bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3482: Validation of novel therapeutic targets for T-cell non-Hodgkin lymphoma
Authors: Ito Daisuke , O'Brien Timothy D. , Modiano Jaime F. 
Published: August 2012

Abstract
T-cell malignancies account for 10-15% of all human non-Hodgkin lymphomas (NHL). T-cell lymphomas are incurable, and the development of effective treatment strategies has been hindered by the relatively infrequency of these conditions. T-cell lymphomas occur spontaneously in dogs; they are morphologically similar to human T-cell lymphomas, resemble their biological behavior, and are relatively common (∼35% of all NHL), providing opportunities to improve our understanding of the pathogenesis of these tumors as well as to develop more effective therapies. Tumor-initiating cells (TICs) influence tumor progression and response to therapy in many cancers, so eliminating these cells may be necessary to achieve durable remissions. However, the existence of TICs and their potential significance have not been conclusively established in T-cell NHL. The objective of this study was to evaluate the existence of progenitor-like lymphoma cells (PLCs) in naturally occurring canine T-cell NHL. We identified a reproducible population of tumor-related PLCs in spontaneous T-cell malignancies. The cells expressed the hematopoietic progenitor antigen CD34 and tumor-specific T-cell receptor gene rearrangements. Somewhat unexpectedly, these cells also express B-cell surface proteins (CD20 and CD22), but not the major T-cell surface antigens (CD3 and CD5) that were expressed by the bulk of the tumor cells (BTCs). We have adapted a xenotransplantation assay for primary canine T-cell NHL using NOD/SCID/IL-2Rgammanull mice and genetically modifying the tumor cells to express luciferase as a means monitor tumor growth and distribution by in vivo imaging. This model allows us to expand and serially transplant primary canine T-cell NHL for more detailed studies, including limiting dilution assays and therapeutic targeting using anti-B-cell reagents. In summary, we propose a novel concept in which a small population of tumor cells with “B-cell progenitor” phenotypes may paradoxically contribute to the pathogenesis of T-cell lymphoma, potentially representing a novel therapeutic target. We already use dogs with naturally occurring disease in the pathway for therapy development, allowing us to expand these studies into clinical trials that can then be rapidly translated to benefit human patients (for example, by using approved agents such as anti-CD20 antibodies or CD22-targeted immunotoxins).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3482. doi:1538-7445.AM2012-3482
Abstract 3496: Self-renewal as a therapeutic target in human colorectal cancer
Authors: Kreso Antonija , van Galen Peter , Davis Thomas , Szentgyorgyi Eva , O'Brien Catherine , Dick John E. 
Published: August 2012

Abstract
Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (C-ICs) in tumors that survive therapy. Together with recent reports showing that C-IC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key stemness property unique to C-ICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation, and more specifically human colorectal C-IC function are dependent on the canonical self-renewal regulator BMI-1. Down-regulation of BMI-1 inhibits the ability of colorectal C-ICs to self-renew resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with small molecule BMI-1 inhibitors resulted in colorectal C-IC loss with long-term and irreversible impairment of tumor growth. Targeting the Bmi-1 related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3496. doi:1538-7445.AM2012-3496
Abstract 35: Breast cancer cell interactions
Authors: Georgoulia Nefeli E. , Mitchison Timothy J. 
Published: August 2012

