bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1589: Zinc inhibits androgen receptor expression to inhibit prostate cancer cell growth
Authors: To Phuong Kim , Cho Young-Suk , Kwon Se-Young , Kang Taek Won , Kim Kyung Keun , Jung Chaeyong 
Published: July 2017

Abstract
Background: Prostate gland contains high level of intracellular zinc which is dramatically diminished during cancer development. Due to the obscure role of zinc in this process, therapeutic application using zinc and its supplement is very limited. This study aims to clarify the role(s) of zinc and its intervening mechanism.
Material and methods: Treated by zinc chloride (15-150 µM), several prostate cancer cell lines were applied to confocal microscopy for intracellular trafficking of exogenous zinc, in vitro proliferation assays for their growth, prostate specific antigen (PSA)-based reporter-mediated transactivation, and Western blot for detection of androgen receptor (AR), PSA and ubiquitination. Further in vivo studies were performed to demonstrate the effect of zinc (10-20 mg/kg) on xenograft cancer growth using syngeneic animals followed by tumor analyses.
Results: Zinc chloride suppressed androgen-dependent proliferation of human prostate cancer cells and accordingly zinc chloride dramatically inhibited androgen-mediated transactivation and several androgen target protein expressions, including PSA and p21. Further investigation showed that addition of zinc chloride strikingly downregulated AR protein levels after 4 hours up to 24 hours in both human LNCaP and murine TRAMP C2 prostate cancer cell lines. AR downregulation resulted from facilitated protein degradation instead of transcriptional control. Further in vivo study was carried out using syngeneic mice bearing C2 subcutaneous tumors. Peritoneal injection of zinc chloride significantly reduced tumor size. Analysis of these tumors revealed that there were reduced expression of AR and increased cell death.
Conclusions: Zinc has been shown to inhibit incumbent oncogenic NF-κB pathway. These results also suggest that intracellular zinc inhibits cell growth via downregulation of AR to inhibit growth of prostate cancer. Considering that AR functions as a major effector in prostate cancer development and progression into castration resistant prostate cancer, loss of zinc may be a critical step for this devastating disease and further studies can be performed to develop zinc-based cancer therapeutics.
Citation Format: Phuong Kim To, Young-Suk Cho, Se-Young Kwon, Taek Won Kang, Kyung Keun Kim, Chaeyong Jung. Zinc inhibits androgen receptor expression to inhibit prostate cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1589. doi:10.1158/1538-7445.AM2017-1589
Abstract 1618: Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma
Authors: Feng Po-Hao , Lee Kang-Yun 
Published: July 2017

Abstract
Background: Host immunity affect treatment effect of lung cancer. Peripheral blood S100A9+ monocytic myeloid derived suppressor cells (MDSCs) is a predictive factor for treatment response of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) of lung adenocarcinoma patients. Bevacizumab have immune-modulating effect, including decreasing MDSCs, and improve treatment effect in combination with immunotherapy. However, the effect of immune modulation in combination of bevacizumab and EGFR-TKI in EGFR mutated lung adenocarcinoma patients is not clear.
Methods: Stage IV lung adenocarcinoma harboring sensitive EGFR mutation patients receiving first line EGFR-TKI or combination EGFR-TKI and bevacizumab were enrolled. The peripheral blood mononuclear cell (PBMCs) were collected, and S100A9+ MDSCs percentage was calculated by flow cytometry from CD14+S100A9+ in PBMC. Clinical data was collected.
Results: Eight patients receiving EGFR-TKI and bevacizumab, as combination group, and twenty patients received EGFR-TKI alone, as control group, were enrolled. PBMC S100A9+ MDSC decreased in combination group (decrease 39±18% from baseline), but not in control group. Combination group had longer progress free survival (PFS) comparing with control group. (Median PFS combination vs control group: 15.2 vs 9.9 months, Log Rank test, p=0.05) Increased of peripheral blood cytotoxic T cells also had trend in combination group but not in control group.
Conclusion: Besides the anti-angiogenesis effect, bevacizumab had immune modulated effect, especially in decreasing circulating S100A9+ MDSC in EGFR mutated lung adenocarcinoma patients. This might partially explain the longer PFS in combination of EGFR-TKI of anti-angiogenesis agent treatment.
Citation Format: Po-Hao Feng, Kang-Yun Lee. Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2017-1618
Abstract 1631: Sequencing the circulating and infiltrating T-cell repertoire on the Ion S5TM
Authors: Lowman Geoffrey , Linch Elizabeth , Miller Lauren , Topacio-Hall Denise , Looney Timothy , Pankov Alex , Sun Yongming , Peng Xinzhan , Andersen Mark , Hyland Fiona , Mongan Ann 
Published: July 2017

