bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2513: Anti-tumor therapeutic effects in mice treated with Listeria monocytogenes (Lm)-LLO immunotherapy in combination with PD-L1
Authors: Molli Poonam , Wallecha Anu 
Published: August 2015

Abstract
Published reports have shown that Listeria monocytogenes (Lm) LLO immunotherapies can be combined with different cytotoxic modalities such as radiation, chemotherapy or immunotherapy for treatment of cancer. In a recent study, the combination of Lm-LLO immunotherapy (ADXS11-001) with an anti-PD-1 antibody significantly inhibited tumor growth and prolonged survival in animals. The combined treatment significantly increased the generation of antigen-specific immune responses in the periphery, and the infiltration of CD8 T cells into the tumor. These findings demonstrated that Lm-LLO immunotherapy combined with blocking of the PD-1/PD-L1 interaction was a feasible approach. The expression of PD-L1 by tumor cells serves as a protective function that can lead to suppression of tumor-infiltrating effector lymphocytes, thus allowing tumors to escape immune surveillance. We hypothesized that the combination of an Lm-LLO immunotherapy with an anti-PD-L1 antibody may potentially increase the therapeutic efficacy of either single agent alone and may be translatable to the clinical setting. To evaluate this hypothesis, a tumor regression study was initiated in a mouse model where established tumors were treated with ADXS11-001, PD-L1 antibody or combination ADXS11-001/PD-L1 antibody and tumor growth was monitored. In addition to tumor regression, serum samples were collected at different timepoints post-treatment to evaluate the changes in expression of various cytokines and chemokines using mouse inflammation map (Myriad RBM). The initial results indicated that the combination of ADXS11-001 and PD-L1 was better at controlling tumor growth kinetics than the single agent treatments. Serum cytokine analysis indicated treatment-related differences in the kinetics of cytokines and chemokines induced after single agent or combination treatments during different days of the study. Currently, we are evaluating the anti-tumor effects and immune responses generated in the periphery as well as in the tumor microenvironment. The results of this study will provide further insight as to the anti-tumor potential of combination of Lm-LLO immunotherapies with PD-1/PD-L1 specific antibodies.
Citation Format: Poonam Molli, Anu Wallecha. Anti-tumor therapeutic effects in mice treated with Listeria monocytogenes (Lm)-LLO immunotherapy in combination with PD-L1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2513. doi:10.1158/1538-7445.AM2015-2513
Abstract 2515: Tumor presenting cells: a new strategy for cancer immunotherapy
Authors: Kreutz Fernando T. 
Published: August 2015

Abstract
Solid tumor cells as other non-immunological cells do not present MHC Class II. The MHC class II is a critical molecule responsible for peptide presentation to T helper cells. The presence of a not-self peptide on a MHC II molecule trigger the production of cytokines responsible for different steps on T cell expansion and maturation. Without the appropriate cytokine stimulation, cytotoxic T cells that identified a not-self peptide associate to a MHC class I molecules, may not proliferate or even be induce to anergy. We hypothesized that lack of anti-tumor immune responses on the majority of cancer patients (too little, too late) is due to a not appropriate MHC II peptide presentation. In our model, solid tumor cells (prostate cancer) are induce to express MHCII on their surface. In this novel approach of Cell Based Cancer Immunotherapy, patient's tumor cells were expanded in tissue culture and treated causing de novo expression of MHC II and activation of the MHC II peptide presentation pathway. Thus, the modified cancer cells are bifunctional, being capable of activating both helper T cells (MHC II) and cytotoxic T cells (MHCI), leading to cytokine production and a surprisingly robust and cancer-specific immune response. The modified solid tumor cell by itself will now behave as an antigen-presenting cell creating a Tumor Presenting Cell (TPC). As previous reported on a Phase IIb clinical trial done in Brazil (FK-Biotec/UFRGS/PUCRS), a population of local advance prostate cancer patients were treated with TPC. The study showed a significant (p = 0,03) increase in number of patients with undetectable levels of PSA (biochemical cure) after 5 years, 85% versus 48% on the control group. Also shown a trend of lowering mortality by prostate cancer, 9% in the threated group versus 19% in the control group. In conclusion, we are describing a novel Cell Based Cancer Immunotherapy that could be apply to several different tumor types.
Citation Format: Fernando T. Kreutz. Tumor presenting cells: a new strategy for cancer immunotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2515. doi:10.1158/1538-7445.AM2015-2515
Abstract 2517: Effects of toll-like receptor 4 agonist on the anti-tumor immune response to the GVAX vaccine
Authors: Korrer Michael J. , Bulte Jeff W.m. , Levitsky Hyam I. 
Published: August 2015

