bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A124: Protumoral effects of TLR7 in lung tumors
Authors: Dajon Marion , Iribarren Kristina , Cremer Isabelle 
Published: November 2016

Abstract
TLR7 agonists are currently under investigations for their ability to enhance anti-tumor immune responses. However, in some tumor models, these agonists can also stimulate tumor cells, which express high levels of TLR7. In Non-Small-Cell Lung Carcinoma (NSCLC), we have demonstrated that high expression of TLR7 conferred poor clinical outcome and was strongly associated with resistance to chemotherapy. This protumorigenic effect of TLR7 has been validated in murine models in which the injection of TLR7 agonists in NOD/SCID mice, in C57BL/6 wild-type or in TLR7-deficient mice grafted with lung adenocarcinoma tumor cells led to increased tumor progression and chemotherapeutic resistance. TLR7 stimulation resulted in a significant increase of Myeloid-Derived Suppressor Cells (MDSC) in the tumor microenvironment. Depletion experiments of MDSC indicated that these cells appeared to be responsible to the in vivo pro-tumoral effect induced upon TLR7 stimulation. Finally, we have demonstrated that the pro-tumoral effect of TLR7 stimulation, mediated by the MDSC recruitment, was independent of stimulation of TLR7 of immune cells.
Our results reveal the mechanism by which TLR7 stimulation induce the pro-tumoral effect in mice, and open the way to the development of novel cancer therapeutics including TLR7 inhibitors, for NSCLC patients.
Citation Format: Marion Dajon, Kristina Iribarren, Isabelle Cremer. Protumoral effects of TLR7 in lung tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A124.
Abstract A134: Identification of novel Treg-specific molecule targets
Authors: Kim Jung-Ho , Moon Jae-Seung , Lee Sang-Kyou 
Published: November 2016

Abstract
Regulatory T cells (Treg cells) play as a specialized cell lineage that has an essential role in the immunological tolerance and maintenance of immune homeostasis, and it has been reported that Treg cells are enriched within the tumor microenvironment for immune evasion due to their immunosuppressive functions. Currently studies have revealed the heterogeneity or developmental plasticity in the Treg cells lineage, acquisition of alternative effector or hybrid fates. In this study, we conducted next generation sequencing (NGS) to identify the molecular interaction of Treg cells and Th17 cells genetic programs in response to cytokine regulation. We found that 41 differential expression genes (DEGs) are related common TGF-β signaling, 129 DEGs are involved specific Treg cells fate determination and maintenance and 144 DEGs are linked pro-inflammatory Th17 cells response. Also we identified Treg cell-specific molecular targets such as TregP1, TregL1, TregG, and TregAP2 by systemic and classical biologic approaches. These genes highly expressed in Treg cells independently of Foxp3 expression, and conferred unique role on Treg cells. Thus, we propose that these genes targeting have potential therapeutic applications in cancer, and other conditions which Foxp3+Treg cells limit protective host immune responses.
Note: This abstract was not presented at the conference.
Citation Format: Jung-Ho Kim, Jae-Seung Moon, Sang-Kyou Lee. Identification of novel Treg-specific molecule targets [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A134.
Abstract A147: Differential transcriptional profiling of tumor cell populations
Authors: Duttke Sascha H. , Glass Christopher K. 
Published: November 2016

Abstract
Tumors compass remarkably diverse cell populations as a result of genetic and environmental influences. Macrophages are a type of white blood cell with pivotal roles in immunity and tissue homeostasis that were reported to constitute up to 50% of the tumor mass. Macrophages also present a central line of defense against cancer by preventing inflammation as well as specific elimination of tumor cells. However, tumors can manipulate macrophages to switch their function from tumor-suppressing to tumor-supporting. Tumor-supporting macrophages are pro-angiogenic, immunosuppressive and aid the neoplastic progression. My aim is to characterize the core transcriptional network of “supporting” or “repressing” tumor associated macrophages in mice and humans. At phase 1 of the project, I am testing methods to differentially analyze cell populations from tumors with minimal perturbations as well as ways to reduce input for GROseq and RNAseq analysis.
Citation Format: Sascha H. Duttke, Christopher K. Glass. Differential transcriptional profiling of tumor cell populations [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A147.
Abstract B022: Intratumoral CD40 activation and checkpoint blockade induces systemic anti-melanoma immunity that eradicates disseminated tumors
Authors: Singh Manisha , Vianden Christina , Diab Adi , Hwu Patrick , Overwijk Willem W. 
Published: November 2016

