bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1580: Combined neuroendocrine differentiation and androgen receptor hyperactivity in MAP37 and CHD1 null prostate cancer
Authors: Rider Leah C. , Rodrigues Lindsey U. , Karimpour-Fard Anis , Romero Lina , Gillette Claire , Costello James C. , Cramer Scott D. 
Published: July 2017

Abstract
We recently functionally validated a clinically aggressive subtype of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. This subtype accounts for up to 25% of prostate cancer deaths. Androgen signaling is a critical component of prostate tumorigenesis and disease progression, which is exploited in treatment of prostate cancer with androgen deprivation and anti-androgen therapies. Neuroendocrine differentiation is thought to provide a selective growth advantage of prostate cancer in androgen-depleted conditions such as surgical or chemical castration. REST is a transcriptional repressor of neuronal gene expression and has been implicated in neuroendocrine differentiation of prostate cancer. The impact of combined MAP3K7 and CHD1 loss on androgen signaling and neuroendocrine differentiation has not been determined. Here, we demonstrate that dual loss of MAP3K7 and CHD1 simultaneously stimulates enhanced androgen signaling and enhanced neuronal differentiation correlated with enhanced growth in both androgen-depleted and androgen-replete conditions. These changes occur via increased androgen receptor chromatin binding, loss of CHD1 chromatin binding, loss of REST expression, and reduced chromatin binding by REST. Suppression of CHD1 and MAP3K7 attenuates the antiproliferative activity of the anti-androgen Enzalutamide. Furthermore, we translate these findings to clinical samples and show that decreased expression of CHD1, MAP3K7, and REST is associated with previous therapeutic intervention, castrate-resistant disease, and progression to a neuroendocrine phenotype. Overall, patients with low expression of all three have poorer disease-free survival. Together these data support the lineage plasticity of prostate tumors with loss of CHD1 and MAP3K7 exhibiting both androgen-dependent and -independent phenotypes leading to poor clinical outcome, which poses challenges to conventional therapeutic approaches.
Citation Format: Leah C. Rider, Lindsey U. Rodrigues, Anis Karimpour-Fard, Lina Romero, Claire Gillette, James C. Costello, Scott D. Cramer. Combined neuroendocrine differentiation and androgen receptor hyperactivity in MAP37 and CHD1 null prostate cancer [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 1580. doi:10.1158/1538-7445.AM2017-1580
Abstract 1601: Anti-tumor effect of GAGomer-mediated intra-tumoral IL-2 expression following systemic administration
Authors: Alpert Genia , Altreuter David , Anamandla Sunil , Birt Arlyssa , Cinamon Guy , Merimi Keren Cohen , Or Orli Even , Gefen Nir , Gurvich Nadia , Gyuris Jeno , Lerner Lorena , Mondshine Adi , Wang Hong 
Published: July 2017

Abstract
Cancer immunotherapies are revolutionizing cancer treatment. Unfortunately, a large proportion of patients with solid tumors do not respond to currently available immune-therapeutics. The lack of response is due to a variety of mechanisms tumors adopt to avoid immune mediated clearance. The multiplicity of immunosuppressive mechanisms operational in the tumor microenvironment may not be overcome by single agents and require interventions at multiple control points. However, systemic exposure to combinations of immunoregulators may result in severe, dose limiting, acute and chronic toxicities that might be prevented if the effect of these agents is focused to the tumor microenvironment.
We are engaged in the discovery of a novel class of immuno-oncology drugs aimed at maximizing the effect of immunoregulatory molecules in the tumor microenvironment and minimizing systemic adverse effects. These drugs incorporate plasmids, engineered to program tumor cells to produce and secrete immune-regulatory proteins, within hyaluronic acid (HA) coated lipid nanoparticles, called GAGomers, which specifically target tumor cells that overexpress activated HA receptors (GAG-pDNA). GAG-pDNA based therapeutics promise highly potent but localized activation of the immune system exclusively in the tumor microenvironment following systemic administration, leading to the destruction of tumor cells by activated immune cells without debilitating toxic side effects.
To demonstrate the feasibility of the GAG-pDNA approach we have incorporated a plasmid directing the expression of murine IL-2 into GAGomers (GAG-pIL2) and assessed the anti-tumor activity of the construct after systemic delivery into tumor bearing mice. GAG-pIL2 administration resulted in statistically significant inhibition of tumor growth, which correlated with elevated IL-2 levels in the tumor and increased infiltration of T-cells into the tumor microenvironment.
These experiments demonstrate the feasibility of programming tumor cells using GAG-pDNA to produce and secrete immunoregulatory molecules into the tumor microenvironment and trigger robust anti-tumor immune responses.
Citation Format: Genia Alpert, David Altreuter, Sunil Anamandla, Arlyssa Birt, Guy Cinamon, Keren Cohen Merimi, Orli Even Or, Nir Gefen, Nadia Gurvich, Jeno Gyuris, Lorena Lerner, Adi Mondshine, Hong Wang. Anti-tumor effect of GAGomer-mediated intra-tumoral IL-2 expression following systemic administration [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 1601. doi:10.1158/1538-7445.AM2017-1601
Abstract 1611: Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer
Authors: Kates Max , Nirschl Thomas , Sopko Nikolai , Hahn Noah , McConkey David , Baras Alex , Drake Charles , Bivalacqua Trintiy 
Published: July 2017