Abstract
T-cell repertoire (TCR) sequencing by next-generation sequencing (NGS) is a valuable tool for building a deeper understanding of the adaptive immune system. As immunotherapies, particularly T-cell dependent therapies, show increasing potential in treating cancer, the ability to gain a detailed, unbiased view of the TCR becomes imperative for biomarker discovery, immune response to treatment, and study of tumor microenvironments. A key question the field seeks to understand is the relationship between circulating T-cells and infiltrating T-cells at the tumor site. Here, we present a novel approach for TCR sequencing using the Ion S5 ™ sequencer which leverages simplified library construction workflows and offers a more complete characterization of the entire V(D)J region of TCRB. This method can leverage mRNA as input, minimizing requirements in starting materials and focusing sequencing to productive TCRB arrangements. This approach targets the constant (C) and the FR1 regions, minimizing the potential for primer bias and greatly increasing the phylogenetic information content compared to techniques that exclusively characterize the CDR3 domain. Our results show that the observed circulating T-cell repertoire size is approximately 2 orders of magnitude higher than the infiltrating T-cell repertoire. Accordingly, while it is difficult to fully capture the complete repertoire of circulating T-cells due to its vast diversity, we show that it is possible to reliably capture the complete infiltrating T-cell repertoire with as high as 10 samples on the Ion 530 ™ chip. Replicate sequencing runs of infiltrating T-cells offers correlation of ~0.9, indicating that the results were reproducible, and the samples were sequenced to appropriate depth. In summary, we believe that this workflow will allow researchers to more routinely characterize the infiltrating T-cell repertoire and offers the field a better understanding of the impact of repertoire diversity on tumor elimination.
Citation Format: Geoffrey Lowman, Elizabeth Linch, Lauren Miller, Denise Topacio-Hall, Timothy Looney, Alex Pankov, Yongming Sun, Xinzhan Peng, Mark Andersen, Fiona Hyland, Ann Mongan. Sequencing the circulating and infiltrating T-cell repertoire on the Ion S5TM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1631. doi:10.1158/1538-7445.AM2017-1631
Abstract 1643: Cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy
Authors: Mansure Jose J. , Yu Alice , Solanki Shraddha , Dias Ana B. , Burnier Miguel M. , Brimo Fadi , Kassouf Wassim 
Published: July 2017

Abstract
Purpose: Prognosis after radical cystectomy for bladder cancer can be unpredictable. There is increasing evidence that the presence of cytotoxic T lymphocytes correlates with survival. The Immunoscore, a new approach to classification of cancer using the number, type and distribution of immune cells, is an independent predictor for survival in colon cancer. Our objective was to evaluate the prognostic impact of lymphocyte distribution and the Immnoscore in bladder cancer.
Methods: Cystectomy sections with core tumor (CT) involvement and identifiable invasive margin (IM) were selected and stained for CD3+ and CD8+ lymphocytes. Three non-contiguous areas of highest lymphocyte density were selected from both CT and IM. The number of lymphocytes in each area was used to calculate the Immunoscore based on previously defined criteria. Kaplan-Meier curves were used to determine differences between Disease-free Survival (DFS) and Overall Survival (OS). Multivariate Cox proportional hazards model was used to determine hazard ratios.
Results: Total of 67 patients who had cystectomy for invasive bladder cancer were included in the study. High concentration of CD8+ lymphocytes in the tumour margin was associated with better DFS (P=0.005) and OS (P=0.03). Similar results were found for CD3+ lymphocytes with regards to DFS (P=0.05). A higher Immunoscore was also associated with better DFS (P=0.04). On multivariate analysis, CD8+ in the invasive margin was independently associated with better prognosis.
Conclusions: The host’s own immune system plays a valuable role in clinical outcome. Our data suggests that a strong immune response in the tumor margin is independently associated with better prognosis.
Citation Format: Jose J. Mansure, Alice Yu, Shraddha Solanki, Ana B. Dias, Miguel M. Burnier, Fadi Brimo, Wassim Kassouf. Cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2017-1643
Abstract 1644: Combination of MT-3724 with sirolimus reduces anti-drug antibody response and prolongs drug exposure
Authors: Higgins Jack P. , Robinson Garrett L. , Rajagopalan Sangeetha , Brieschke Brigitte , Liu Jensing , Willert Erin K. 
Published: July 2017