Abstract
Although surgical resection is a reliable treatment for localized melanoma, treatment options for metastatic melanoma are limited. Melanoma Brain metastasis (MBM) is a major clinical problem in patients with advanced melanoma, and the incidence of brain metastasis is increasing every year. Thus, there is a significant unmet need for effective therapies for metastatic melanoma and MBM patients. Agonistic CD40 antibodies generate strong tumor specific CD8 T cell response and anti-tumor activity; however systemic anti-CD40 therapy has been associated with cytokine release syndrome and liver toxicity. We studied the anti-melanoma activity and mechanism of action of a non-replicating adenovirus encoding a CD40-targeting chimeric immunostimulatory protein (ISF35) by local intratumoral delivery approach to treat local and distant melanoma. Mice bearing established B16 melanomas on both right and left flanks or on right flank and in brain were treated intratumorally with ISF35 or rAd.empty to the right flank tumor and received anti-PD1 plus anti-CTLA-4 systemically. Anti-tumor effects of mono or combination therapies were determined by mice survival and tumor growth measurement. The mechanistic contribution of immune cells to this therapy was determined by using antibody blockades. Immune cell infiltrates in tumor and expression of activation markers on these cells were analyzed by flow cytometry. Intratumoral administration of ISF35 generates systemic anti-tumor immunity mediates by CD8 T cells and suppress both injected and distant uninjected wild-type B16.F10 melanomas. However, tumors did not completely regress after therapy. When combined with checkpoint inhibitors, ISF35 generates synergistic systemic anti-melanoma immunity that eradicates both injected and uninjected distant subcutaneous melanoma and uninjected brain melanoma with 40% of mice cured. The systemic anti-tumor activity of ISF35/anti-PD-1/anti-CTLA-4 was associated with greater production of melanoma-specific CD8 T cells with an activated phenotype. Immunotherapy based on intratumoral CD40 activation is potentiated by PD-1 and CTLA-4 blockade and this combination generates functional and long-lasting anti-tumor CD8 T cell immunity that systemically suppresses melanoma metastases. This approach will be a better option for treatment of patients with metastatic melanoma that does not respond to checkpoint blockage monotherapy.
Citation Format: Manisha Singh, Christina Vianden, Adi Diab, Patrick Hwu, Willem W. Overwijk. Intratumoral CD40 activation and checkpoint blockade induces systemic anti-melanoma immunity that eradicates disseminated tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B022.
Abstract B033: A novel IL-2 and IL-15 antagonist shifting the immune balance towards tolerance: Potential therapeutic applications
Authors: Dihia Meghnem , Morisseau Sebastien , Trillet Kilian , Frutoso Marie , Barbieux Isabelle , Quemener Agnes , Jacques Yannick , Mortier Erwan 
Published: November 2016

Abstract
Interleukin-15 and interleukin-2 are two hematopoietic cytokines belonging to γc family and both share the IL2/15Rβ chain and the common γ chain. The IL-15Rα and IL-2Rα chains confer specific binding and signalling for IL-15 and IL-2 respectively. IL-15 and IL-2 induce T-cell proliferation, effector T-cell differentiation and memory T-cell survival. Unlike IL-15, IL-2 plays a crucial role, in development and activation of regulatory T cells, which constitutively express specific IL-2Rα chain. In order to inhibit IL-2 and IL-15 dependent effector functions, we developed an original antagonist called BinhG which target the shared IL-2/15Rβγ receptor. To characterize BinhG's mechanism and therapeutic potential, we first studied its effect in vitro on IL-15 and IL-2-induced proliferation on cell lines and peripheral blood mononuclear cells. We found that BinhG was able to inhibit IL-15 and IL-2-dependent proliferation of effector NK and CD8 T cells expressing the IL-2/15Rβγ dimeric receptor, whereas it was unable to inhibit IL-2 induced-T-reg cells due to ILtheirs IL-2Rα expression. These results were confirmed in vivo, by inhibition of IL-2 or IL-15 induced activation in mice. Moreover, after PolyIC stimulation in vivo, BinhG was able to reduce IFNγ secretion by NK cells and activation marker CD69 surface expression by CD4 T and CD8 T lymphocytes, but has no effect on T-reg cells. In the light of these observations, BinhG was evaluated in order to induce tolerance. Thus, we set up a murine model of skin graft rejection, and we observed that BinhG prolonged the skin graft survival. The use of the BinhG antagonist appears to have much promise, as it is able to shift immune response towards the tolerance side of the balance. However, further studies are needed to maximize the therapeutic outcome, by improving BinhG in vivo half-life. Moreover, it would be of interest to evaluate BinhG's effect in autoimmune contexts.
Citation Format: Meghnem Dihia, Sebastien Morisseau, Kilian Trillet, Marie Frutoso, Isabelle Barbieux, Agnes Quemener, Yannick Jacques, Erwan Mortier. A novel IL-2 and IL-15 antagonist shifting the immune balance towards tolerance: Potential therapeutic applications [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B033.
Abstract B042: Potent and selective small molecule USP7 inhibitors for cancer immunotherapy
Authors: Kumar Suresh , Wu Jian , Wang Liqing , Wang Jack , Sokirniy Ivan , Wang Hui , Fegley Glen , Weinstock Joseph , Mattern Michael , Hancock Wayne W. 
Published: November 2016

