bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2803: Preclinical models for the development of HER2-specific T-cell therapy
Authors: Kreutzer Christiane , Conrad Heinke , Meyerhuber Peter , Uckert Wolfgang , Beckhove Philipp , Bernhard Helga 
Published: May 2015

Abstract
The adoptive transfer of autologous, tumor-reactive T cells to treat cancer patients is a promising tool in immunotherapy. One of our clinical goals is the adoptive transfer of autologous T cells transduced with a human epidermal growth factor receptor 2 (HER2)-directed TCR in patients with advanced breast cancer. We successfully established cytotoxic T-cell clones and CD8+ T cells transduced with a TCR specific for the tumor and self-antigen HER2 and tested their lytic capability in vitro.
Since HER2 is a self antigen that is not only expressed by malignant cells but also in normal tissue, e.g. the heart, we tested the recognition of normal HER2+-cell lines by HER2-directed T cells in vitro. For this purpose HER2-directed CD8+ T cells were used to analyze the recognition and lysis of HLA-A2+ cardiomyocyte cell lines in IFNγ-ELISA and chromium-release-assay. Compared to HER2-overexpressing breast cancer cell lines recognition of the cardiomyocytes by HER2-directed T cells was much lower. From these data we hypothesize that there might be a therapeutic window, which may allow the treatment with HER2-directed T cells without having any unwanted side effects, like cardiac dysfunction.
To further analyse this, we are establishing a mouse model using HLA-A2-transgenic NOD/SCID-HHDII mice. We injected a human breast cancer cell line s.c. into NOD/SCID-HHDII mice, waited until a solid tumor had been established, and evaluated the responsiveness of tumor cells towards adoptive T cell transfer. Our data show an improvement in tumor growth inhibition after adoptive T cell transfer and IL-15 treatment; however, no significant tumor reduction was observed yet. Furthermore, in the NOD/SCID-HHDII mice we are able to detect potential autoimmune reactions. Subsequent experiments will analyze the combination therapy of transferred HER2-directed T cells with HER2-directed antibody treatment (Trastuzumab and/or Pertuzumab) in order to increase the anti-tumor response. These pre-clinical studies, as well as the in vitro tests, are important for the evaluation of possible unwanted side effects after adoptive transfer of TCR-transduced T cells specific for self-antigens like HER2.
Citation Format: Christiane Kreutzer, Heinke Conrad, Peter Meyerhuber, Wolfgang Uckert, Philipp Beckhove, Helga Bernhard. Preclinical models for the development of HER2-specific T-cell therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2803. doi:10.1158/1538-7445.AM2014-2803
Abstract 2804: Expression of miR-17-92 enhances antitumor activity of T cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts
Authors: Ohno Masasuke , Ohkuri Takayuki , Kosaka Akemi , June Carl H. , Natsume Atsushi , Okada Hideho 
Published: May 2015

Abstract
Background
Expression of miR-17-92 confers type-1 phenotype and enhanced survival of T-cells. We have previously reported that miR-17-92 is down-regulated in T-cells derived from glioblastoma (GBM) patients. We hypothesized that transgene-derived co-expression of miR17-92 and chimeric antigen receptor (CAR) in T-cells improves the efficacy of adoptive transfer therapy against GBM.
Methods
We constructed novel lentiviral vectors for miR-17-92 (FG12-EF1a-miR-17/92) and a CAR consisting of epidermal growth factor receptor variant III (EGFRvIII)-specific single-chain variable fragment (scFv) coupled to the T-cell receptor CD3ζ chain signaling module and co-stimulatory motifs of CD137 (4-1BB) and CD28 in tandem (pELNS-3C10-CAR). Human T-cells were transduced with these lentiviral vectors and their anti-tumor effects were evaluated both in vitro and in vivo.
Results
In addition to antigen-specific and potent cytotoxic activities against U87 GBM cells stably expressing EGFRvIII (U87-EGFRvIII), CAR-transduced T-cells (CAR-T-cells) co-transduced with miR-17-92 exhibited improved survival in the presence of temozolomide (TMZ) compared with CAR-T-cells without miR-17-92 co-transduction. In mice bearing intracranial U87-EGFRvIII xenografts, CAR-T-cells with or without transgene-derived miR-17-92 expression demonstrated similar levels of potent therapeutic effects without demonstrating any uncontrolled growth of CAR-T-cells. However, when these mice were re-challenged with U87-EGFRvIII cells in the brains, mice receiving co-transduced CAR-T-cells exhibited improved protection compared with mice treated with CAR-T-cells without miR-17-92 co-transduction.
Conclusion
These results warrant development of novel CAR-T-cell strategies by incorporation of miR-17-92 to improve the therapeutic potency, especially in patients with GBM.
Citation Format: Masasuke Ohno, Takayuki Ohkuri, Akemi Kosaka, Carl H. June, Atsushi Natsume, Hideho Okada. Expression of miR-17-92 enhances antitumor activity of T cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2804. doi:10.1158/1538-7445.AM2014-2804
Abstract 2805: Cancer-specific T cell receptor isolation for cancer immunotherapy
Authors: Weigand Luise U. , Paston Samantha , Hibbert Linda , Ryan Ruth K. , Baker Debbie E. , Simmons Ruth A. , Harper Jane V. , Dukes Joseph D. , Bossi Giovanna , Grand Francis , Hickman Emma , Powlesland Alex , Vuidepot Annelise , Hassan Namir J. , Jakobsen Bent K. 
Published: May 2015

