bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3765: An anti-CD137 antibody can show greater efficacy in syngeneic mouse tumor models when combined with other immuno-oncology (IO) therapies
Authors: Robinson Matthew J. , Osma-Garcia Ines , Coates-Ulrichisen Jane , Watkins Amanda , Mosely Suzanne , Lloyd Chrisopher , Williams Geoff , Morrow Michelle , Dovedi Simon , Herbst Ronald , Wilkinson Robert 
Published: August 2018

Abstract
CD137 is a costimulatory molecule associated with tumour infiltrating lymphocytes and cytotoxic T lymphocytes in particular. Murine anti-CD137 monoclonal antibodies (mAbs) have shown potent anti-tumour effects in syngeneic tumour models, which can be further enhanced by combination with checkpoint inhibitor (CPI) mAbs to PD-1, or CTLA-4 and OX40. Two anti-CD137 monoclonal antibodies (mAbs), Urelumab and Utomilumab, are in development for both haematological and solid cancers, and studies include combinations with other IO therapies such as anti-PD-1, anti-PD-L1 and anti-OX40 mabs. We studied the impact of combining anti-CD137 with CPIs anti-PD-L1, anti-CTLA4, and IO agonist GITRL fusion protein (GITRL-FP) and anti-OX40 on pharmacodynamic responses, tumour growth and survival in mouse syngeneic models. In a responsive model, CT26, combining anti-CD137 with anti-PD-L1 had a greater impact on tumour growth inhibition, which correlated with an enhanced proliferation of CD8 T cells, as determined Ki67 expression using flow cytometry. In MC-38, a model that is less sensitive to both monotherapies, the combination was synergistic and resulted in enhanced tumour growth inhibition. Next, we compared the anti-CTLA4, anti-OX40 and GITRL-FP as monotherapies and in combination with anti-CD137 in the CT26 model. As before, anti-CD137 alone induced CD8 T cell proliferation, whereas anti-OX40 and GITRL-FP stimulated expansion of CD8 and CD4 T cells. Interestingly, in all combinations anti-CD137 appeared to enhance both CD8 and CD4 T cell proliferation. Anti-CTLA4 and GITR-FP had a greater impact on tumour growth inhibition when combined with anti-CD137. In summary, in vivo models indicate that anti-CD137 mAbs are a promising therapy in cancer, but the most benefit may be obtained in combination with other IO therapies.
Citation Format: Matthew J. Robinson, Ines Osma-Garcia, Jane Coates-Ulrichisen, Amanda Watkins, Suzanne Mosely, Chrisopher Lloyd, Geoff Williams, Michelle Morrow, Simon Dovedi, Ronald Herbst, Robert Wilkinson. An anti-CD137 antibody can show greater efficacy in syngeneic mouse tumor models when combined with other immuno-oncology (IO) therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3765.
Abstract 3785: Loss of vacuolar ATPase in hematopoietic stem cells promotes breast tumor progression and pathogenesis
Authors: Sahoo Manoranjan , Katara Gajendra K. , Bilal Mahamood Y. , Fleetwood Sara , Kulshrestha Arpita , Ibrahim Safaa A. , Beaman Kenneth D. 
Published: August 2018