Abstract
Immunotherapy using biological agents such as anti-PD1 antibody has revolutionized cancer treatment. Nevertheless, patient response has been highly variable, with many patients showing no response. Although the precise mechanism of resistance is unknown, the complex immunosuppressive tumor milieu necessitates development of additional therapeutic agents to potentiate active drugs and expand the scope of the revolutionary cancer immunotherapy. Regulatory T cells (Tregs) present in tumors dampen the anti-tumor activities of effector T cells and are correlated with poor prognosis. Therefore, depletion of Tregs or impairment of Treg function is considered an attractive therapeutic approach. USP7, a deubiquitylase (DUB) implicated as a critical node in several cancer signaling pathways, is essential for maintaining Treg function, and Treg specific deletion of USP7 results in impaired Treg functions and lethal autoimmunity. Progenra has identified selective small molecule USP7 inhibitors that were subsequently lead optimized and evaluated in ADME/PK studies. Potent, selective and irreversible USP7 inhibitors have been shown to impair Treg functions and exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice. In addition, Progenra's USP7 inhibitors synergize with anti-PD1 antibody and cancer vaccines. These studies suggest that USP7 inhibitors alone or in combination can improve the efficacy and expand the scope of cancer immunotherapy
Citation Format: Suresh Kumar, Jian Wu, Liqing Wang, Jack Wang, Ivan Sokirniy, Hui Wang, Glen Fegley, Joseph Weinstock, Michael Mattern, Wayne W. Hancock. Potent and selective small molecule USP7 inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B042.
Abstract B043: Systems pharmacology modeling of anti-CD20/CD3 T-cell dependent bispecific antibody and its application to clinical trial design
Authors: Hosseini Iraj , Gadkar Kapil , Stefanich Eric , Li Chi-Chung , Sun Laura , Chu Yu-Waye , Ramanujan Saroja 
Published: November 2016

Abstract
Objectives: To develop and apply a quantitative systems pharmacology (QSP) model to support clinical trial design for anti-CD20/CD3 T-cell dependent bispecific antibody in non-Hodgkin lymphoma (NHL).
Methods: We developed a mechanistic model to describe the dynamics of B- and T-lymphocytes and their interactions in multiple physiological compartments (peripheral blood, tumor, and lymphoid tissues including the spleen, lymph nodes, and bone marrow) in the presence of an anti-CD20/CD3 T-cell dependent bispecific antibody (CD20-TDB) and the CD19-targeting bispecifc T-cell engager blinatumomab (a molecule with a similar mechanism of action, approved for ALL). The model is based on physiological, mechanistic, pharmacokinetic, and pharmacodynamic data and includes: 1) multiple activation states of CD8+ T-cells; 2) CD19+CD20- (pro-B), and CD19+CD20+ (pre- to mature-B) B-lymphocytes; and 3) the pharmacokinetics of CD20-TDB and blinatumomab and their mechanistic effects (activation of CD8+ T-lymphocytes and consequent killing of CD20+ and CD19+ B-lymphocytes, respectively).
Results: The model was calibrated using in vitro potency data and circulating cell measurements in cynomolgous monkeys treated with CD20-TDB [1]. Preclinical and translational validation was performed using additional CD20-TDB preclinical data and blinatumomab clinical data [2, 3]. The model replicated the effects of CD20-TDB on cell dynamics in circulation, and predicted CD20-TDB preclinical data at lower doses and in tissues, and blinatumomab clinical data in patients with ALL and NHL. The model will be used to evaluate and propose dosing strategies for CD20-TDB in patients with NHL and to inform other clinical development considerations.
Conclusions: The mechanism-based systems model accurately captures and predicts the pharmacodynamics of CD20-TDB in cynomolgous monkeys and in patients with ALL and NHL. The model provides a novel approach for evaluation of clinical dosing strategies for CD20-TDB and can be extended to related molecules and/or other B cell malignancies.
References: [1] Sun LL, et al. Sci Transl Med. 2015; 7(287): 1-10. [2] Klinger M, et al. Blood. 2012;119(26):6226-3. [3] Hijazi Y, et al. Abstract: 3051. ASCO; May 31-June 4, 2013.
Citation Format: Iraj Hosseini, Kapil Gadkar, Eric Stefanich, Chi-Chung Li, Laura Sun, Yu-Waye Chu, Saroja Ramanujan. Systems pharmacology modeling of anti-CD20/CD3 T-cell dependent bispecific antibody and its application to clinical trial design [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B043.
Abstract B047: Combining natural killer T cell immunotherapy with chemotherapy induced immunogenic cell death to target post-surgical breast cancer metastasis
Authors: Gebremeskel Simon , Tanner Kaitlyn , Lobert Lynnea , Johnston Brent 
Published: November 2016