Abstract
Malignant cells may be recognized by T cells binding cell surface Class I HLA-peptide complexes presenting disease-associated epitopes. Many cancer patients generate CD8 cytotoxic T cell responses to tumor-associated antigens, however due to the low avidity of these T cells and cancer cells developing escape mechanisms for avoiding destruction by T cells, the immune system fails to clear tumors. To overcome these issues, we have engineered novel, bi-functional protein therapeutics termed ImmTACs (Immune Mobilising monoclonal TCR Against Cancer) which re-direct the immune system to target and destroy tumor cells with a high degree of potency and specificity. An ImmTAC comprises a high affinity ‘monoclonal’ T cell Receptor (mTCR) targeting a cancer-associated HLA-peptide complex, fused to an anti-CD3 scFv domain which activates an anti-tumor T cell response.
In order to produce ImmTACs, we have developed an integrated in-house process leading to the isolation of TCRs specific for validated cancer epitopes. The critical steps in this process are: antigen selection, epitope identification, T cell cloning, TCR isolation and binding to soluble peptide:MHC on the BIAcore. We describe each of these steps in more detail and present data to illustrate the successful isolation of a number of TCRs specific for various tumor associated antigens such as prostate and cancer testis antigens leading from this procedure.
Citation Format: Luise U. Weigand, Samantha Paston, Linda Hibbert, Ruth K. Ryan, Debbie E. Baker, Ruth A. Simmons, Jane V. Harper, Joseph D. Dukes, Giovanna Bossi, Francis Grand, Emma Hickman, Alex Powlesland, Annelise Vuidepot, Namir J. Hassan, Bent K. Jakobsen. Cancer-specific T cell receptor isolation for cancer immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2014-2805
Abstract 2806: A phase Ia/Ib trial of chemotherapy followed by infusions of activated T cells armed with OKT3 x trastuzumab bispecific antibody, IL-2 and GM-CSF for stage II/ III, Her2+ or Her2- high risk breast cancer (more than 10+ nodes)
Authors: Jagtap Deepa B. , Rathore Ritesh , Thakur Archana , Colvin Gerald , Kouttab Nicola , Maizel Abby , Deol Abhinav , Lum Lawrence G. 
Published: May 2015

