer OS(adjusted HRs=4.65,95%CI=0.93 to 23.37). There was no significant relationship between the BMI and some other factors in OS. In conclusion, the findings of our current study indicate that BMI might play a role in the prognosis of female breast cancer in China, but the evidence was not strong enough.
Citation Format: Yunqiu Dong, Franzel J. B. van Duijnhoven, Lu Wang, Ming Wu, Yun Qian, Ellen Kampman. BMI and other factors in relation to overall survival of female breast cancer in China [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 3282.
Abstract 33: Ex vivo drug sensitivity assay with a panel of cancer patient-derived spheroids of small cell neuroendocrine carcinoma of uterine cervix
Authors: Tanaka Mie , Kubota Satoshi , Ito Yu , Kiyohara Yumiko , Endo Hiroko , Kondo Jumpei , Nakagawa Satoshi , Okazawa Akiko , Matsuzaki Shinya , Kimura Toshihiro , Kobayashi Eiji , Ueda Yutaka , Yoshino Kiyoshi , Kamiura Shoji , Kimura Tadashi , Inoue Masahiro 
Published: August 2019

Abstract
Small cell neuroendocrine carcinoma (SCNEC) of uterine cervix is a rare tumor accounting for approximately 1-2% of uterine cervical tumors. SCNEC of uterine cervix is highly invasive and has an extremely poorer prognosis than other histologic types for which no standard treatment is established. To establish a new management strategy against SCNEC of uterine cervix, we developed a drug sensitivity assay based on a 3D primary culture system. We previously developed the cancer tissue-originated spheroid (CTOS) method, a primary culture method from patients’ tumors. To date, we established a panel of 12 SCNEC CTOS lines with the success rate of 100%. For each line, multiple CTOSs were placed in one well of a 96 well plate and dose response analysis was performed for seven anticancer drugs; paclitaxel, carboplatin, irinotecan, SN-38, cisplatin, etoposide and gemcitabine. After 7 days of culture, the CTOSs viability was evaluated by measuring intracellular ATP levels, corrected by the size of CTOS at day0. All drugs had substantial variations in sensitivity among the lines. Cerv54 was far more sensitive to irinotecan than other lines while was similarly sensitive to SN-38. We revealed that cancer cells of cerv54 had high levels of carboxylesterase(CES)1 expression, which converts irinotecan to SN38. Since cerv54 with CES1 knockdown by pGFP-C-shCES1 lentivirus had lower sensitivity than sh-scramble, CES1 expression is related to the irinotecan sensitivity in cerv54. CES1 expression in cancer cells may be useful for predicting the effect of irinotecan based chemotherapy. In addition, this study indicates that sensitivity test using CTOS might be applicable to precision medicine by selecting sensitive drugs for each patient.
Citation Format: Mie Tanaka, Satoshi Kubota, Yu Ito, Yumiko Kiyohara, Hiroko Endo, Jumpei Kondo, Satoshi Nakagawa, Akiko Okazawa, Shinya Matsuzaki, Toshihiro Kimura, Eiji Kobayashi, Yutaka Ueda, Kiyoshi Yoshino, Shoji Kamiura, Tadashi Kimura, Masahiro Inoue. Ex vivo drug sensitivity assay with a panel of cancer patient-derived spheroids of small cell neuroendocrine carcinoma of uterine cervix [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 33.