Abstract
Breast cancer is the most common cancer in Canadian women and the second leading cause of cancer deaths. Given that most mammary tumors are surgically resectable and over 90% of breast cancer-associated deaths are due to metastasis, new therapeutic strategies targeting metastasis are required. Natural killer T (NKT) cells are a rare population of immune cells that have been shown to limit primary tumor growth and target distant metastatic disease in various animal models. We have shown that NKT cell activation improves survival in a model of post-surgical metastatic breast cancer. We are now expanding this work to determine whether NKT cell activation can be combined with chemotherapies to improve outcomes. In our model, 4T1 mammary carcinoma cells were injected into the mammary fatpad of syngeneic BALB/c mice. Tumors were resected at day 12, and mice were treated with cyclophosphamide or gemcitabine. On day 17, NKT cells were activated by transfer of dendritic cells loaded with the glycolipid antigen α-GalCer. We also examined whether Gemcitabine or mafosphamide (active component of cyclophosphamide) would induce immunogenic cell death of 4T1 cells in culture. Chemotherapeutics did not affect NKT cell activation as measured by serum IFNγ levels. Treatment with cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cells alone reduced metastasis and prolonged survival. Combined treatments significantly enhanced survival. NKT cell activation decreased the frequency and immunosuppressive function of myeloid derived suppressor cells (MDSCs). Treatments resulted in enhanced tumor specific immunity as surviving mice exhibited slower tumor growth following secondary tumor challenge. Gemcitabine and mafosphamide also increase the immunogenicity of cancer cells in vitro by increasing the exposure/release of MHCI, MHCII, CD1d, Calreticulin, HMGB1 and ATP. NKT cell activation therapy can successfully be combined with low doses of Gemcitabine or cyclophosphamide to enhance protection against tumor metastasis and recurrence. This work provides a clear rationale for combining chemotherapy with NKT cell immunotherapy to target metastatic disease in the clinical setting.
Citation Format: Simon Gebremeskel, Kaitlyn Tanner, Lynnea Lobert, Brent Johnston. Combining natural killer T cell immunotherapy with chemotherapy induced immunogenic cell death to target post-surgical breast cancer metastasis [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B047.
Abstract B055: Augmentation of OX40-dependent NK mediated antitumor activity is dependent on antibody cross-linking
Authors: Lim Sean H. , Turaj Anna H. , Willoughby Jane , Chan Claude H.T. , Penfold Christine A. , Johnson Peter W.M. , Glennie Martin J. , Cragg Mark S. , Levy Ronald 
Published: November 2016

Abstract
Introduction: The TNF superfamily (TNFSF) member OX40 (CD134) has been shown to enhance T cell function but its role on NK cells is poorly understood. CD137, another TNFSF member has been shown to enhance the anti-tumor activity of NK cells in various malignancies. This study examines the expression and function of OX40 on human and murine NK cells, and assesses its therapeutic efficacy as a target in murine B-cell lymphoma models.
Methods: In vitro flow cytometry-based assays using primary NK cells from healthy volunteers and syngeneic lymphoma mouse models were used.
Results: OX40 was transiently upregulated upon NK activation. In contrast to CD137, the induction of OX40 on human NK cells was dependent on cell-to-cell contact with either monocytes or T cells. Stimulation with agonistic anti-OX40 mAb, but not multimeric OX40 ligand, induced IFNγ and TNFα production by human NK cells, suggesting that the OX40 effects are dependent on antibody:FcγR mediated clustering. Whilst we observed increased human NK degranulation, there was no evidence of increased antibody-dependent cellular cytotoxicity (ADCC). In complementary murine studies, intravenous inoculation with BCL1 lymphoma into immunocompetent syngeneic mice resulted in transient upregulation of OX40 on murine NK cells. Combination treatment with anti-CD20 and anti-OX40 mAb produced a synergistic effect with more durable remissions.
Conclusion: The upregulation of OX40 on NK cells is more complex than CD137 and conditional upon interaction with other cell types. Anti-OX40 agonists may enhance NK-mediated anti-tumor activity in a cytokine-dependent manner instead of conventional ADCC, through antibody:FcγR-mediated receptor clustering.
Citation Format: Sean H. Lim, Anna H. Turaj, Jane Willoughby, Claude H.T. Chan, Christine A. Penfold, Peter W.M. Johnson, Martin J. Glennie, Mark S. Cragg, Ronald Levy. Augmentation of OX40-dependent NK mediated antitumor activity is dependent on antibody cross-linking [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B055.