Abstract
Vacuolar ATPase (V-ATPase) is expressed intracellularly on vesicular membranes, and controls intracellular pH and acidification of various intracellular vesicles. Most cancer cells express V-ATPase on their cell surface where they appear to acidify the extracellular environment and help cancer cells to metastasize. We have previously demonstrated that the a2 isoform of V-ATPase (a2V) of mammary epithelial cells plays a key role during breast tumor progression and metastasis. However, the role of a2V of hematopoietic stem cells during breast tumor pathogenesis is not known. Therefore, to understand the role of a2V in hematopoietic stem cells during breast tumor progression, we conditionally knocked out a2V (cKO) from the hematopoietic stem cells of mice. We observed that deletion of a2V leads to a significant reduction of CD4+ and CD8+ T cells in the periphery and spleen of the a2V cKO mice compared to control mice. We hypothesized that reduction of helper CD4+ cells, or cytotoxic CD8+ T cells would result in larger and faster-growing tumors in the a2V-cKO mice. After implantation of a syngeneic tumor cell line (E0771) in the breast tissue of mice, we observed that deletion of a2V led to larger and faster-growing breast tumors compared to control mice. Further investigation of the tumor microenvironment revealed that there was a significant reduction in percentage of CD4+ and CD8+ T cells in the a2V-cKO mice compared to control mice. Targeted RNAseq of tumor microenvironment demonstrated that out of 499 genes that were analyzed, only 3 genes were significantly upregulated while 144 genes were significantly downregulated in the a2V cKO mice. The 144 downregulated genes included genes for pro-inflammatory cytokines, T cell specific genes, death receptors and proapoptotic genes. Collectively, these results demonstrate that deletion of a2V from the hematopoietic stem cells leads to a decrease in CD4+ and CD8+ T cells in the periphery, which results in a faster-growing and larger breast tumor. Further study is needed to understand the relative contribution of CD4+ or CD8+ T cells during breast tumor pathogenesis.
Citation Format: Manoranjan Sahoo, Gajendra K. Katara, Mahamood Y. Bilal, Sara Fleetwood, Arpita Kulshrestha, Safaa A. Ibrahim, Kenneth D. Beaman. Loss of vacuolar ATPase in hematopoietic stem cells promotes breast tumor progression and pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3785.
Abstract 3791: Triggering receptor expressed in myeloid cells 1 (TREM1) is a predictive marker for breast cancer therapeutics
Authors: Pullikuth Ashok K. , Chifman Julia , Routh Eric D. , Chou Jeff , Jin Guangxu , Black Michael A. , Miller Lance D. 
Published: August 2018

Abstract
Triggering receptor expressed on myeloid cells-1 (TREM1) is a cell surface immunoglobulin that amplifies pro-inflammatory responses in myeloid cell populations and has been implicated in carcinogen-induced liver cancer. However, its role in breast cancer is unknown. In a recent screen to identify gene expression patterns associated with breast cancer outcomes, we identified a significant and reproducible positive association between TREM1 expression and breast cancer recurrence in two large breast cancer cohorts comprising 1,984 and 616 patients (p&lt;0.001 and p=0.003, respectively). TREM1 expression was significantly associated with recurrence in both basal-like (p&lt;0.001) and luminal tumor subtypes (Luminal A, p=0.047; Luminal B, p=0.022) and remained significant (p&lt;0.001) in a multivariate Cox regression model, independent of histologic grade, tumor size, nodal status, patient age, treatment and molecular subtype. In pre-treatment biopsies of patients treated with neoadjuvant chemotherapy, high TREM1 expression was associated with a significant decrease in pathologic complete response (pCR) rate (p&lt;0.001), especially in those tumors estimated to have high levels of lymphocytic infiltrate that otherwise associated with an increased pCR rate, consistent with an immune regulatory function for TREM1. Bioinformatics analysis of genes reproducibly correlated with TREM1 expression in breast tumors revealed significant enrichment in myeloid immune cell populations (p&lt;0.001) in general, and neutrophils (p&lt;0.001), M0 macrophages (p&lt;0.001) and M2 macrophages (p&lt;0.001), in particular. Immunohistochemical analysis of breast tumor tissues confirmed colocalization of TREM1 protein expression with the pan-macrophage marker, CD68. These findings, together with the established role for TREM1 in promoting inflammation, fit a model where tumor-infiltrating TREM1-positive myeloid cells impact breast cancer outcomes by promoting immune evasion.
Citation Format: Ashok K. Pullikuth, Julia Chifman, Eric D. Routh, Jeff Chou, Guangxu Jin, Michael A. Black, Lance D. Miller. Triggering receptor expressed in myeloid cells 1 (TREM1) is a predictive marker for breast cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3791.
Abstract 3798: Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells
Authors: Uribe-Herranz Mireia , Bittinger Kyle , Rafail Stavros , Guedan Sonia , Pierini Stefano , Tanes Ceylan , Gill Saar A. , Tany Janos , Morgan Mark A. , Bushman Frederic D. , June Carl H. , Facciabene Andrea 
Published: August 2018

