bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 543: Preclinical combination strategies to enhance the efficacy of the anti-PD-1 antibody pembrolizumab
Authors: Pinheiro Elaine M. , Hinton Marlene , Mangadu Ruban , Cai Mingmei , Phan Uyen , Nebozhyn Michael , Hirsch Heather , Loboda Andrey , Javaid Sarah , Wang Yaolin , Sriram Venkataraman , Phillips Joseph H. , McClanahan Terri , Long Brian 
Published: July 2016

Abstract
Pembrolizumab (MK-3475), a humanized monoclonal IgG4 antibody against programmed death receptor 1 (PD-1), has shown activity in multiple types of cancer. Although pembrolizumab is showing a dramatic impact in patients that respond, a large fraction of patients do not respond to single agent therapy. Combination approaches may be the key to improving response rates in these patients. One of the challenges is how best to tailor combination strategies to provide maximal benefit to patients. How we prioritize new combinations will require an understanding of which mechanism is best for which tumor. To elucidate mechanisms that may create an immunogeneic tumor microenvironment and enhance the antitumor activity of PD-1 blockade, we have tested combination strategies with muDX400, a murine anti-PD-1 antibody. The murine preclinical syngeneic tumor models selected for these studies had varied tumor microenvironment compositions and displayed a range of responses to therapy with single agent anti-PD-1. Here we show enhanced anti-tumor activity when PD-1 blockade is combined with conventional chemotherapies, small molecule therapies and additional immunotherapy approaches that target multiple steps in the immune-oncology pathway. Pre and post treatment tumors from these models were extensively characterized by gene expression profiling, whole exome sequencing, flow cytometry and immunohistochemistry analysis. Molecular and cellular correlates of response to anti-PD-1 as a single agent and in combination with these agents were evaluated. These data support potential combination strategies that could either increase efficacy or expand the patient population in which pembrolizumab will demonstrate benefit.
Citation Format: Elaine M. Pinheiro, Marlene Hinton, Ruban Mangadu, Mingmei Cai, Uyen Phan, Michael Nebozhyn, Heather Hirsch, Andrey Loboda, Sarah Javaid, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Terri McClanahan, Brian Long. Preclinical combination strategies to enhance the efficacy of the anti-PD-1 antibody pembrolizumab. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 543.
Abstract 560: Development of a novel class of traps that potently block transforming growth factor-beta (TGF-beta) thereby counteracting TGF-beta mediated immunosuppression and promoting T-cell infiltration into tumors
Authors: O’Connor-McCourt Maureen D. , Lenferink Anne E.G. , Zwaagstra John , Sulea Traian , Baardsnes Jason , Collins Catherine , Cantin Christiane , Durocher Yves , Singh Renu , Koropatnick James 
Published: July 2016

Abstract
Introduction: Elevated TGF-β ligand markedly augments cancer progression primarily by suppressing the immune system in the tumor microenvironment, in particular by suppressing T-cell recruitment and/or activation. We developed a novel class of decoy receptor traps to potently block TGF- β and induce T-cell infiltration into tumors. This promotes the “T-cell-inflamed” tumor state, which is expected to render tumors sensitive to immune checkpoint inhibitors and other immunotherapeutics.
Experimental Procedures: We have computationally designed a class of avidity-enhanced receptor-ectodomain-based traps which bind and neutralize TGF-β. Several trap formats have been produced and tested, with each format exhibiting varying characteristics, including differing circulating half-lives and in vitro blocking potencies (from nM to pM). Representative therapeutic candidates from the different trap formats were evaluated for efficacy in in vivo studies using the syngeneic 4T1 triple negative breast cancer (TNBC) tumor model. Additionally, ex vivo studies were performed on CD4+ and CD8+ T-cells harvested from the draining lymph nodes of treated animals.
Results: In efficacy studies using the syngeneic 4T1 TNBC model, novel TGF-β traps were shown to promote significant T-cell infiltration into tumors. This infiltration resulted in reduced primary tumor growth as well as significant reductions in metastatic lesions. Additionally, ex vivo studies revealed that trap treatment decreased T-cell apoptosis, promoted T-cell proliferation in response to tumor cell lysates in the presence of dendritic cells, as well as increased the capacity of T-cells to specifically lyse 4T1 tumor cells.
