bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2264: Synergistic combination of oncolytic virotherapy and immunotherapy for glioma
Authors: Tang Bingtao , Guo Zong Sheng , Bartlett David L. , Yan David , Schane Claire P. , Liu Jia , McFadden Grant , Shisler Joanna L. , Roy Edward J. 
Published: August 2019

Abstract
Oncolytic viral immunotherapy is a novel approach to cancer treatment. Viruses can directly kill cancer cells, provide antigens to dendritic cells to stimulate a T cell response, and make cancer cells express genes of immune-enhancing cytokines locally within the tumor microenvironment. We hypothesized that the combination of oncolytic virus with a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. An oncolytic virus encoding IL15-IL15Rα (the T cell activating stimulus) and the prostaglandin synthesis inhibitor celecoxib (the anti-immunosuppressant) were combined with adoptive transfer of tumor-specific T cells. Two oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein IL15-IL15Rα and a fluorescent protein (YFP or tdTomato Red). Viral gene expression was tested in the murine glioma line GL261 in vitro and in vivo. Orthotopic GL261 tumors in immunocompetent C57BL/6 mice were treated with vvDD-IL15-Rα vaccinia virus or vMyx-IL15Rα-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T cell therapy. We found that vvDD-IL15-Rα and vMyx-IL15Rα-tdTr each infected and killed GL261 cells in vitro. In vivo, NK cells and CD8+ T cells were increased in the tumor due to the expression of IL15-IL15Rα. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15-IL15Rα expressed by the virus, a source of T cells (whether by pre-vaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce total elimination of gliomas in a majority of mice. vvDD-IL15-Rα occasionally caused encephalitis, but vMyx-IL15Rα-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice. All these facts suggest that IL15-IL15Rα-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T cell therapy, rapamycin and celecoxib.
Citation Format: Bingtao Tang, Zong Sheng Guo, David L. Bartlett, David Yan, Claire P. Schane, Jia Liu, Grant McFadden, Joanna L. Shisler, Edward J. Roy. Synergistic combination of oncolytic virotherapy and immunotherapy for glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2264.
Abstract 2268: Agonistic T cell non depleting ICOS antibody strongly enhances anti-tumor activity with CTLA4 blocking monoclonal antibody without exacerbating colitis
Authors: Coutzac Clélia , Jouniaux Jean , Vozy Aurore , Ballas Marc , Brett Sara , Yadavilli Sapna , Angevin Eric , Hoos Axel , Chaput Nathalie 
Published: August 2019

Abstract
Background: ICOS is a member of the CD28 superfamily mainly expressed on activated T cells. An up-regulation of ICOS+ T cells is observed in patients treated with ipilimumab. These findings prompt further studies examining the synergy between CTLA-4 blockade and ICOS stimulation in generating optimal anti-tumor T cell immunity.
Methods: Peripheral blood mononuclear cells (PBMC) were collected from French patients with metastatic melanoma and treated with ipilimumab at baseline (V1) and after 1-2 ipilimumab infusion and restimulated in vitro with anti-CD3 plus anti-human non-depleting agonist ICOS IgG4 isotype antibodies. T cell proliferation and cytokine secretion was determined after 24 and 48h incubation. For in vivo experiments, C57Bl/6 and BALB/c mice were inoculated subcutaneously with MC38 and CT26 tumor cell lines respectively. Mice received intraperitoneal injections of anti-CTLA4 or its isotype control along with anti-mouse ICOS or corresponding isotype at D7, D10 and D13 with tumor growth assessments three times a week.
Results: PBMC collected from patients that respond to anti-CTLA-4 mAb exhibited stronger activation of T cells at baseline compared to patients with poor benefit. Treatment with a non-depleting agonist ICOS IgG4 mAb was able to rescue T cell activation in PBMC from patients with poor benefit. Furthermore, ICOS IgG4 with concurrent TCR engagement favored IL-10 secretion in patients that do not develop colitis during ipilimumab treatment suggesting that these patients may be protected from colitis due to a stronger capacity to secrete IL-10 after ipilimumab blockade particularly when ICOS is stimulated. In both mouse tumor models, combination with agonist non-depleting ICOS mAb increased the anti-CTLA-4 tumor activity without any colitis development.
Conclusion: This study provides evidence in mice and in humans that non-depleting agonistic ICOS mAb may increase anti-CTLA-4 tumor activity particularly in patients that do not benefit from anti-CTLA-4 alone without exacerbation of colitis.
Citation Format: Clélia Coutzac, Jean Jouniaux, Aurore Vozy, Marc Ballas, Sara Brett, Sapna Yadavilli, Eric Angevin, Axel Hoos, Nathalie Chaput. Agonistic T cell non depleting ICOS antibody strongly enhances anti-tumor activity with CTLA4 blocking monoclonal antibody without exacerbating colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2268.
Abstract 2290: Expression pattern of androgen receptor (AR), splice variant 7 (AR-V7) and splice variant 567 (AR-567) in circulating tumor cells and paired plasma-derived exosomes in metastatic castration resistant prostate cancer
Authors: Strati Areti D. , Zavridou Martha , Bournakis Evangelos , Mastoraki Sophia , Lianidou Evi S. 
Published: August 2019