Abstract
Intravesical BCG Immunotherapy is the standard of care in treating non-muscle invasive bladder cancer (NMIBC), yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. While prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Fischer 344 rats aged 7 weeks received 1.5mg/kg N-Nitroso-N-methylurea (MNU) every other week for 6 weeks (4 doses). Bladder dysplasia began by week 8 and by week 16 the majority of rats had a NMIBC phenotype. Beginning week 8 following the first MNU dose, rats were intravesically administered 0.3ml of BCG (Tice), cisplatin (1mg/ml), Mitomycin C (2mg/ml), MMC+ BCG, or saline (n=10 for all groups) weekly for 6 total doses. Animals were sacrificed at week 16, and bladders were processed for histopathology and digested into single cell suspensions for flow cytometry. Whole transcriptome expression profiling was then performed on sorted CD4 and CD8 cells of post-BCG tumors vs untreated tumors to assess T cell differentiation after BCG. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer is characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. By contrast, treatment with intravesical BCG leads to a large, transient rise in the CD4+ T cell population in the urothelium, and is both more effective and immunogenic compared to intravesical chemotherapy. Interestingly, whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that while BCG induces T cell recruitment to the bladder, the T cell phenotype does not markedly change, implying that combining T cell activating agents with BCG might improve clinical activity.
Citation Format: Max Kates, Thomas Nirschl, Nikolai Sopko, Noah Hahn, David McConkey, Alex Baras, Charles Drake, Trintiy Bivalacqua. Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer [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 1611. doi:10.1158/1538-7445.AM2017-1611
Abstract 1613: Genetically modified neuronal stem cells expressing IL-12 and TNFSF14 attenuate highly metastatic mammary tumors in a mouse model
Authors: Shrestha Tej B. , Lu Dezhang , Basel Matthew T. , Pyle Marla , Bossmann Stefan H. , Troyer Deryl L. 
Published: July 2017

Abstract
Interleukin 12 (IL-12) is a heterodimeric cytokine encoded by two genes, p35 and p40. IL-12, also known as T cell-stimulating factor, induces proliferation of T-lymphocytes and natural killer (NK) cells, while also demonstrating an anti-angiogenic effect and inhibition of regulatory T cells. Similarly, LIGHT (TNFSF14) is a transmembrane protein which acts as a costimulatory factor for the activation lymphoid cells and stimulates the proliferation of T cells, leading to increased apoptosis of tumor cells. Expression of IL-12 and LIGHT specifically in the tumor region could activate T cells and stimulate the immune system to attenuate the tumor. Tumor homing neuronal stem cells C17.2 (NSC) were genetically engineered to express the mouse-LIGHT gene and IL-12 using a retrovirus. The expression of LIGHT and IL-12 genes in NSC was confirmed by PCR, ELISA and Western blot. To test the antitumor effects of the engineered cells, Balb/C mice bearing 4T1 mammary tumors were treated with NSC-LIGHT, NSC-IL-12 and NSC-LIGHT/IL-12 cells intratumorally (I.T.) at day nine. Repeated tumor measurement over time showed attenuation of mammary tumor growth in the both NSC/IL-12 and NSC/LIGHT groups in comparison with control groups PBS and NSC. Tumor growth was further reduced by treating the mice with NSC expressing both cytokines LIGHT and IL-12. Tumor metastasis was also evaluated by removing the primary tumor surgically and observing mice for any sign of metastatic burden. Treatment groups had less metastatic tumor burden and survived longer than the control group. Therefore, tumor homing NPC-LIGHT/IL-12 cells could be effective for the treatment of highly metastatic mammary tumors.
Citation Format: Tej B. Shrestha, Dezhang Lu, Matthew T. Basel, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer. Genetically modified neuronal stem cells expressing IL-12 and TNFSF14 attenuate highly metastatic mammary tumors in a mouse 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 1613. doi:10.1158/1538-7445.AM2017-1613
Abstract 1616: S100A4 blockage alleviates agonistic anti-CD137 antibody induced liver pathology without disruption of anti-tumor immunity
Authors: Zhang Jinhua , Song Kun , Qin Zhihai 
Published: July 2017