Conclusion: Novel computationally-designed TGF-β traps are capable of promoting the “T-cell-inflamed” tumor state. Combination studies in which this novel class of anti-TGF-β immunotherapy is combined with immune checkpoint inhibitors are ongoing.
Citation Format: Maureen D. O’Connor-McCourt, Anne E.G. Lenferink, John Zwaagstra, Traian Sulea, Jason Baardsnes, Catherine Collins, Christiane Cantin, Yves Durocher, Renu Singh, James Koropatnick. Development of a novel class of traps that potently block transforming growth factor-beta (TGF-beta) thereby counteracting TGF-beta mediated immunosuppression and promoting T-cell infiltration into tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 560.
Abstract 562: Dinaciclib induces immunogenic cell death and enhances anti-PD-1 mediated tumor suppression
Authors: Hossain Dewan Mohammed Sakib , Ugarte Fernando , Sawant Anandi , Cai Mingmei , Sriram Venkataraman , Pinheiro Elaine , Sadekova Svetlana , Chackerian Alissa 
Published: July 2016

Abstract
Blockade of the checkpoint inhibitor PD-1 has demonstrated remarkable success in the clinic for the treatment of a growing list of different cancers. However, several tumor types are resistant to anti-PD-1 monotherapy. This observation has spurred numerous combination studies to reveal what additional therapeutic interventions may complement anti-PD1 blockade. Recently it has been shown that immunogenic cell death (ICD), induced by radiation and/or chemotherapy, improves T cell responses against different tumor types. ICD is characterized by damage-associated molecular patterns (DAMPs) including surface expression of calreticulin, and release of ATP and HMGB1. Recognition of DAMPs triggers dendritic cell maturation and functions that are critical for tumor antigen-specific T cell activation. Thus therapies that evoke ICD may further augment anti-tumor immunity elicited by anti-PD-1.
In mouse syngeneic tumor models, we observed combinatorial anti-tumor activity of anti-PD1 and the cyclin-dependent kinase inhibitor, dinaciclib. We hypothesized that dinaciclib potentiates the effects of anti-PD-1 by eliciting ICD. Indeed, tumor cells treated with dinaciclib express the hallmarks of ICD including HMGB1 and ATP release and surface expression of calreticulin. Dinaciclib treatment also increases tumor cell phagocytosis and induces dendritic cell maturation. Furthermore, mice immunized with dinaciclib-treated tumor cells are resistant to subsequent tumor challenge. Tumors from mice receiving anti-PD1 and dinaciclib have increased T cell infiltration and dendritic cell activation, indicating the overall quality of the immune response generated may be improved with the combo. Taken together, these findings suggest a potential mechanism for the observed synergy between dinaciclib and anti-PD1. Dinaciclib induces immunogenic cell death, converting the tumor cell into an endogenous vaccine and thereby boosting the effects of anti-PD-1.
Citation Format: Dewan Mohammed Sakib Hossain, Fernando Ugarte, Anandi Sawant, Mingmei Cai, Venkataraman Sriram, Elaine Pinheiro, Svetlana Sadekova, Alissa Chackerian. Dinaciclib induces immunogenic cell death and enhances anti-PD-1 mediated tumor suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 562.