Abstract
INTRODUCTION: Androgen-receptor splice variant 7 (AR-V7)is a highly promising liquid biopsy predictive biomarker indicating primary or acquired resistance to novel androgen receptor signaling inhibitors in metastatic castration resistant prostate cancer (mCRPC). We present for the first time the expression pattern of AR-FL, AR-V7, and AR-567es at a quantitative level in circulating tumor cells (CTCs) and paired plasma-derived exosomes in mCRPC.
METHODS: We first developed and analytically validated a novel multiplex RT-qPCR assay for AR full length (AR-FL), AR-V7, AR-567es and AR-total. We then quantified the expression levels of AR-splice variants, CK-19 (epithelial marker) and B2M (reference gene) in EpCAM+ CTCs and paired plasma-derived exosomes isolated from peripheral blood (20mL) of 62 mCRPC patients and 10 healthy donors.
RESULTS: In CTCs AR-FL was detected in 57/62(92%),AR-V7 in 32/62(52.0%),AR-567es in15/62(24.2%) and AR-total in 56/62(90.0%). In paired plasma-derived exosomes, AR-FL was detected in 45/62(72.5%), AR-V7 in 4/62(6.5%), AR-567 in 2/62(3.2%) and AR total in 47/62(75.8%).CK-19 expression was detected in 18/62(29.0%) of CTCs and in 28/62(45.2%) of exosomes. In all cases AR splice variants were expressed at higher levels in CTCs than in paired exosomes, while AR-V7 was detected at higher percentages than AR-567es.
CONCLUSIONS: Our results reveal for the first time a remarkable heterogeneity on the expression levels of AR-FL, AR-V7 and AR-567es in EpCAM+ CTCs and paired exosomes between individual mCRPC patients. The clinical significance of this finding will be further investigated in large patient cohorts in respect to therapy response.
Citation Format: Areti D. Strati, Martha Zavridou, Evangelos Bournakis, Sophia Mastoraki, Evi S. Lianidou. Expression pattern of androgen receptor (AR), splice variant 7 (AR-V7) and splice variant 567 (AR-567) in circulating tumor cells and paired plasma-derived exosomes in metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2290.
Abstract 23: Small molecule targeting of gankyrin reduces cell migration and proliferation in certain cancers
Authors: Farrales Pamela , Muth Aaron 
Published: August 2019

Abstract
Introduction: Gankyrin is an oncoprotein involved in regulating numerous pathways important to cell growth, signaling, proliferation and death. The overexpression of gankyrin and subsequent increased protein-protein interactions have been identified as key to increased proliferation in a variety of cancers. Consequently, small molecules that bind to and disrupt these protein-protein interactions are promising therapeutic strategies for the treatment of certain cancers. The first small molecule binder of gankyrin, cjoc42, was recently developed and exhibited efficacy in inhibiting the gankyrin-26S proteasome interaction. The aim of this work is to determine the effects of cjoc42 and its derivatives on cell migration and proliferation in gankyrin-overexpressing cancers.
Methods: Wound healing and CyQuant proliferation assays were used to determine the ability of cjoc42 to inhibit migration and proliferation in the gankyrin-overexpressing cell lines A549, MDA-MB231 and Huh6 cells. A protein thermal shift assay was used to screen new cjoc42 derivatives for their ability to bind gankyrin. Western blot experiments will determine if binding of cjoc42 and its derivatives to gankyrin is the mechanism of action in cells.
Results: Cjoc42 demonstrated an ability to inhibit the migratory and proliferative activity of A549 and MDA-MB231 cells. While only a modest inhibition of migration was observed, cjoc42 exhibited a significant antiproliferative effect against these cell lines. Utilization of a protein thermal shift assay yielded cjoc42 derivatives with more potent gankyrin-binding ability. These compounds will be evaluated in-cellulo for their ability to inhibit cell migration and proliferation. Western blot experiments will confirm that gankyrin-binding of cjoc42 attributes to the anti-migration and anti-proliferative effects observed.
Conclusions: These studies show that cjoc42 directly inhibits cell migration and proliferation by inhibiting the interaction between gankyrin and the 26S proteasome. Consequently, this work provides background for the development of small molecule inhibitors as a gankyrin-mediated therapy for the treatment of lung, breast and liver cancers.
Citation Format: Pamela Farrales, Aaron Muth. Small molecule targeting of gankyrin reduces cell migration and proliferation in certain cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 23.
Abstract 2305: Tumor MUC1 glycoprotein-highly specific CAR T cells control triple-negative breast cancer
Authors: Zhou Ru , Yazdanifar Mahboubeh , Roy Lopamudra Das , Maher John , Mukherjee Pinku 
Published: August 2019