Abstract
Adoptive T-Cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T-cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome, treatment with antibiotics or by heterologous fecal transfer. Depletion of bacteria with vancomycin, decreased the rate of tumor growth in mice receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ dendritic cells, which mediated a sustained systemic expansion of adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest new avenues to improve response to ACT by altering the gut microbiota.
Citation Format: Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Sonia Guedan, Stefano Pierini, Ceylan Tanes, Saar A. Gill, Janos Tany, Mark A. Morgan, Frederic D. Bushman, Carl H. June, Andrea Facciabene. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3798.
Abstract 3802: Human NKG2D ligand regulation of Natural Killer cell function and its implications in cancer and inflammation
Authors: Dhar Payal , Wu Jennifer 
Published: August 2018

Abstract
The significance of ligand-induced activation of Natural Killer cell activating receptor NKG2D in controlling tumor growth has been well established in various experimental animal models. Amongst different types of NKG2D ligands, MHC I chain related molecule MICA/B is expressed most prevalently in various human malignancies, but has not been found in rodent family. Proteolytic-mediated shed-form of soluble MICA/B (sMIC) has been shown to suppress the immune system and correlate with advanced disease stages in cancer patients. Previous studies in our lab using two humanized bi-transgenic mice, one expressing native ligand (TRAMP/MICB) and alternatively expressing the shedding-resistant mutant (TRAMP/MICB.A2) revealed opposite roles of membrane-bound and soluble form of MIC in regulating tumor immunity. Mice with high levels of sMIC exhibited increased tumor progression, whereas mice expressing membrane-bound MICB.A2 in tumors enjoyed tumor-free survival. These findings raised the intriguing question of why do these structurally similar forms of MIC have vastly different effects on tumor immunity. To address this question, we investigated the signaling events and functional outcomes in NK cells upon stimulation by the two forms of ligands. In vitro co-culture studies of NK cells with tumor cell lines expressing sMICB and MICB.A2 revealed elevated pro-inflammatory cytokine production by NK cells upon stimulation with sMICB. In contrast, NK cells stimulated with MICB.A2 displayed enhanced expression of cytotoxicity mediators and signaling molecules of cytotoxicity pathway. This suggests that signaling through sMICB may polarize the NKG2D signaling pathways with preferential activation of inflammatory cytokine pathways. Our data has uncovered a new potential mechanism whereby sMIC promotes tumor progression and supports the notion that sMIC is a viable target for cancer immunotherapy.
Citation Format: Payal Dhar, Jennifer Wu. Human NKG2D ligand regulation of Natural Killer cell function and its implications in cancer and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3802.
Abstract 381: Uptake of biguanides in mitochondria appears to be related to increased glucose uptake and medium acidification but not necessarily related to inhibition of growth of bladder and colon cancer cells
Authors: Lea Michael A. , Kim Haneulsol , desBordes Charles 
Published: August 2018