Abstract
Liver-related autoimmune toxicities triggered by anti-CD137 agonist antibodies have greatly limited their use in clinic applications. Here we found that anti-CD137 monoclonal antibody (mAb) treatment in mice induced the infiltration of a large number of S100A4+ macrophages into the liver. Depletion of these cells or deficiency of S100A4 decreased inflammatory cytokine profiles, and drastically reduced the number of liver pathogenic CD8+ T cells. Mechanistically, soluble S100A4 directly activated the Akt pathway and specifically prolonged CD8+ T cell survival. Interestingly, one S100A4 neutralizing monoclonal antibody selectively alleviated liver abnormalities but did not affect the anti-tumor immunity induced by anti-CD137 therapy. Thus, our study presents a novel molecular link to the liver pathology induced by an immune stimulatory antibody, and proposes that combinational immunotherapies targeting those pathways could potentially elicit optimal anti-tumor immunity with minimal side effects.
Note: This abstract was not presented at the meeting.
Citation Format: Jinhua Zhang, Kun Song, Zhihai Qin. S100A4 blockage alleviates agonistic anti-CD137 antibody induced liver pathology without disruption of anti-tumor immunity [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 1616. doi:10.1158/1538-7445.AM2017-1616
Abstract 1620: Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenic CD4+ T-cells and induction of antitumor CD8+ T-cell activity
Authors: GU TAO , DeJesus Magdia , Burris Thomas P. , Egilmez Nejat K. 
Published: July 2017

Abstract
An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APCmin/+ / Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4+RORγt+Foxp3-IL-17+ T-helper cell, CD4+RORγt+Foxp3+IL-17+ pathogenic T-regulatory cell (pgTreg) and CD4+RORγt-Foxp3+IL-17- conventional T-regulatory cell (cTreg) numbers; and a concurrent enhancement of CD8+ T-cell cytotoxicity in the colonic lamina propria. Selective subset depletion and functional blockade studies demonstrated that CD4+RORγt+IL-17+ T-cell subsets and CD4+Foxp3+ cTreg supported tumorigenesis/tumor progression whereas CD8+ cytotoxic T-lymphocytes suppressed tumor growth. These findings establish the utility of oral particulate IL-10 as a potential new therapeutic in the management of colon cancer and shed light on the cellular mechanisms that underlie its antitumor activity.
Note: This abstract was not presented at the meeting.
Citation Format: TAO GU, Magdia DeJesus, Thomas P. Burris, Nejat K. Egilmez. Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenic CD4+ T-cells and induction of antitumor CD8+ T-cell activity [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 1620. doi:10.1158/1538-7445.AM2017-1620
Abstract 1621: Adoptively transferred B cells directly kill tumor cells via the CXCR4/CXCL12 & perforin pathways
Authors: Xia Leiming , Xia Yang , Chen Quanning , Wang Yi , Bao Yangyi , Lundy Steven K. Lundy , Dai Fu , Chang Alfred E , Li Qiao 
Published: July 2017

Abstract
Over the years, the role of B cells in the host immune response to malignancy has been overshadowed by our focus on T cells. The role played by B cells in cancer immunology is complex and controversial. The observation made by our lab that activated B cells alone can mediate tumor regression in the adoptive immunotherapy of solid tumors is innovative (JI 2009; CCR 2011; JSO 2012; EJI 2015). One novel mechanism by which activated B cells mediate tumor regression is via direct tumor cell cytotoxicity in the absence of antibodies. We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL-2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemotraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12-producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor, and clearly indicated that transferred effector B cells can act independently of T cells in causing tumor destruction in adoptive immunotherapy.
Citation Format: Leiming Xia, Yang Xia, Quanning Chen, Yi Wang, Yangyi Bao, Steven K. Lundy Lundy, Fu Dai, Alfred E Chang, Qiao Li. Adoptively transferred B cells directly kill tumor cells via the CXCR4/CXCL12 & perforin pathways [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 1621. doi:10.1158/1538-7445.AM2017-1621
Abstract 164: Enhanced antitumor efficacy by recruiting macrophages as effector cells via bispecific antibodies mediated by CD89
Authors: Li Bingyu , Xu Lijun , Xie Kun , Tao Fei , Li Renhao , Gu Hua , Fang Jianmin 
Published: July 2017

Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) is one of key mechanisms through which antibody therapeutics can lyse tumor target cells. ADCC is usually mediated by IgG through recruiting effector cells, mostly NK cells, via IgG Fc receptor. In order to enhance specific tumor lysis by ADCC, a common strategy is to design a bispecific antibody that binds a tumor cell surface antigen and T cell marker CD3, thus to recruit T cells as effector cells. An example of this type of design is the FDA-approved bispecific antibody blinatumomab. We are interested in designing novel bispecific strategies to achieve improved ADCC effect. Since tumors are often infiltrated by macrophages and neutrophils, it would be advantageous to turn these types of cells into effector cells for ADCC. We have designed several bispecific strategies that can target a tumor associated antigen (TAA) and CD89 (FcαRI). The aim is to lyse tumors through connecting tumor cells to CD89-expressing immune effector cells, such as macrophages and neutrophils. The CD89 bispecific antibodies were produced by HEK293 cells and showed binding activities to both CD89 and TAA. The CD89 bispecific antibodies can recruit CD89-expressing immune cells and induced enhanced tumor cells-killing in human whole blood ADCC assays. Since mouse does not express human CD89 homologue, we generated a transgenic mouse strain with specific expression of CD89 on macrophages and monocytes. In this transgenic mouse model, the CD89 bispecific antibodies showed significant anti-tumor activities, demonstrating that the bispecific antibodies can redirect macrophages, including M2 macrophages, to mediate additional effector function in tumor microenvironment.
Citation Format: Bingyu Li, Lijun Xu, Kun Xie, Fei Tao, Renhao Li, Hua Gu, Jianmin Fang. Enhanced antitumor efficacy by recruiting macrophages as effector cells via bispecific antibodies mediated by CD89 [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 164. doi:10.1158/1538-7445.AM2017-164
Abstract 1642: Evaluation of ENMD-2076 in combination with anti-PD1 in syngeneic cancer models
Authors: Fletcher Graham C. , Kiarash Reza , Bray Mark R. , Hu Amanda S. , Ren Ken K. 
Published: July 2017

Abstract
ENMD-2076 is a clinical stage compound with potent activity towards Aurora A and angiogenic kinases. ENMD-2076 has shown promising activity in multiple Phase 1 clinical trials, as well as in a Phase 2 trial in advanced ovarian cancer. ENMD-2076 is currently the subject of several ongoing Phase 2 clinical trials including fibrolamellar carcinoma, triple-negative breast cancer (TNBC), advanced/metastatic soft tissue sarcoma (STS), and advanced ovarian clear cell carcinomas (OCCC). ENMD-2076 has been developed to date as a single agent, however ENMD-2076 inhibits a spectrum of targets including Aurora A, FAK, CSF1R, c-Kit, and KDR, that are potentially involved in immune evasion mechanisms. These kinases have been shown in published studies, when inhibited, to enhance or augment the activity of immune checkpoint inhibitors such as anti-PD1. A study was thereby conducted in syngeneic models to determine the utility of ENMD-2076 combined with immune checkpoint inhibition as a rational strategy for cancer therapy. The study evaluated the efficacy of ENMD-2076 administered daily by oral gavage in the MC38 and CT26 colon cancer models, alone and in combination with an anti-PD1 antibody. Xenografts were established in the appropriate mouse strain (C57BL/6 and BALBc, respectively) by the subcutaneous inoculation of MC38 or CT26 cells into the right flank of female mice. Treatment was initiated 7 days following inoculation when tumor volumes had reached a mean volume of approximately 85 mm3. All treatments were well tolerated, with no significant body weight loss seen during either study. While CT26 tumors were relatively refractory to single agent ENMD-2076, tumor regression was observed in several MC38-bearing animals suggesting an immune activating mechanism. In both models a trend was observed for an augmentation of anti-tumor response in combination relative to single agent ENMD-2076 and anti-PD1 alone. Further studies to evaluate mechanism and an assessment of re-challenge experiments in animals exhibiting complete regression of tumors will be discussed. These studies support the further evaluation of ENMD-2076 in combination with immune checkpoint inhibition as a strategy for cancer therapy.
Citation Format: Graham C. Fletcher, Reza Kiarash, Mark R. Bray, Amanda S. Hu, Ken K. Ren. Evaluation of ENMD-2076 in combination with anti-PD1 in syngeneic cancer models [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 1642. doi:10.1158/1538-7445.AM2017-1642