Abstract
Antibody-derived Chimeric Antigen Receptor (CAR) T cells have great success in reduction of liquid form of tumor, but not solid tumor. Our novel antibody TAB004 can specifically recognize the tumor form of MUC1 (tMUC1) while sparing the normal MUC1 in several subtypes of breast cancers including &gt;95% of triple negative breast cancer (TNBC). In vivo delivery of TAB004 specifically accumulates in the xenograft TNBC tumor only. Therefore, we hypothesize that TNBC can be specifically targeted with TAB004-derived tMUC1-specific CAR T cells. A panel of 45 human breast cancer cell lines were tested for tMUC1 level, and 11 out of 13 TNBC cell lines showed higher frequency of tMUC1 expression compared to that on normal cells. We engineered a 2nd generation human CAR using TAB004 that was coupled to the CD28-CD3zeta, named as MUC28z CAR. MUC28z was well expressed on activated human T cells. Compared to their mock control, MUC28z CAR T cells retained higher CD25 and CD11c, particularly on CD8 T cells. The susceptibility of TNBC cells to MUC28z CAR T cell cytolysis was dramatic while still corresponding to their tMUC1 level. Only the tMUC1-specific MUC28z CAR T cells expressed and released large amount of IFN-gamma after antigen recognition on TNBC cells. However, IFN-gamma was only involved in the tumor killing by MUC28z CAR T cells at lower E:T ratio. The in vivo treatment of TNBC tumor by MUC28z CAR T cells dramatically controlled HCC70 TNBC tumor growth in a xenograft model. Taken together, our TAB004-derived MUC28z CAR T cells are very potent at killing TNBC tumor cells both in vitro and in vivo, which is very promising to provide a safe, effective and tumor antigen-specific novel immunotherapeutic intervention.
Citation Format: Ru Zhou, Mahboubeh Yazdanifar, Lopamudra Das Roy, John Maher, Pinku Mukherjee. Tumor MUC1 glycoprotein-highly specific CAR T cells control triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2305.
Abstract 2312: Anti-CS1 x anti-CD3 bispecific antibody (BiAb)-armed anti-CD3 activated T cells (CS1-BATs) specifically kill CS1+ myeloma cells and release type-1 cytokines
Authors: Huang Manley , Thakur Archana , Lum Lawrence G. 
Published: August 2019