Abstract
We evaluated the immune response elicited by co-administration of a novel toll-like receptor 4 agonist, glucopyranosyl lipid A (GLA), with a genetically modified tumor cell based vaccine (GVAX) in mice. We have previously reported that the addition of GLA to the GVAX vaccine in mice resulted in a paradoxical decrease in delivery of tumor antigen to the draining lymph node, yet an increase in therapeutic benefit. The addition of GLA to GVAX altered the distribution of the vaccine induced anti-tumor T cell response. In mice vaccinated with GVAX + GLA adjuvant tumor-specific T cells accumulated in the spleen, liver and footpad as soon as two days following vaccination. In contrast, in mice vaccinated with GVAX alone, tumor-specific T cells accumulated primarily only in the dLN.
Since our previous study established that incorporation of GLA into the GVAX vaccine did not alter the magnitude of the anti-tumor T cell response, we set out to determine if the co-administration of GLA with GVAX altered the functional capabilities of the anti-tumor T cell response. We found that GLA did not increase in vivo tumor-specific cytotoxic activity or increase the number of anti-tumor interferon-γ expressing T cells found in the tumor or spleen following vaccination. We next determined if the addition of GLA to GVAX altered the kinetics of the anti-tumor T cell response. We found that the addition of GLA to the GVAX vaccine resulted in rapid accumulation of activated anti-tumor T cells in the spleen. Our results suggest that addition of GLA to the GVAX vaccine does not increase the magnitude or significantly improve functional capabilities of the anti-tumor immune response. These findings are consistent with the hypothesis that the addition of GLA to the GVAX vaccine increases therapeutic benefit by altering the distribution of the response, resulting in a more systemic anti-tumor immune response.
Citation Format: Michael J. Korrer, Jeff W.m. Bulte, Hyam I. Levitsky. Effects of toll-like receptor 4 agonist on the anti-tumor immune response to the GVAX vaccine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2517. doi:10.1158/1538-7445.AM2015-2517
Abstract 2518: Effective vaccination against melanoma in an animal study: Combination of laser-assisted dermal skin delivery and cross-presenting XCR1+ dermal DCs targeting
Authors: Terhorst Dorothea , Fossum Even , Baranska Anna , Tamoutounour Samira , Malosse Camille , Garbani Mattia , Lechat Elmira , Crameri Reto , Winteler Roland , Bogen Bjarne , Malissen Bernard , Henri Sandrine 
Published: August 2015

Abstract
Background/Aim/Method
The induction of CD8+ cytotoxic T lymphocytes (CTL) is critical to eradicate tumor cells. In mouse skin, a subset of dendritic cell characterised by the expression of the chemokine receptor XCR1 is highly potent to activate CD8+ T cells. By combining PLEASE-assisted laser poration of the skin allowing dermal delivery and the use of dimeric vaccine molecule in which the XCR1 ligand, Xcl1, was fused to the antigen, we targeted specifically this XCR1+ dermal subset.
Results
Dermal delivery of this vaccine molecule after skin laser-poration induced specific strong T cell proliferation in an XCR1-dependent manner. A single immunization allowed protecting against melanoma in both therapeutic and prophylactic protocols.
Discussion & Conclusion
Thus, specific targeting of cross-presenting skin DCs represents a promising vaccine strategy for induction of CD8+ T cell responses and protection against cancers.
Citation Format: Dorothea Terhorst, Even Fossum, Anna Baranska, Samira Tamoutounour, Camille Malosse, Mattia Garbani, Elmira Lechat, Reto Crameri, Roland Winteler, Bjarne Bogen, Bernard Malissen, Sandrine Henri. Effective vaccination against melanoma in an animal study: Combination of laser-assisted dermal skin delivery and cross-presenting XCR1+ dermal DCs targeting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2518. doi:10.1158/1538-7445.AM2015-2518
Abstract 2525: MLN4924 synergistically enhances cisplatin-induced cytotoxicity via JNK and Bcl-xL pathways in human urothelial carcinoma - In vitro and in vivo study
Authors: Ho I-Lin , Kuo Kuan-Lin , Chou Chien-Tso , Hsu Chen-Hsun , Pu Yeong-Shiau , Hsieh Ju-Ton , Huang Kuo-How 
Published: August 2015