Abstract
In this study, a cell culture approach is employed to identify patterns of pair-wise interaction between cancer cells over a panel of 20 established epithelial breast cancer cell lines. It is our hypothesis that different clones within a tumor, as well as different cell lines in cultured conditions, interact in one of two ways: a) by competitive growth or, b) by synergistic growth. We investigate this by culturing cell lines in serum-free conditioned medium (CM), i.e. medium which has already been used on other cell lines. Cell population growth is monitored by incubating cultures with 5-Ethyl-2′-deoxyuridine (EdU). Cell apoptosis is obtained by labeling fixed cultures with a cleaved Poly ADP Ribose Polymerase (c-PARP) monoclonal antibody. Results yield two 20x20 matrices of cell to CM interaction, and confirm that cancer cells interact through secreted substances in the medium. In an effort to trace these phenomenological interactions back to specific biochemical pathways, the interaction matrices are correlated to gene expression data available for these cell lines. Furthermore, the experiment reveals two cell lines, HCC38 and BT20, whose media produce a strong apoptotic and strong anti-proliferative effect respectively. By employing molecular weight fractionation, we attempt to isolate specific components from the media retaining the strong interaction activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 35. doi:1538-7445.AM2012-35
Abstract 3504: Generation and optimization of a chimeric antigen receptor against human CD22: A new immunotherapeutic agent for adoptive immunotherapy
Authors: Haso Waleed , Lee Daniel , Morgan Richard , Pastan Ira , Mackall Crystal , Orentas Rimas J. 
Published: August 2012

Abstract
CD22 is expressed on a number of hematologic malignancies. A recombinant immunotoxin composed of an anti-CD22 Fv fused to a 38 kDa fragment of Pseudomonas exotoxin A (Moxetumomab pasudodtox, HA22) is currently being evaluated in the treatment of B cell malignancies. We used the Fv sequence to construct a series of chimeric antigen receptors (CARs) to determine the optimal affinity, domain structure, and signaling required for optimal anti-leukemic activity. The original anti-CD22 binding domain, BL22, or a newer generation high-affinity domain, HA22, were fused to transmembrane and signaling sequences derived from the TCR zeta-chain, CD28, and CD137. In some constructs we extended the binding domain away from the membrane using constant domains from IgG (CH2CH3). Retroviral gene vectors were used to transduce activated primary T cells with CAR constructs. We found: HA22 Fv, 2 as opposed to 3 signaling motifs, and non-CH2CH3 containing CARs were superior in short-term in vitro tumor cell cytolysis assays, indicating that Fv affinity, signaling, and 3-D structure of the CAR all impact the anti-leukemic effectiveness of CARs. Finally, direct comparison to CD19-specific CAR showed an equivalent or superior killing activity in 2 out of 3 ALL lines tested. Using Scatchard analysis to define the number of CD22 molecules on the surface, the ALL line with the lowest number of CD22 molecules was also the least able to be killed by CAR-transduced T cells. The superior lytic activity of CD19-CAR for this single cell line was due to preservation of high levels of CD19 at the cell surface. We are currently testing the in vivo activity of anti-CD22 CAR in an immunodeficient mouse model bearing human cell lines and primary patient-derived ALL. Our results indicate that CD22-CAR should be developed for the immunotherapy of CD22+ malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3504. doi:1538-7445.AM2012-3504
Abstract 3524: A novel approach to targeting mutated colorectal adenocarcinomas with T cell-engaging CEA/CD3-bispecific BiTE investigational antibody MEDI-565
Authors: Oberst Michael D. , Fuhrmann Stacy , Mulgrew Kathy , Amman Maria , Cheng Lily , Lutterbuese Petra , Richman Laura , Coats Steven , Baeuerle Patrick A. , Hammond Scott A. 
Published: August 2012

Abstract
Colorectal cancer (CRC) cells can harbor somatic mutations with strong impact on cancer cell signaling that limit the effectiveness of both chemotherapy and targeted therapies including monoclonal antibodies and kinase inhibitors. Therefore, novel therapeutic modalities are needed that are not impacted by the presence of such genetic mutations. We have here evaluated a CEA/ CD3-bispecific BiTE antibody termed MEDI-565 (also known as MT111) for its ability to redirect cytotoxic T cells for lysis in co-cultures and in xenograft models of human CRC lines harboring oncogenic mutations. Redirected lysis of CEA-positive tumor cells by MEDI-565 occurred in a manner dependent on CEA surface antigen density but independent of exogenously added soluble CEA. Importantly, the potency of lysis was independent of the mutational status of genes commonly mutated or lost in colorectal and other cancers, including frequent mutations in KRAS, BRAF, PI3KCA, PTEN and TP53 genes. In mouse xenograft models, the ability of MEDI-565 to inhibit tumor growth was likewise independent of the mutational status of the human tumor xenograft models. Our findings suggest that MEDI-565 warrants further clinical investigation as a potential treatment option for patients with CEA-positive tumors harboring somatic mutations that are less responsive to traditional chemotherapy or targeted agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3524. doi:1538-7445.AM2012-3524
Abstract 3527: Potent anti-tumor activity of AbGn-100, an anti-CD326 x anti-TCR bispecific antibody to CD326-expressing solid tumors
Authors: Chiang Evelyn , Lee Shu-Hua , Tsai Yu-Ying , Liu Meng-Ru , Hsieh Yu-Chi , Huang Chiu-Chen , Lin Shih-Yao 
Published: August 2012