Abstract
Background: Anti-CD3 x anti-HER2Bi bispecific antibody (HER2Bi) targeted monoclonal antibody (mAb) activated T cells (ATC) exhibit anti-HER2 cytotoxicity, proliferate, and secrete immunokines upon tumor engagement. This study reports a phase I immunotherapy trial in 9 women with locally advanced breast cancer consisting of infusions of HER2Bi armed ATC (aATC) in combination with interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor (GM-CSF) to evaluate safety, feasibility, time to progression (TTP), overall survival (OS), T cell trafficking, and immune responses. Methods: ATC were produced by stimulating peripheral blood mononuclear cells (PBMC) obtained by leukapheresis with anti-CD3 monoclonal antibody and expanding the ATC in IL-2. ATC were harvested, armed with HER2Bi and cryopreserved in aliqouts. Groups of 3 patients received 20, 40, 80 or 160 x 109 aATC per infusion twice a week for four weeks(Table 1). Results: Eight of 9 patients were ER positive, 2 of 9 were Her 2 overexpressing tumors. The median OS for all patients was 103.5 months (14.3 to 134.7months). Six of 9 patients are alive. Four out of the six patients have no evidence of disease and 2 patients relapsed (one at 77.27 months and the other at 104.67months). It was feasible to grow up to 160 x 109 ATC and both patients assigned to this dose level were able to reach it. There were no cell-based dose limiting toxicities. aATC persisted in the blood for at least a week. aATC infusions induce cellular anti-tumor responses and cytokine responses. Interpretation: Targeting Her2 positive and negative tumors induced cytotoxic anti-tumor responses, increases in Th1 cytokines and IL-12 serum levels, clinical responses that suggest aATC infusions provided a survival benefit. These results are being confirmed in a phase II trial for metastatic breast cancer.
Table 1Planned doseActual Dose20Bill21.640Bill42.7540Bill37.640Bill42.480 Bill80.080Bill70.3580Bill96.0160Bill176.75160Bill160.0
Citation Format: Deepa B. Jagtap, Ritesh Rathore, Archana Thakur, Gerald Colvin, Nicola Kouttab, Abby Maizel, Abhinav Deol, Lawrence G. Lum. A phase Ia/Ib trial of chemotherapy followed by infusions of activated T cells armed with OKT3 x trastuzumab bispecific antibody, IL-2 and GM-CSF for stage II/ III, Her2+ or Her2- high risk breast cancer (more than 10+ nodes). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2014-2806
Abstract 2808: GD2-specific genetically engineered NK cell therapy is effective in a drug-resistant neuroblastoma xenograft mouse model
Authors: Seidel Diana , Shibina Anastasia , Reynolds C. Patrick , Wels Winfried S. , Huebener Nicole , Lode Holger N. 
Published: May 2015

Abstract
Background:
Drug-resistant neuroblastoma remains a major challenge in pediatric oncology. A human NK cell line NK-92-scFv(ch14.18)-z engineered to express a GD2-specific chimeric antigen receptor (CAR) may help to address this problem. We investigated the cytotoxicity of NK-92-scFv(ch14.18)-z in a panel of GD2+ drug-resistant neuroblastoma cell lines and analyzed the anti-tumor efficacy of NK-92-scFv(ch14.18)-z in a drug-resistant neuroblastoma xenograft mouse model.
Methods
Cytotoxic activity of GD2-specific NK-92-scFv(ch14.18)-z towards a panel of GD2+ cell lines (CHLA-20, SK-N-BE(2), CHLA-136, CHLA-79, LA-N-1, LA-N-5), some of which exhibit partial or multidrug resistance, was analyzed in a 51Cr release assay. We investigated the impact of GD2 recognition on NK-92-scFv(ch14.18)-z-mediated lysis by blocking the CAR through the addition of an anti-idiotype antibody (anti-IdAb) and also by downregulating GD2 on target cells induced by the glucosylceramide synthase (GCS) inhibitor PPPP. We then employed ELISA to determine the production of effector molecules granzyme B and perforin in response to activation with immobilized GD2. Anti-tumor efficacy of NK-92-scFv(ch14.18)-z and IL-2 was analyzed in a drug-resistant GD2+ xenograft mouse model by peritumoral injections of the GD2-specific NK cell line.
Results
NK-92-scFv(ch14.18)-z effectively lysed GD2+ drug-resistant NB cell lines. This effect was almost completely abrogated by blocking the CAR with an anti-IdAb. Decreased GD2 expression on target cells also resulted in diminished lysis mediated by NK-92-scFv(ch14.18)-z. Quantification of granzyme B and perforin production with ELISA revealed that the plate-bound antigen GD2 alone was sufficient to induce activation of NK-92-scFv(ch14.18)-z. Importantly, repeated peritumoral subcutaneous injections of a combination of NK-92-scFv(ch14.18)-zeta and IL-2 significantly prolonged survival time of mice challenged with aggressively growing subcutaneous CHLA-20 tumors in a xenograft mouse model.
Conclusions
These encouraging results indicate that GD2-directed immunotherapy with genetically engineered NK cells is an appropriate treatment strategy especially in relapsed NB that exhibit drug resistance.
Citation Format: Diana Seidel, Anastasia Shibina, C. Patrick Reynolds, Winfried S. Wels, Nicole Huebener, Holger N. Lode. GD2-specific genetically engineered NK cell therapy is effective in a drug-resistant neuroblastoma xenograft mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2808. doi:10.1158/1538-7445.AM2014-2808
Abstract 2811: Allogeneic cell cased vaccine development by shared antigen screening
Authors: Deyev Vadim V. , Schilling Neal , Schreiber Taylor H. 
Published: May 2015