Abstract
Introduction
Cisplatin-based chemotherapy is the main treatment for metastatic bladder urothelial carcinoma; however, the response rate is only approximately 40-65%. Many patients will encounter drug resistance to chemotherapy eventually. Therefore, combination therapies to enhance the efficacy of cisplatin and to overcome drug resistance are imperative for the treatment of urothelial carcinoma. The aim of this study was to investigate the antitumor effect and underlying mechanisms for the combination of cisplatin and MLN4924, a NEDD8-activating enzyme inhibitor, in human bladder urothelial carcinoma.
Materials & Methods
We used MTT assays and CalcuSyn software to calculate the combination index of cisplatin and MLN4924. The expression levels of DNA damage response regulators, apoptotic-related molecules, MAPK and Bcl-xL were revealed by western blot. c-Jun N-terminal kinase (JNK) inhibitor (SP600125) and overexpression of Bcl-xL were used to investigate the relationship between JNK and Bcl-xL. The in vitro findings were further confirmed in vivo via xenograft mouse model.
Results
The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index &lt;1). In addition, MLN4924 potentiated cisplatin-induced apoptosis and activation of caspase-3, 7, phospho-histone H2A.X and PARP. We also observed c-Jun N-terminal kinase (JNK) activation with down-regulation of Bcl-xL during cisplatin and MLN4924 treatment. The inhibition of JNK activation partially restored cell viability as well as the expression of B-cell lymphoma-extra large (Bcl-xL); moreover, the overexpression of Bcl-xL rescued cell viability. In the in vivo study, MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice.
Conclusion
In summary, MLN4924 synergistically enhanced the antitumor effect of cisplatin through increasing DNA damage, JNK activation and down-regulating Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutiuc strategy for bladder cancer.
Citation Format: I-Lin Ho, Kuan-Lin Kuo, Chien-Tso Chou, Chen-Hsun Hsu, Yeong-Shiau Pu, Ju-Ton Hsieh, Kuo-How Huang. MLN4924 synergistically enhances cisplatin-induced cytotoxicity via JNK and Bcl-xL pathways in human urothelial carcinoma - In vitro and in vivo study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2525. doi:10.1158/1538-7445.AM2015-2525
Abstract 2528: Vardenafil is superior to idarubicin in treatment of glioma
Authors: Ashour Abdelkader E. , Alzahrani Abdulrahman Z. , Abdel-Hamied Hala E. , Zoheir Khairy M. , Ahmed Sheikh F. , Al-Rejaie Salem S. , Abd-Allah Adel R. 
Published: August 2015

Abstract
Idarubicin (IDA) is a very potent second generation anthracycline that has shown high efficacy against glioma in vitro. However, this agent has failed to exert satisfactory therapeutic response in patients with brain tumors.
Phosphodiesterase (PDE-5), an enzyme which hydrolyzes intracellular cyclic guanosine monophosphate (cGMP), is highly expressed in many brain tumor cell lines. We proposed that increasing cGMP in the brain by the potent PDE-5 inhibitor vardenafil (VAR) will augment the antitumor efficacy of IDA against glioma. We also proposed that VAR will induce apoptosis of glioma cells. Here we show for the first time that VAR (10 mg/kg) enhanced the antitumor activity of IDA (0.1mg/kg). VAR alone inhibited tumor growth and prolonged survival of glioma bearing rats. Histopathological examination revealed that tumors from glioma bearing rats treated with VAR alone or VAR+ IDA presented a significant reduction in mitotic index, indicating less proliferative tumors, as compared to those which received PBS (control) or IDA. Real time PCR results demonstrated that VAR inhibited mRNA expression of PDE-5 in the brains of animals treated with VAR, compared to control-treated group, implicating an important role for the inhibition of PDE-5 in the antitumor activity of VAR. Interestingly, the antitumor activity of VAR was similar to that of IDA. Moreover, animals receiving either VAR alone or VAR+IDA demonstrated statistically significant improvement in overall survival when compared with control (PBS) or IDA groups. In order to explain such an unexpected finding, we examined the antiproliferative, pro-apoptotic and anti-invasive activities VAR in vitro. MTT assay results showed that VAR significantly inhibited the growth of rat C6 glioma cells. Annexin V propidium iodide assay results revealed that the inhibition of C6 cell growth is mediated at least in part by inducing C6 apoptosis. Wound healing and soft agar colony formation assays showed that VAR inhibited the migration and anchorage-independent growth of C6 cells, respectively. This suggests that the enhanced antitumor effect of VAR could be due to a combined antiproliferative, pro-apoptotic and anti-invasive activities.
Together, our data support anti-glioma properties of VAR, and provide a proof-of-concept basis for further development of VAR as potential adjuvant for treatment of brain tumors.
Citation Format: Abdelkader E. Ashour, Abdulrahman Z. Alzahrani, Hala E. Abdel-Hamied, Khairy M. Zoheir, Sheikh F. Ahmed, Salem S. Al-Rejaie, Adel R. Abd-Allah. Vardenafil is superior to idarubicin in treatment of glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2528. doi:10.1158/1538-7445.AM2015-2528
Abstract 2529: Debio 1143 synergizes with taxanes, topoisomerase and bromodomain inhibitors to inhibit growth of lung adenocarcinoma
Authors: Langdon Casey G. , Wiedemann Norbert , Held Matthew A. , Platt James T. , Mamillapalli Ramanaiah , Iyidogan Pinar , Theodosakis Nicholas , Levy Frederic , Robichon Denis , Zanna Claudio , Vuagniaux Gregoire , Sorensen Mel , Wang Shaomeng , Bosenberg Marcus W. , Stern David F. 
Published: August 2015