Abstract
Molecular Templates is developing engineered toxin bodies (ETBs), potent recombinant immunotoxins that combine the specificity of an antibody fragment with the powerful direct cytotoxicity of the Shiga-like toxin A subunit. ETBs can induce their own internalization, route through the cell in a predictable manner, enzymatically and irreversibly destroy ribosomes to shutdown protein synthesis and induce apoptosis of tumor cells. This mechanism of action is distinct from that of other therapeutics, making ETBs an attractive treatment for patients who have become resistant to chemotherapy and other treatment modalities.
MT-3724 is Molecular Templates’ first-generation ETB targeting CD20, a surface receptor that is highly expressed on malignant B cells in hematological malignancies. Pre-clinical and clinical studies have shown promising results for non-Hodgkin’s lymphoma cell lines and patients; however anti-drug antibodies are formed in experimental animals and patients after repeat dosing. Sirolimus (rapamycin) is a macrolide compound approved to prevent organ rejection and in LAM, and has been used in tolerization protocols with replacement enzymes. In pre-clinical studies, we have co-administered sirolimus in combination with MT-3724 in rodents as well as in a non-human primate model in order to reduce the anti-drug antibody response to MT-3724. These studies demonstrated that the combination of sirolimus with MT-3724 decreased anti-drug antibody response, prolonged serum exposure of MT-3724, and improved B-cell depletion as compared to MT-3724 alone.
Molecular Template’s ETB technology has resulted in potent and targeted therapeutic agents that have a unique mechanism of action in the field of oncology. Our first-generation, CD20-targeted therapeutic, MT-3724, has promising clinical results in the refractory setting for non-Hodgkin’s lymphoma. The combination of sirolimus with MT-3724 is an attractive and feasible regimen which will be further explored in clinical studies.
Citation Format: Jack P. Higgins, Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jensing Liu, Erin K. Willert. Combination of MT-3724 with sirolimus reduces anti-drug antibody response and prolongs drug exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1644. doi:10.1158/1538-7445.AM2017-1644
Abstract 1646: Highly cytotoxic, completely human constructs targeting HER2 and containing the immuno-oncology payload granzyme B
Authors: Cheung Lawrence H. , Zhao Yunli , Mohamedali Khalid A. , Alvarez-Cienfuegos Ana , Hittelman Walter N. , Rosenblum Michael G. 
Published: July 2017