Abstract 563: Combined treatment with PD-L1 blockade and a TLR7/8 agonist dramatically enhances antitumor immunity
Authors: Nishii Naoto , Kondo Yuta , Li Lixin , Lau Walter , Harada Hiroyuki , Azuma Miyuki 
Published: July 2016

Abstract
[Aim] Toll like receptor (TLRs) are expressed in many types of immune cells and function as a key sensor of microbial products. Ligand binding to TLRs leads to activation of signaling pathways in innate immune cells, particularly dendritic cells and subsequent induction of adaptive immune responses. TLR7/8 agonists have been shown to enhance antiviral and antitumor immune responses via multiple cytokine production such as IFN-α, IL-1β, IL-6 and TNFα. Resiquimod (R-848) is a synthetic imidazoquinoline-like molecule that binds to TLR7 and TLR8. Presently, resiquimod has been used as a topical drug for skin cancer and viral infection, because of severe side effects of systemic administration. Thus far, the clinical results of anti-PD-1 or anti-PD-L1 therapy have showed great benefits by inducing tumor regression and improving survival. However, the patients obtained the benefits of this treatment are around one third. An additional approach is required to enhance the efficacy of PD-1 blockade therapy. In this study, we examined the effects of combined treatment with anti-PD-L1 antibody and a low dose of resiquimod administration in two murine tumor models (a squamous cell carcinoma cell line, SCCVII and a colon carcinoma cell line, Colon26). [Methods] Anti-PD-L1 mAb (MIH5, 200 μg/mouse) and/or resiquimod (1.73 μg/mouse) were intraperitonealy administrated at three times a week and tumor growth was evaluated. [Results and Discussion] In a Colon26 model, either anti-PD-L1 (MIH5) mAb or resiquimod treatment alone slightly decreased tumor growth, but the combined treatment dramatically reduced the tumor growth and completely eradicated the tumor in some of mice. In a SCCVII model, monotherapy with resiquimod markedly reduced the tumor growth and completely eradicated the tumor in some of mice. The combined treatment further enhanced the efficacy. The delayed combined treatment at day 7 also showed the reduction of tumor size. Functional analyses at 3-4 wks after the tumor inoculation revealed that monotherapy with resiquimod in the SCCVII model and the combined treatment in both models significantly enhanced the percentages of IFN-γ+-expressing CD8+ T cells, but did not clearly affect the percentages of Foxp3+ regulatory T cells. Our results suggest that TLR7/8 agonist administration alone markedly enhanced antitumor responses in a selected tumor model and the combined treatment with PD-L1 blockade and a TLR7/8 agonist further amplify their effects.
Citation Format: Naoto Nishii, Yuta Kondo, Lixin Li, Walter Lau, Hiroyuki Harada, Miyuki Azuma. Combined treatment with PD-L1 blockade and a TLR7/8 agonist dramatically enhances antitumor immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 563.
Abstract 568: FAK/PYK2 inhibition enhances immune checkpoint inhibitor efficacy
Authors: Wang Yan , Ring Jennifer E. , Sprott Kam , Weaver David T. , Pachter Jonathan A. 
Published: July 2016

Abstract
Although durable responses to single agent immune checkpoint inhibitors have been reported, additional approaches are needed to improve upon this therapeutic benefit. Combinations of immunotherapy agents with tumor microenvironment modulators have the potential to overcome barriers that tumor cells develop to evade the immune system, and provide benefit to a greater proportion of patients. Focal Adhesion Kinase (FAK) and its family member, PYK2, are potentially valuable targets due to their roles in regulating key cellular populations in the tumor microenvironment. In addition to targeting cancer stem cells, the FAK/PYK2 dual inhibitors, VS-6063 and VS-4718, have been shown to inhibit monocyte-derived macrophages, reduce tumor-associated macrophages in xenograft models, and promote a CD8+ T cell-mediated anti-tumor response in squamous cell carcinoma models.
We now report that the combination of VS-4718 with an anti-PD-1 mAb shows improved efficacy over anti-PD-1 mAb alone and extends survival of MC38 syngeneic tumor bearing animals. Analysis of MC38 tumors at day 12 of treatment revealed a significant increase in the CD8+ T cells/Treg ratios in tumors in the VS-4718 + anti-PD-1 combination group, providing a mechanistic understanding for the enhanced efficacy of this combination.
To explore additional combination options, we tested the combination of VS-4718 with anti-4-1BB in the MC38 model. Consistent with what was observed with the anti-PD-1 combination, VS-4718 also enhanced the efficacy of an anti-4-1BB mAb.