Abstract
Efficient induction of cell death is essential for efficacy of cancer therapies, and may be enhanced in combination therapies that promote apoptosis. Small molecule mimetics of the pro-apoptotic protein SMAC antagonize Inhibitor of Apoptosis Proteins (IAPs). Debio 1143 is a potent oral SMAC mimetic currently assessed in clinical trials in combination with chemo- and radiotherapy in different cancer indications.
We have conducted a “one vs. many” drug combination screen in which Debio 1143 is combined pairwise with a panel of 128 candidate partner agents in order to identify drug combinations that inhibit growth of lung adenocarcinoma cells. Several synergistic Debio 1143 combinations were selected for further analysis. We confirmed that Debio 1143 synergistically inhibited growth in combination with taxanes paclitaxel and docetaxel, topoisomerase inhibitor SN-38, and the bromodomain inhibitor JQ1. The combination of Debio 1143 with any of these agents further inhibited clonogenic colony formation and induced apoptosis more than either agent alone. In two Debio 1143-sensitive cell lines Debio 1143 also induced formation of the cell-death inducing complex - the ripoptosome. Interestingly, while Debio 1143 broadly reduced protein levels of cIAP1 across cell lines, specifically the combination with JQ1 also reduced cIAP2 and XIAP levels and inhibited the canonical NF-κB pathway while inducing the non-canonical NF-κB pathway.
Overall, these data support utility of several combinations of Debio 1143 with other agents, especially bromodomain inhibitors, in lung adenocarcinoma and other cancers. Specifically, these findings indicate that the synergy between JQ1 and Debio 1143 may derive from JQ1 contributing on different levels to key mechanisms relevant for SMAC mimetic antitumor activity.
Citation Format: Casey G. Langdon, Norbert Wiedemann, Matthew A. Held, James T. Platt, Ramanaiah Mamillapalli, Pinar Iyidogan, Nicholas Theodosakis, Frederic Levy, Denis Robichon, Claudio Zanna, Gregoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern. Debio 1143 synergizes with taxanes, topoisomerase and bromodomain inhibitors to inhibit growth of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2529. doi:10.1158/1538-7445.AM2015-2529
Abstract 2530: Bcl-2 and Bcl-xL dual inhibitor, ABT-737, circumvents JNK mediated upregulation of anti-apoptotic molecules in cisplatin treated non-small cell lung cancer models
Authors: KIM Eun Young , Kim Arum , Chang Yoon Soo 
Published: August 2015