Abstract
Recent immunotherapeutic approaches designed to augment T- and B-cell mediated killing of tumor cells has met with clinical success suggesting that immuno-oncology (IO) approaches have tremendous potential for treatment in a broad spectrum of tumor types. After complex recognition of target cells by T and B cells, delivery of the serine protease granzyme B (GrB) to tumor cells comprises the cytotoxic insult resulting in a well-characterized, multimodal apoptotic cascade. We designed a recombinant fusion construct composed of a human anti-Her2 scFv fused to active GrB for recognition and delivery of GrB to tumor cells simulating T and B-cell therapy. The GrB-Fc-4D5 dimeric construct (mw 160 kDa) was generated and expressed in stably-transfected CHO-S cells at ~60 mg/L and purified to homogeneity. The enzymatic activity of the fusion construct was similar to commercially-available GrB and the affinity of the construct for purified Her2 extracellular domain (ECD) was 0.328 nM, comparable to that of Herceptin (0.150 nM). The GrB-Fc-4D5 construct was highly cytotoxic to Her2-positive cells such as SKBR3, MCF7 and MDA-MB-231 with IC50 values of 56, 99 and 27 nM respectively. Using immunofluorescence, the fusion construct internalized rapidly into target (SKBR3 or SKOV3) cells within 1 h of exposure, rapidly delivering GrB to the cytoplasmic compartment in a similar manner to that of immune T and B-cell targeting but without the action of the transmembrane pore-forming agent perforin. Against a large panel of various tumor types, GrB-Fc-4D5 was highly cytotoxic to virtually all cells regardless of natural expression levels of the nominal endogenous GrB inhibitor PI-9. Contemporaneous studies with Kadcyla demonstrate similar levels of in vitro activity against virtually all HER2-positive cells tested. GrB-Fc-4D5 demonstrated activity against both log-phase and confluent tumor cells. In keeping with its relatively high molecular weight (~160 kDa), the construct demonstrated a terminal-phase half-life of 13.6 hrs. In vivo efficacy studies are currently ongoing in several orthotopic xenograft models. Also ongoing are pre-IND toxicology, histopathology and clinical chemistry studies. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: Lawrence H. Cheung, Yunli Zhao, Khalid A. Mohamedali, Ana Alvarez-Cienfuegos, Walter N. Hittelman, Michael G. Rosenblum. Highly cytotoxic, completely human constructs targeting HER2 and containing the immuno-oncology payload granzyme B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1646. doi:10.1158/1538-7445.AM2017-1646
Abstract 1651: Targeting phosphatidylserine in combination with adoptive T cell transfer eliminates advanced tumors without off-target toxicities in a melanoma preclinical model
Authors: Hirschhorn-Cymerman Daniel , Schad Sara Sara , Budhu Sadna , Hong Zhong , Yang Xia , Jeff Hutchins T. , Freimark Bruce D. , Gray Michael J. , Wolchok Jedd , Merghoub Taha 
Published: July 2017

Abstract
A viable strategy to treat advanced cancers includes transferring of tumor-specific T cells. T cells that recognize tumor antigens can be expanded and reinvigorated ex-vivo. Furthermore, autologous T cells can be genetically modified to express anti-tumor T cell receptors or chimeric antigen receptors. Although the potency and specificity of tumor-specific T cells can be manipulated ex-vivo, once re-infused into patients, the T cells are subjected to immunosuppressive mechanisms established by the tumor. An important immune checkpoint regulator within tumors is phosphatidylserine (PS). Innate immune cells exposed to PS secrete suppressive cytokines and chemokines that can significantly impair the function and activation of anti-tumor T cells. Therefore, monoclonal antibodies that block PS activity can increase the anti-tumor potency of transferred T cells to treat aggressive cancers. Here we show that a PS targeting monoclonal antibody in combination with CD4+ T cells that recognize the melanoma antigen Trp1 can regress very advanced melanomas in all treated mice. Combination of anti-Trp1 CD4+ T cells with other immunomodulatory modalities such as anti-OX40 antibodies, can achieve equivalent treatment rates but these are typically accompanied by severe immune related adverse events. In contrast, in this setting, PS blockade did not show any off-target toxicities. Flow cytometry analysis revealed lower levels of CD206 expression concomitant with higher activation markers in macrophages and neutrophils in tumors from anti-PS treated mice. These results suggest that diminishing suppressive mechanisms locally in adoptive transfer protocols is a highly desirable strategy that can eliminate tumors while minimizing related adverse events.
Citation Format: Daniel Hirschhorn-Cymerman, Sara Sara Schad, Sadna Budhu, Zhong Hong, Xia Yang, Hutchins T. Jeff, Bruce D. Freimark, Michael J. Gray, Jedd Wolchok, Taha Merghoub. Targeting phosphatidylserine in combination with adoptive T cell transfer eliminates advanced tumors without off-target toxicities in a melanoma preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1651. doi:10.1158/1538-7445.AM2017-1651
Abstract 1652: Optogenetic immunoengineering to develop improved anti-cancer immunotherapy
Authors: He Lian , Nguyen Nhung , Han Gang , Huang Yun , Zhou Yubin 
Published: July 2017