To further delineate direct effect of FAK inhibition on human T cells, in vitro T cell proliferation assays were conducted. VS-6063 and VS-4718 dose-dependently stimulated proliferation of CD8+ cytotoxic T cells isolated from healthy donors. This is in distinct contrast to other protein kinase inhibitors, such as the SRC inhibitor dasatinib which impaired the proliferation of CD8+ cytotoxic T cells. In addition, both VS-4718 and VS-6063 decreased CD8+ T cell exhaustion markers, and increased T cell-mediated tumor cell killing in vitro.
These data provide a rationale for clinical trials in cancer patients to test whether a FAK/PYK2 inhibitor in combination with an immune checkpoint inhibitor could increase the breadth of responsive tumor types, increase the number of responders, and confer more durable anti-tumor responses.
Citation Format: Yan Wang, Jennifer E. Ring, Kam Sprott, David T. Weaver, Jonathan A. Pachter. FAK/PYK2 inhibition enhances immune checkpoint inhibitor efficacy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 568.
Abstract 573: Preclinical evaluation of JTX-2011, an anti-ICOS agonist antibody
Authors: Michaelson Jennifer S. , Harvey Christopher J. , Elpek Kutlu G. , Duong Ellen , Wallace Matthew , Shu Chengyi J. , Sathyanarayanan Sriram , Mabry Robert , Shallberg Lindsey , Zi Tong , Deshpande Amit , Sazinsky Stephen L. , Apgar Joshua , Law Deborah 
Published: July 2016

Abstract
ICOS (inducible co-stimulator molecule) is a co-stimulatory molecule and a member of the CD28 superfamily expressed primarily on T lymphocytes. Analysis of cancer patient samples as well as rodent preclinical data have implicated a role for the ICOS pathway in cancer immunotherapy. We have generated a panel of anti-ICOS monoclonal antibodies with in vitro agonistic properties. The anti-ICOS antibodies are efficacious as monotherapies and in combination with anti-PD1 in multiple syngeneic tumor models. Mechanistic studies demonstrate that tumor regression is associated with enhanced ratios of cytotoxic CD8:T regulatory (Treg) cells as well as preferential reduction in ICOS-high Tregs in the tumor microenvironment. JTX-2011, a species cross-reactive high affinity humanized agonist monoclonal antibody, has been selected for development. Evaluation of JTX-2011 in nonhuman primate models will be presented, including data informing safety and PK parameters. Our preclinical data provides rational for clinical development of JTX-2011 as a cancer immunotherapeutic to be tested as both a monotherapy as well as in combination with immunotherapies in solid tumor indications.
Citation Format: Jennifer S. Michaelson, Christopher J. Harvey, Kutlu G. Elpek, Ellen Duong, Matthew Wallace, Chengyi J. Shu, Sriram Sathyanarayanan, Robert Mabry, Lindsey Shallberg, Tong Zi, Amit Deshpande, Stephen L. Sazinsky, Joshua Apgar, Deborah Law. Preclinical evaluation of JTX-2011, an anti-ICOS agonist antibody. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 573.
Abstract 585: Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy
Authors: Nolan-Stevaux Olivier , Fajardo Flordeliza , Liu Lily , Coberly Suzanne , McElroy Patricia , Nazarian Aaron , Bott Franziska , Nahrwold Elisabeth , Raum Tobias , Kischel Roman , Lutterbuese Ralf , Hoffmann Patrick , Kufer Peter 
Published: July 2016

Abstract
BiTE® therapeutics are single chain antibody constructs harboring two binding moieties: one directed at a tumor associated antigen and one directed at the CD3e protein, which trigger T cell dependent cellular cytotoxicity (TDCC) against targeted cancer cells. Here, we evaluated the suitability of ENPP3 as a potential BiTE® target. The ENPP3 mRNA is highly differentially expressed in clear cell Renal Cell Carcinoma (ccRCC) and the ENPP3 protein is detected with high uniformity and intensity in ccRCC tumor samples by immunohistochemistry. We demonstrated the surface expression of this protein in Renal Cancer cell lines and confirmed that the ENPP3 protein was highly restricted to the luminal side of normal epithelial layers in which it was detected (proximal renal tubules, bronchial epithelium, salivary glands). We developed highly potent anti-ENPP3 BiTE® molecules and demonstrated the in vitro TDCC activity of these molecules. Two anti-ENPP3 BiTE® molecules further demonstrated tumor formation inhibition activity in a human T cell / human target cell admixture mouse xenograft model.