Abstract
Although advances in multiple myeloma (MM) therapy such as stem cell transplantation and newly approved biological agents have shown promising results, MM remains a terminal disease. Thus, new strategies to eliminate or control MM cells are needed. Elotuzumab, a humanized monoclonal antibody approved for treatment of MM, targets myeloma cells expressing CS1/SLAMF7. We heteroconjugated anti-CD3 (OKT3) and elotuzumab to develop a BiAb, CS1Bi, to target activated T cells (ATC) to CS1+ MM cells. To examine the potential therapeutic activity of BATs against MM, we tested the ability of ATC armed with CS1Bi to bind to MM cell lines, specifically kill MM cells lines expressing different levels of CS1, and produce Th1 cytokines upon engaging MM tumor targets. Initial studies showed that CS1-BATs bound to MM cells by flow cytometry and specifically killed CS1+ targets as measured in a 6 hour 51Cr-release assay. Cytokine secretion by CS1-BATs vs. unarmed ATC (n=2) of interferon-γ (IFN- γ: 512 pg/mL vs. 260pg/mL), tumor necrosis factor-α (TNF- α: 450pg/mL vs. 110pg/mL), granulocyte-macrophage colony-stimulating factor (GM-CSF: 217 pg/mL vs. 135 pg/mL), macrophage inflammatory protein-1α (MIP-1α: 8250 pg/mL vs. 400 pg/mL), macrophage inflammatory protein-1β (MIP-1β: 14750 pg/mL vs. 600 pg/mL), and RANTES (3550 pg/mL vs. 2600 pg/mL) were induced when CS1-BATs were co-cultured with CS1+ cell line, L-363 for 24h at E:T of 25:1. A more sensitive quantitative flow cytometry-based cytotoxicity assay was developed based on comparing of the number of eFluor 450-labeled target cells pre- and post-incubation with either CS1Bi-BATs or unarmed ATC prepared from healthy donors, or culture media alone. The number of eFluor450+/7AAD- viable cells/unit volume post-incubation were compared to the number of viable cells in untreated wells to calculate the percent cytotoxicity. This assay reproducibly demonstrated significant killing of five MM cell lines by CS1-BATS (armed with 50ng CS1Bi/106 ATC at an E:T ratio of 1:1) ranging up to 60%, depending on the target line, (n=8). Between 78- 95% of MM.1S cells were eliminated at an E:T ratio of 3:1 (n=2). These data demonstrate the clinical relevance of this anti-MM strategy for use in a Ph1/II clinical trial in patients with relapsed and/or refractory MM.
Citation Format: Manley Huang, Archana Thakur, Lawrence G. Lum. Anti-CS1 x anti-CD3 bispecific antibody (BiAb)-armed anti-CD3 activated T cells (CS1-BATs) specifically kill CS1+ myeloma cells and release type-1 cytokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2312.
Abstract 233: Bispecific HER2 ADC: Making more potent HER2 ADC by improving target internalization
Authors: Bay Andres Perez , Kalsy Anuj , Tiwari Shiwani , Luan Bo , Kunz Art , Chen Zhaoyuan , Zhang Li , Potocky Terra , Nittoli Thomas , Thurston Gavin , Daly Christopher , Andreev Julian 
Published: August 2019

Abstract
Trastuzumab-emtansine (T-DM1) targets the well-characterized breast cancer oncogene HER2, and has shown success in the clinic, but tumors expressing intermediate levels of HER2 remain resistant to T-DM1 therapy, apparently due to insufficient lysosomal trafficking of T-DM1. Here, we engineered bispecific HER2-DM1 conjugates that bridge HER2 with the rapidly internalizing receptor APLP2. The high affinity arm of HER2xAPLP2 bispecific antibodies mediates surface binding to HER2+ tumor cells (but not to HER2- normal cells). After binding to HER2, the low affinity APLP2 arm promotes antibody internalization and lysosomal degradation. The strength of the APLP2 arm allows for modulation of the degree of internalization, degradation and killing. In in vitro killing assays, HER2xAPLP2-DM1 were significantly more potent than T-DM1 in cell lines expressing high (IHC3+) and intermediate (IHC 2+) levels of HER2, albeit induced little or no killing in cell lines expressing low HER2 levels (IHC 1+). Monovalent APLP2-ADCs induced little or no killing in all cell lines tested. Selected HER2xAPLP2-DM1 conjugates had acceptable PK profile in APLP2 humanized mice while significantly outperforming T-DM1 in inhibiting growth of IHC2+ tumor xenografts. These data pave the way to generate clinical candidate ADCs that will improve on T-DM1. In addition, our study opens up a possibility to exploit internalizing proteins such as APLP2 in combination with bispecific antibodies to enhance efficacy of ADCs.
Citation Format: Andres Perez Bay, Anuj Kalsy, Shiwani Tiwari, Bo Luan, Art Kunz, Zhaoyuan Chen, Li Zhang, Terra Potocky, Thomas Nittoli, Gavin Thurston, Christopher Daly, Julian Andreev. Bispecific HER2 ADC: Making more potent HER2 ADC by improving target internalization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 233.
Abstract 2330: Preclinical evaluation of TC-110: CD19-specific T cell receptor (TCR) fusion construct (TRuC™) T cell for the treatment of hematologic malignancies
Authors: Horton Holly , Ding Jian , Shah Seema , Gierut Jessica , Thorausch Niko , Morath Anna , Shamel Wolfgang , Maus Marcela , Baeuerle Patrick , Hofmeister Robert , Getts Daniel R. 
Published: August 2019