Abstract
Biguanides including metformin have been used in the treatment of Type 2 diabetes and they are under investigation as anti-cancer agents. Investigation on the mechanism of action of biguanides has largely focused on inhibition of complex 1 in the mitochondrial electron transport chain with subsequent activation of AMP-dependent protein kinase. Studies by Bridges et al. (BMC Biology 14:65, 2016) indicate that inhibitory effects on complex 1 in cells require uptake of biguanides into the mitochondria. In the present work the action of two biguanides that enter the mitochondria (buformin and phenformin) were compared with the action of two biguanides with poor uptake (phenyl biguanide and proguanil). Effects on growth, glucose uptake and medium acidification were studied with two human colon cancer cells (Caco-2 and HT29) and seven bladder cancer cell lines (5637, HT1197, HT1376, RT4, T24, TCCSUP and UM-UC-3). After incubation for 72 hours with 25 µM and 50 µM concentrations of the biguanides, growth inhibition was greatest with proguanil followed by phenformin and with little or no growth inhibition at these concentrations with buformin and phenylbiguanide. In contrast, increased glucose uptake and acidification of the medium was observed with buformin and phenformin with no change or decreased medium acidification with phenyl biguanide and proguanil. Studies with buformin over a concentration range from 10 µM to 500 µM indicated that there was generally growth inhibition at concentrations greater than 50 µM. Studies on medium acidification and glucose uptake revealed biphasic responses with increases at lower concentrations that were reversed at higher concentrations of buformin where growth inhibition was observed. The data suggested that the effect of biguanides on glucose metabolism requires mitochondrial uptake while the mechanism for growth inhibition by biguanides remains to be established.
Citation Format: Michael A. Lea, Haneulsol Kim, Charles desBordes. Uptake of biguanides in mitochondria appears to be related to increased glucose uptake and medium acidification but not necessarily related to inhibition of growth of bladder and colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 381.
Abstract 3815: Decomposition of parameters contributing to the improved therapeutic index of ADCs obtained by GlycoConnect™ and HydraSpace™ Technologies
Authors: Delft Floris van , Janssen Brian , Geel Remon van , Wijdeven Marloes , Verkade Jorge , Berkel Sander van 
Published: August 2018

Abstract
We have found that conjugation of toxic payloads to the native glycan of a monoclonal antibody by chemoenzymatic remodeling (GlycoConnect™ technology) consistently provides antibody-drug conjugates (ADCs) with enhanced therapeutic index (TI) increases versus those of ADCs prepared by mainstream clinical technologies. For example, head-to-head comparison of GlycoConnect™ ADCs -based on the same antibody and payload components- with the marketed drugs Adcetris and Kadcyla revealed an improvement in both efficacy and safety, which is further enhanced by use of a polar HydraSpace™ technology. Importantly, a similar improvement in TI was noted for comparison of a GlycoConnect™ ADC versus or a site-specific ADC derived from a cysteine-engineered antibody, the most important emerging technology in the clinic. With the aim to better understand the superiority of ADCs based on combined GlycoConnect™ and HydraSpace™ technologies, we have performed in-depth in vitro and in vivo investigation into factors contributing to the overall performance of ADCs prepared by glycan conjugation with a polar spacer. For example, it is found that stability is significantly improved versus mainstream technologies in terms of aggregation and linker stability. Rapid aggregation was observed for both Kadcyla and Adcetris, as well as ADC decomposition due to retro-Michael reaction resulting in free payload (for Adcetris) or albumin-conjugated DM1 (for Kadcyla), as indicated by LC-MS and immunoassay analysis. The latter image is confirmed by in vivo pharmacokinetic analysis, showing a dramatic difference in total antibody versus total conjugated antibody by premature release of payload. Finally, analysis with a solid 3D tumoroid model indicates enhanced penetration of site-specific versus randomly conjugated ADC, which may also contribute to better efficacy in solid tumors. The data generated further underline the importance of conjugation and linker technology as critical quality attributes for next-generation ADCs with higher therapeutic index.
Citation Format: Floris van Delft, Brian Janssen, Remon van Geel, Marloes Wijdeven, Jorge Verkade, Sander van Berkel. Decomposition of parameters contributing to the improved therapeutic index of ADCs obtained by GlycoConnect™ and HydraSpace™ Technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3815.
Abstract 3820: Novel PD-1/GITRL bispecific fusion protein delivering concurrent T cell co-stimulation and checkpoint pathway inhibition
Authors: Dovedi Simon J. , Seaman Jonathan , Osma-Garcia Ines , Deschler Katharina , Poon Edmund , Herbst Ronald , Wilkinson Robert 
Published: August 2018