Abstract
Introduction; Non-small cell lung cancer (NSCLC), which does not have druggable driver oncogene, is treated with cytotoxic chemotherapy, but clinical outcome is suboptimal. Cisplatin is still one of the most commonly used drugs for the treatment of NSCLC, and, however, there are limitations of the therapeutic effect because of the multiple resistance mechanisms. In particular, elevated level of anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1) triggered by cisplatin-induced DNA damage response correlate with the drug resistance. In this study, we investigated synergic effects of combined treatment with cisplatin and dual inhibitor of Bcl-2/Bcl-xL, ABT-737, in NSCLC models.
Materials and Methods; H460 and A549 NSCLC cells, and LSL K-Ras G12D mouse model were used. Protein expression was evaluated by immunoblotting and cytotoxicity was measured by FACS followed by annexin-V and PI staining. LSL Kras G12D mouse were inhaled 5 × 107 PFU AdCre virus at 8 weeks after birth and, in 24 weeks after inhalation, were taken microCT, randomized into 4 groups, and then treated with ABT-737 (50mg/kg, i.p., daily) and/or cisplatin (5 mg/kg, i.p., weekly) for two weeks.
Results; There was a dose dependent phosphorylation of JNK, which is most prominent between 6 to 24hr after cisplatin treatment. Expression of anti-apoptotic molecules, Bcl-2, Bcl-w, Bcl-xL, and Mcl-1 were increased by cisplatin treatment in a dose and time dependent manner. JNK specific activator, anisomycin, increased mRNA level of anti-apoptotic molecules. ABT-737 displaced BCL-xL to the cytoplasm and aggregated Bak. Furthermore, ABT-737 released cytochrome C from mitochondria to the cytoplasm. ABT-737 itself showed cytotoxic effects and combination of ABT-737 potentiates cytotoxic effects of cisplatin with strong synergism. Combination of ABT-737 with cisplatin treatment induced significant tumor regression in 2 weeks in LSL K-ras G12D mouse model when compared those treated with single agents or vehicle.
Conclusion; Combination of ABT-737 with cisplatin showed synergistic cytotoxic effects and anti-tumor activities in NSCLC preclinical models. These findings suggest that clinical trials using combination with ABT-737 and cisplatin may be beneficial in advanced NSCLC patients.
Citation Format: Eun Young KIM, Arum Kim, Yoon Soo Chang. Bcl-2 and Bcl-xL dual inhibitor, ABT-737, circumvents JNK mediated upregulation of anti-apoptotic molecules in cisplatin treated non-small cell lung cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2530. doi:10.1158/1538-7445.AM2015-2530
Abstract 2534: Sequenced combinations of platinum drugs and phytochemicals towards overcoming drug resistance in ovarian cancer
Authors: Althurwi Safiah I. , Yu Jun Qing , Beale Philip , Chan Charles , Huq Fazlul 
Published: August 2015

Abstract
Background and aims
Resistance to platinum-based chemotherapy remains a major obstacle in the treatment against human ovarian cancer. In this study, binary combinations of platinum compounds: cisplatin, carboplatin and oxaliplatin with phytochemicals: artemisinin, thymoquinone, curcumin, lupeol and oleanolic acid have been applied to human ovarian cancer cell lines: A2780, A2780cisR, and A2780ZD0473R using three different sequences of administration (0/0h, 0/4h and 4/0h) where 0/0h means both the drugs added at the same time, 0/4h means platinum added first followed phytochemical 4 h later and 4/0h means the converse.
Methods
Cytotoxicity was determined based on MTT reduction MTT assay. Median effect analysis was done to characterize combined drug action and combination Index (CI) was used as a measure of synergism or antagonism whereas cellular accumulation of platinum, platinum to DNA binding levels and proteomic studies were done to provide insight into drug resistance and synergism from combined drug action.
Results
The combinations of platinum and the phytochemicals produced sequence- and concentration-dependent synergism in the ovarian tumour models. The degree of synergism was greater in the resistant cell lines than the parent cell line. It was found that combination with phytochemicals also increased intracellular accumulation of platinum and the level of platinum binding with DNA. Proteomic study identified a number of proteins believed to be associated with cisplatin resistance in ovarian cancer cells A2780 and A2780cisR. The expression of the proteins were either down- or up-regulated in A2780cisR cell line as compared to A2780 cell line but fully or partially restored after treatment with synergistic combinations.
Conclusion
The results of the study indicate that appropriately sequenced combinations of platinum drugs and phytochemicals can provide a means of overcoming drug resistance in ovarian cancer.
Citation Format: Safiah I. Althurwi, Jun Qing Yu,, Philip Beale, Charles Chan, Fazlul Huq. Sequenced combinations of platinum drugs and phytochemicals towards overcoming drug resistance in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2015-2534