Abstract
T cells expressing chimeric antigen receptors (CARs) have demonstrated clinical benefit in certain hematological malignancies albeit with disease relapse as well as side effect such as cytokine release syndrome. To overcome potential hurdles of CAR-T cells and other T cell receptor modalities, we have designed a novel T cell engineering platform. Specifically, we have generated T Cell Receptor Fusion Constructs (TRuC™) that fuse a binder domain to subunits of the T cell receptor. These constructs when introduced using lentiviral technology, integrate into endogenous TCR, reprograming T cells to target tumor antigen in a non-major histocompatibility complex (MHC) restricted fashion and harnessing the full spectrum of TCR signaling.
Here, we present the results of the preclinical evaluation of TC-110, a CD19-specific ϵ-TRuC™ variant. In vitro, TC-110 T cells are equally potent as CAR T cells in eliminating tumor cells, while producing less inflammatory cytokines. In preclinical mouse models of ALL and Burkitt’s lymphoma, TC-110 T cells demonstrate better efficacy than 2nd generation CAR-T cells bearing CD28 or 41BB co-stimulatory domains. Of note, the efficacy of TC-110 T cells, both in vitro and in vivo, is not dependent on co-stimulatory signal. Overall, we demonstrate the efficacy of TC-110 T cells both in vitro and in preclinical mouse models, indicating the clinical potential of TRuC™ platform for treating hematologic malignancy.
Citation Format: Holly Horton, Jian Ding, Seema Shah, Jessica Gierut, Niko Thorausch, Anna Morath, Wolfgang Shamel, Marcela Maus, Patrick Baeuerle, Robert Hofmeister, Daniel R. Getts. Preclinical evaluation of TC-110: CD19-specific T cell receptor (TCR) fusion construct (TRuC™) T cell for the treatment of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2330.
Abstract 2331: Intratumor adoptive transfer of IL-12 mRNA transiently engineered anti-tumor CD8+ T cells
Authors: Etxeberria Inaki , Bolaños Elixabet , Teijeira Alvaro , Azpilicueta Arantza , Quetglas Jose Ignacio , Sanchez-Paulete Alfonso Rodriguez , Otano Itziar , Mancheño Uxua , Hervas-Stubbs Sandra , Inoges Susana , Garasa Saray , Alvarez Maite , Berraondo Pedro , Melero Ignacio 
Published: August 2019

Abstract
Adoptive T-cell therapy with TILs, CAR-T cells, and TCR-engineered T-cells is achieving remarkable clinical efficacy. Retroviral gene transfer of IL-12 into the T cell cultures markedly enhances efficacy but has shown unacceptable severe side effects in the clinic. To ensure transient gene transfer, tumor specific CD8 T cells were engineered by electroporation of mRNA encoding single chain IL-12 into OT1 and Pmel-1 TCR transgenic lymphocytes. Engineered T cells were injected intratumorally and achieved complete rejections not only of the injected lesion but also of distant concomitant tumors. Efficacy was further enhanced if a small dose of agonist anti-CD137 mAb was co-injected or if CD137-ligand mRNA was co-electroporated. Importantly, intratumor T-cell administration was more efficacious that the intravenous or subcutaneous routes. Therapeutic effects were dependent on IFNγ, cDC1 dendritic cells and endogenous T cells. Interestingly, treatment induced epitope spreading of the immune response to antigens not recognized by the adoptively transferred lymphocytes. Efficacy was also achieved when mouse TILs cultures were used and human TIL cultures can also be transiently IL-12 mRNA engineered. Intratumor release, transient IL-12 mRNA-engineering and repeated administration jointly constitute a safe, feasible and powerful cancer immunotherapy strategy.
Note: This abstract was not presented at the meeting.
Citation Format: Inaki Etxeberria, Elixabet Bolaños, Alvaro Teijeira, Arantza Azpilicueta, Jose Ignacio Quetglas, Alfonso Rodriguez Sanchez-Paulete, Itziar Otano, Uxua Mancheño, Sandra Hervas-Stubbs, Susana Inoges, Saray Garasa, Maite Alvarez, Pedro Berraondo, Ignacio Melero. Intratumor adoptive transfer of IL-12 mRNA transiently engineered anti-tumor CD8+ T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2331.