Abstract
Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is a co-stimulatory receptor, and programmed cell death protein 1 (PD-1) is an important co-inhibitory receptor involved in controlling T-cell activation and function. Preclinical studies using murine cross-reactive molecules demonstrate that the combination of an αPD-1 monoclonal antibody (mAb) with a GITR-ligand (GITRL) fusion protein can elicit synergistic antitumor activity and long-term survival benefit in syngeneic mouse tumor models. Here we describe the activity of two bispecific fusion proteins, each comprising two GITR ligand trimers fused to the Fc region of an αPD1 mAb, in an IgG1 (MEDI5771) or IgG4P (MEDI3387) format. We show that these bispecific molecules are able to concurrently engage both targets and are effective in cell-based PD-1 and GITR reporter assays, and in a range of human primary T-cell assays. Furthermore, the PD-1/GITRL FP bispecific constructs elicit T-cell responses in vitro that are at least equivalent to a combination of a) the parental molecules and b) MEDI1873 (a GITR agonist currently undergoing clinical evaluation) and an αPD-1 mAb. Moreover, using surrogate molecules we demonstrate that IV administration leads to dose-dependent pharmacodynamic responses on CD4+ and CD8+ T cells for both isotypes of the bispecific molecule. These data demonstrate that the antitumor activity for these novel molecules is equivalent to the combination of GITRL-FP and PD-1 mAb in the B16 model. In summary, the simultaneous dual targeting of PD-1 and GITR pathways mediated by these two novel bispecific molecules induces robust T-cell activity that is at least equivalent to a combination of molecules targeting these pathways, thereby demonstrating strong potential as a novel anticancer therapy.
Citation Format: Simon J. Dovedi, Jonathan Seaman, Ines Osma-Garcia, Katharina Deschler, Edmund Poon, Ronald Herbst, Robert Wilkinson. Novel PD-1/GITRL bispecific fusion protein delivering concurrent T cell co-stimulation and checkpoint pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3820.
Abstract 3838: Inhibition of the spectraplakin protein MACF1 sensitizes glioblastomas to BCNU
Authors: Borlay Danielle , Bonner Kala , Kutten Orica , Atkinson Katelyn , Quick Quincy A. 
Published: August 2018

Abstract
Glioblastoma heterogeneity and diversity is recognized as a major contributing factor to the resistance of these cancers to clinical chemo- and radiotherapy treatment regimens. This diversity is attributed in part to a plethora of novel unevaluated proteins whose functions participate in glioblastoma etiology, progression, and recurrence. One such protein is the cytoskeletal cross-linker, Microtubule Actin Crosslinking Factor 1 (MACF1), which we have previously shown was expressed at high levels in glioblastoma tissue as compared to its absence in normal brain tissue. In support of these findings immunoblotting expression analysis in this study showed that MACF1 protein expression was upregulated in response to BCNU exposure in glioblastoma cells. Subsequently, experiments were conducted to assess the combinatorial effect of MACF1 inhibition in conjunction with BCNU treatment. A CRISPR-Cas9 genome editing approach was used to inhibit MACF1 function prior to drug exposure. Cell proliferation analysis revealed a cooperative synergistic effect of MACF1 inhibition and BCNU treatment on the reduction of glioblastoma cells as compared to cells treated with either BCNU or CRISPR inhibition of MACF1 alone. In conclusion, upregulation of MACF1 in response to BCNU suggests that this spectraplakin protein may play a role in the mechanistic resistance of glioblastomas to BCNU and the therapeutic prognosis of glioblastomas treated with this drug. Additionally, this study demonstrated that MACF1 inhibition is a novel neoadjuvant approach that enhances the therapeutic efficacy of BCNU.
Citation Format: Danielle Borlay, Kala Bonner, Orica Kutten, Katelyn Atkinson, Quincy A. Quick. Inhibition of the spectraplakin protein MACF1 sensitizes glioblastomas to BCNU [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3838.