Abstract
The application of current channelrhodopsin-based optogenetic tools is limited by the lack of strict ion selectivity and the inability to extend the spectra sensitivity into the near-infrared (NIR) tissue transmissible range. Here we present an NIR-stimulable optogenetic platform (termed “Opto-CRAC”) that selectively and remotely controls Ca2+ oscillations and Ca2+-responsive gene expression to regulate the function of model cellular systems, as well as cells of the immune system. When coupled to upconversion nanoparticles, the optogenetic operation window is shifted from the visible range to NIR wavelengths to enable wireless and remote photoactivation of Ca2+-dependent signaling and optogenetic modulation of immunoinflammatory responses. In a mouse model of melanoma by using ovalbumin as surrogate tumor antigen, Opto-CRAC has been shown to act as a genetically-encoded “photoactivatable adjuvant” to improve antigen-specific immune responses to specifically destruct tumor cells. In addition, we have extended similar engineering approaches to photomanipulate membrane contact sites that play critical roles in controlling lipid metabolism and calcium signaling in cancer cells. Our study represents a solid step forward towards the goal of improving spatial and temporal control of anti-cancer therapy through optogenetic immunoengineering.
Note: This abstract was not presented at the meeting.
Citation Format: Lian He, Nhung Nguyen, Gang Han, Yun Huang, Yubin Zhou. Optogenetic immunoengineering to develop improved anti-cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1652. doi:10.1158/1538-7445.AM2017-1652
Abstract 1655: Organotypic 3D models to characterize the molecular requirements for NK and T-cell infiltration
Authors: Sommergruber Wolfgang , Osswald Annika , Hedrich Viola , Majewska Marta , Dolznig Helmut 
Published: July 2017

Abstract
Multiple studies have demonstrated that the presence of tumor infiltrating lymphocytes is strongly correlated with increased survival. However, the level of infiltration within a specific tumor entity and between various tumor types varies widely. Increasing the degree of lymphocyte infiltration in a tumor represents an innovative drug concept. Organotypic 3D models consisting of tumor spheroids, stromal fibroblasts and Natural Killer (NK) or T-cells could represent valuable models to appropriately model infiltration and establish novel therapeutic concepts in the area of immune-oncology. As a first step in the development of a model for lymphocyte infiltration, the cytotoxicity and infiltration of human NK cells in 3D tumor spheroids were analyzed. Different NK cell lines and primary NK cells had a toxic effect on 3D tumor spheroids upon co-culture. Cryosections of co-cultured tumor spheroids showed infiltrated NK cells inside tumor spheroids. Infiltrated NK cells recovered from tumor spheroids were characterized by flow cytometry. Results showed that a higher infiltration correlates with cytotoxicity on tumor spheroids and transcriptomes of infiltrated vs. non infiltrated NK cells differ substantially. IL-12 stimulation increased the killing effect of NK cells on tumor spheroids, inducing higher expression of Perforin, IFNγ and GranzymeB levels. 3D tumor spheroids were embedded in a Matrigel/Collagen mixture with fibroblasts and the effect of compounds on NK cell infiltration was monitored. It was demonstrated that not only IL-12 increased NK cell infiltration, but also several compounds. Moreover, encapsulated 3D models with different cell types (tumor cells, fibroblasts, NK or T-cells) were established at a bioreactor scale to mimic the in vivo situation of complex tumor tissues. We could demonstrate NK and T-cell infiltration into these encapsulated 3D tumor spheroids. These encapsulated model systems permit long-term cultures to study the effect of compounds and/or NK or T-cells on later stages of tumorigenesis. In conclusion, this study demonstrates that organotypic 3D models are a valuable tool for the analysis of the molecular mechanisms that regulate lymphocyte infiltration into tumors.
Citation Format: Wolfgang Sommergruber, Annika Osswald, Viola Hedrich, Marta Majewska, Helmut Dolznig. Organotypic 3D models to characterize the molecular requirements for NK and T-cell infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1655. doi:10.1158/1538-7445.AM2017-1655