Citation Format: Olivier Nolan-Stevaux, Flordeliza Fajardo, Lily Liu, Suzanne Coberly, Patricia McElroy, Aaron Nazarian, Franziska Bott, Elisabeth Nahrwold, Tobias Raum, Roman Kischel, Ralf Lutterbuese, Patrick Hoffmann, Peter Kufer. Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 585.
Abstract 588: Inhibition of liver inflammation and tumorigenesis by blocking Ccl2-Ccr2 axis in a mouse model
Authors: Teng. Kun-Yu 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC), the second cancer-related deadly disease, commonly arises in the setting of chronic liver inflammation. CC chemokine ligand 2 (CCL2), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in HCC patients. Here, we examined the therapeutic efficacy of inhibitors of the Ccl2-Ccr2 axis against hepatitis and HCC in the miR-122 knockout (aka KO) mouse model, in which upregulation of Ccl2 promotes liver inflammation that progresses to HCC with age. To determine whether blocking the Ccl2-Ccr2 axis has any therapeutic potential, we treated KO mice with Ccl2 neutralizing antibody (nab) or a small molecule inhibitor of Ccr2 and monitored liver pathology. Both agents were able to reduce the bridging inflammation in these mice by reducing the population of CD11highGr1+ cells, and expression of IL-6 and TNF-alpha in KO livers. Furthermore, treatment of tumor-bearing KO mice with Ccl2 nab for 8 weeks significantly reduced the recruitment of CD11bhighGr1+ monocytes, IL-6 and TNF-alpha production, and HCC incidence as well as tumor burden. The down-regulation of pStat3 and c-Myc (IL-6 downstream) as well as NF-kappaB (TNF-alpha downstream) upon targeting Ccl2 positively correlated with tumor growth suppression. In addition, inhibition of tumorigenesis by Ccl2 nab also correlated with enhanced cytotoxicity and IFN-gamma expression of NK cells isolated from the tumor microenvironment. Collectively, our results demonstrate that blocking the Ccl2-Ccr2 axis can be an effective therapeutic approach against both hepatitis and HCC.
Citation Format: Kun-Yu Teng. Inhibition of liver inflammation and tumorigenesis by blocking Ccl2-Ccr2 axis in a mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 588.
Abstract 597: Defining the role of macrophage mediated trogocytosis in the clearance of antibody-opsonized tumor cells
Authors: Velmurugan Ramraj , Challa Dilip , Ram Sripad , Ober Raimund J. , Ward E. Sally 
Published: July 2016

Abstract
Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fcγ receptor (FcγR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is pro-tumorigenic. However, there is limited information concerning the role of trogocytosis in antibody-based treatment of solid tumors such as breast cancer.
We have used advanced microscopy methods and quantitative flow cytometric assays to study the effect of antibody-mediated trogocytosis on breast cancer cells and whether they can lead to tumor cell death.
Our results show that long-term coculture with macrophages can reduce cancer cell numbers in an antibody-dependent manner even at low effector:target ratios. Quantitation from simultaneous long-term imaging of macrophage:cancer cell interactions reveals that this cell death is caused by both macrophage-mediated phagocytosis and trogocytosis, with the contribution of each process differing by the phenotype of the effector macrophages.
Together, our results add to our understanding of the numerous interactions macrophages can have with cancer cells, and how therapeutic antibodies modulate their effects. Our recent observations in this area will be presented.
Citation Format: Ramraj Velmurugan, Dilip Challa, Sripad Ram, Raimund J. Ober, E. Sally Ward. Defining the role of macrophage mediated trogocytosis in the clearance of antibody-opsonized tumor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 597.