Abstract
CD326 is one of the first and prominent immunotherapeutic targets in cancer therapy due to its frequent and high-level expression on most carcinomas of various origins. The dominant role of cytotoxic T cells for tumor suppression and surveillance in vivo is well documented in literature. A novel bi-specific antibody AbGn-100 was constructed, in which the antigen-binding domain of an anti- human CD326 antibody was linked to the antigen-binding domain of an anti-human T cell receptor (TCR) ≤ chain antibody. Human serum albumin was incorporated into this construct to prolong the half life in vivo. This bi-specific antibody is able to direct T cells toward CD326-expressing cancer cells to execute T cell cytotoxic function after TCR cross-linking mediated by CD326 expressed on cancer cells while it remains harmless when either T cells or CD326-expressing cancer cells is absent. In vitro cytotoxicity assays with PBMCs from different donors have demonstrated potent (up to 60% above the background) cytotoxicity eliciting activity of AbGn-100 to lung (NCI-H358), ovarian (OMC3) and colorectal (COLO205) cancer cells lines. In the absence of cancer cells, the addition of AbGn-100 didn't trigger the up-regulation of T cell activation markers such as CD25 or CD69, nor did it increase the secretion of cytokines such as IL-2 and Interferon β, demonstrating the safety profile of AbGn-100. In vivo activity of AbGn-100 was tested with established lung (NCI-H358) and ovarian (OMC-3) cancer xenografts in NOD-SCID mice. AbGn-100, in the presence of human PBMC, significantly reduced the size of the established lung and ovarian tumors. Most notably, in some of the mice, tumor was not detectable after 50 days of treatment, suggesting the possibility of tumor eradication. PK studies in mice showed the half-life of AbGn-100 to be around 20 hours, which is substantially longer than conventional single-chain Fv bi-specific antibodies. These data support the potential of further development of AbGn-100 as therapeutics for the treatment of CD326-expressing solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3527. doi:1538-7445.AM2012-3527
Abstract 3530: Lipid accumulation inhibits DC ability for cross-presentation of antigens in tumor-bearing mice
Authors: Cao Wei , Koomen John M. , Gabrilovich Dmitry I. , Tyurin Vladimir A. , Kagan Valerian E. 
Published: August 2012