Abstract
The fundamental premise of allogeneic vaccines for cancer relies upon the presence of common antigens that are shared between established cell lines and a large proportion of patients with histologically related tumors. Recent results from The Cancer Genome Atlas have clearly demonstrated that somatic mutations in exon region DNA, while potentially immunogenic, do not result in the translation of antigenic proteins that are similar from patient to patient. Instead, these data reinforce the concept that dysregulation of common pathways contributes to the general property of de-differentiation in tumor cells and the acquisition of immature phenotypes as compared to untransformed precursor cells. This phenomenon leads to expression of mucinous and embryonal antigens, collectively known as cancer testis antigens, that are otherwise rare in mature tissues and to which central tolerance remains incomplete. We have developed allogeneic vaccines based on parallel screening of non-small cell lung, bladder, triple-negative breast, ovarian and melanoma tumor cell lines and patient tumor samples. The baseline expression of certain antigens, including SSX2, SSX4, CT10, MAGE-A1, MAGE-A10, LAGE-1 and NY-ESO-1 was found to vary widely both between tumor samples and non-transformed tissue controls. Among all antigens screened, MAGE-A3 was most commonly upregulated across transformed tissue samples, however other antigens including BAGE-1, XAGE-1b and MAGE-A10 were found to be most dramatically upregulated. This analysis provides a screening tool with which to appropriately profile and prioritize individual cell lines for vaccine development in histologically diverse tumor types.
Citation Format: Vadim V. Deyev, Neal Schilling, Taylor H. Schreiber. Allogeneic cell cased vaccine development by shared antigen screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2811. doi:10.1158/1538-7445.AM2014-2811
Abstract 2812: The clinical effects of dendritic cell and cytokine-induced killer cell therapy for lung cancer after surgery
Authors: Gao Daiqing , Li Changyou , Zhao Peng , Wei Xiaofang , Xie Xihe , Sun Weihong , Guo Qingming , Zhu Danni , Gao Tianyi , Alexandrou Aris T. , Li Jian Jian 
Published: May 2015

Abstract
Objective:The aim of the study was to evaluate the safety and therapeutic efficacy of autologous dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) for the treatment of lung cancer patients.
Methods:In the present study, we recruited a group of 40 lung cancer patients after surgery registered in the Biotherapy Center during 2005-2011 and randomly divided patients into two groups: Twenty patients treated with DC-CIK therapy as the treatment group and the other twenty patients served as controls.Subjects were administrated with 1×106 units of IL-2 daily for 5 days before mononuclear cell isolation from peripheral blood. For the treatment group, after primary tumors were removed by surgery, 1-3 doses of DCs and CIKs were perfused via peripheral veins. The immunologic function,short-term therapeutic effects, 5-years overall survival rate (OS), and disease free survival rate (DFS) were compared between the two groups.In addition, the peripheral blood samples were extracted from all patients before and after DC-CIK therapy,analyzed for T cell subsets by flow cytometry,and the intracellular cytokines of T cells were detected simultaneously.
Results:OS for 1, 3, and 5 years of DC-CIK therapy group were 100%, 88%, and 88% respectively which contrasted with 78%,66%, and 25% in the control group. DFS 1, 3, and 5 years of DC-CIK therapy groups were 100%, 85%,65% respectively compared to 73%,58%, 23% in the control groups. Although there were no changes in the subsets of T cells in peripheral blood before and after DC-CIK therapy, the intrace1lular cytokines IFN-γ,IL-2,IL-4, and IL-6 of the immune cells were noticeably improved in the treatment group.
Conclusion:DC-CIK therapy is a potential effective therapeutic modality to improve OS and DFS in post-surgical lung cancer patients.
Citation Format: Daiqing Gao, Changyou Li, Peng Zhao, Xiaofang Wei, Xihe Xie, Weihong Sun, Qingming Guo, Danni Zhu, Tianyi Gao, Aris T. Alexandrou, Jian Jian Li. The clinical effects of dendritic cell and cytokine-induced killer cell therapy for lung cancer after surgery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2014-2812
Abstract 2817: DCVex(TM): A novel DC-targeted vector platform for cancer immunotherapy
Authors: Albershardt Tina C. , Tareen Semih U. , Odegard Jared M. , Campbell David J. , Flynn Patrick , Robbins Scott H. , Berglund Peter , Meulen Jan H. ter 
Published: May 2015

Abstract
Dendritic cells (DCs) are essential for the initiation of T cell responses and are therefore an attractive target for cancer immunotherapy. The DC vaccine, Provenge®, as well as a number of on-going clinical trials, have in principle validated this concept. However, the currently pursued strategy of ex vivo immunization of DCs is time-consuming and costly. We have developed a 3rd generation, integration-deficient lentivector platform, DCVex(TM), which is designed to deliver tumor antigen-encoding genes directly to DCs in vivo by targeting the DC-SIGN receptor. Mice immunized with DCVex(TM) vectors expressing a variety of model antigens developed strong, dose-dependent poly-functional and cytotoxic antigen-specific CD8 T cell responses, as assessed by intracellular cytokine staining and in vitro cytotoxic T lymphocyte assays. Repeated immunizations resulted in boosting of the T cell responses, indicating the absence of induction of inhibitory anti-vector immunity. Importantly, in stringent therapeutic tumor models (e.g., B16F10 footpad melanoma and CT26 lung metastasis models), immunization with tumor antigen-encoding vectors protected the majority of animals from death in a dose-dependent manner. These findings demonstrate the potential of DCVex(TM) as a novel cancer vaccine platform suitable for in vivo DC immunization.
Citation Format: Tina C. Albershardt, Semih U. Tareen, Jared M. Odegard, David J. Campbell, Patrick Flynn, Scott H. Robbins, Peter Berglund, Jan H. ter Meulen. DCVex(TM): A novel DC-targeted vector platform for cancer immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2817. doi:10.1158/1538-7445.AM2014-2817
Abstract 282: Smoking and increased age in hematuric patients significantly confound the accuracy of classifiers for the diagnosis of urothelial cancer
Authors: Williamson Kate E. 
Published: May 2015

Abstract
Smoking and increased age in hematuria patients significantly confound the accuracy of classifiers for the diagnosis of urothelial cancer
Ricardo de Matos Simoes (a), Brian Duggan(b), Mark W. Ruddock (c), Frank Emmert-Streib (a), Declan O'Rourke (d), Hugh F. O'Kane (b), Funso Abogunrin (e), Cherith N. Reid (c), Neil H Anderson (f), David Curry (b), Kate E. Williamson (a). a Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, UK. b Department of Urology, Belfast Health and Social Care Trust, Belfast, UK. c Randox Laboratories Ltd., County Antrim, UK. d Department of Pathology, Belfast City Hospital, Belfast, UK. e Department of Urology, Craigavon Area Hospital, Northern Ireland, f Department of Pathology, Royal Victoria Hospital, Belfast, UK.
There is an urgent need for evidence-based risk stratification of hematuria patients. Currently, we have insufficient understanding of the characteristics which confound the accuracy of diagnostic classifiers for urothelial cancer (UC). Between November 2006 and October 2008 156 hematuric patients were recruited to a case control study. We defined UC diagnostic classifiers for 16 stratified subpopulations. Using a random forest classification based on ∼29 biomarkers measurements in urine, serum and plasma and random sub-sampling we generated 1000 training and test patient datasets to estimate probabilities of correct, incorrect and inconsistent classification for each patient. We defined classifiers for control and UC classified subpopulations. The distribution of characteristics across classifiable and non-classifiable patient subpopulations was explored using Fisher's exact test. The non-smoking stratified subpopulation achieved the greatest accuracy AUC = 0.95 (sd = 0•1). One hundred patients (64%) were classified correctly; 46/156 (30%) were non-classifiable, and 10/156 (6%) were inconsistently classified. The 23 non-classifiable UCs comprised 21 pTa, one pT1 and one CIS; two pTa and one pT1 were inconsistently classified. Five patients with newly diagnosed cancers other than UC, seven with “no diagnosis” and 11 with benign conditions were misclassified as UC. Consideration of smoking, increased age and antihypertensive medication in addition to biomarker profiles may achieve more accurate classification of UC in hematuria patients. This novel approach to diagnostic classifiers, once fine-tuned, may have the potential to correctly classify low risk bladder tumours and to reduce false positive cases.
Citation Format: Kate E. Williamson. Smoking and increased age in hematuric patients significantly confound the accuracy of classifiers for the diagnosis of urothelial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 282. doi:10.1158/1538-7445.AM2014-282