Abstract
Professional antigen presenting cells dendritic cells (DCs) play an important role in the initiation and maintenance of immune responses. Numerous studies have demonstrated defective function of DCs in cancer. However, the mechanisms of those defects remain not clear. Previously, we have demonstrated that DCs in tumor-bearing hosts accumulate lipids via up-regulation of the expression of scavenger receptor A (CD204). This resulted in inability of DCs to effectively process exogenous antigens. In this study we found that the DCs exposed to tumor-derived factors (TDF) in vitro or isolated from tumor-bearing (TB) mice had increased uptake of soluble protein ovalbumin (OVA). No defect in the activity of lysosomal and endosomal proteases was detected. Using mass-spectrometry we determined that TDF did not affect processing of OVA by DCs. At the same time, DCs exposed to TDF or isolated from TB mice expressed lower levels of OVA-derived peptide-MHC class I (pMHC) complexes and decreased ability to stimulate OVA peptide specific CD8+ T cells (OT1). Using lipid mass-spectrometry we found substantial accumulation of oxidized lipids in DCs obtained from TB mice or generated in vitro in the presence of TDF. To mimic accumulation of oxidized lipids in vitro, we treated bone marrow derived DCs with linoleic fatty acid (LA) and oxidized agent azobis-(2,4-dimethylvaleronitrile) (AMVN). DCs easily picked LA and form lipid bodies similar to the process observed in the presence of TDF. However, accumulation of LA did not result in defective processing of OVA-derived epitope as was determined by measuring the level of pMHC on DC surface and by stimulation of OT1 cells. AMVN at selected concentration also did not affect OVA processing and presentation. In contrast, combination of LA and AMVN significantly reduced the ability of DCs to process antigens associated with OVA. No changes in the expression of MHC class I and co-stimulatory molecules were observed. These data indicate that oxidized lipids accumulated in DCs in tumor-bearing hosts prevent cross-presentation of antigens, which may have important implications for DC ability to induce tumor-specific immune responses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3530. doi:1538-7445.AM2012-3530
Abstract 3532: The effect of B cell depletion on tumor phenotype
Authors: Wakatsuki Kohei , Sheu Eric G. , Moore Francis D. 
Published: August 2012

Abstract
Introduction There are past indications that the adaptive immune response of B cells plays a role in tumor development. We examined this issue in vivo by examining the growth of Lewis Lung Carcinoma (LLC) and murine melanoma in B cell knockout (Bcell ko) mice. Methods Cultured LLC or melanoma cells were implanted into hindlimbs of C57BL/6 (B6) and Bcell ko mice. Tumors were measured every 3-4 days, and tissue was harvested for histological examination 2-3 weeks after tumor implantation. Tissues were stained with labeled anti-IgG, -CD4, -CD8, and -CD31 antibody. Results Melanomas in B6 and B cell ko mice enlarged at the same rate. However, tumor growth of LLC was significantly slower in B cell KO mice compared to B6 (p=0.02). Though both tumor-infiltrating CD4+ T cells and CD8+ T cells were identified in B6 mice, tumor-infiltrating CD4+ T cells but no tumor-infiltrating CD8+ T cells were seen in B cell KO mice in LLC. Angiogenesis was significantly inhibited in LLC in B cell KO mice. Conclusions The absence of B cells selectively inhibited tumor growth for LLC, and was associated with less tumor angiogenesis and an absence of CD8+ T cells. Blocking this aspect of the B cell response might be useful therapy for selected tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3532. doi:1538-7445.AM2012-3532
Abstract 3536: Depletion of regulatory T lymphocytes reverses the imbalance between Pro- and anti-tumor immunities via enhancing antigen-specific T cell immune responses
Authors: Chen Yu-Li , Chang Ming-Cheng , Huang Chia-Yen , Chang Ying-Cheng , Chen Yun-Yuan , Wang Ju-Ming , Cheng Wen-Fang 
Published: August 2012

Abstract
Immunogenicity is the ability of antigens to elicit an immune response. The host immunity for anti-tumor can be induced because of the existence of tumor-specific and/or tumor-associated antigens. However, the most effective immune manipulation for ovarian carcinoma is eagerly awaited. To explore the systemically and locally kinetic changes of immunologic profiles during tumor progression and to elucidate the inhibition of tumor growth and the reverse of immunologic profiles by depletion of Treg cells in ovarian carcinomas, ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. Including the anti-inflammatory cytokines IL-4 and TNF-α significantly decreased, TGF-β, IL-6, IL-10 significantly elevated in human ascites when the disease progressed to advanced diseases. The ratios of CD8+ T cell/Treg cell in the tumor asociated lymphocytes of the human ascites were lower in advanced diseases than those in early diseases. These alterations of immune components during tumor progression were proved in our animal model. Mice, when treated with kinetic low dose of mAb PC61, showed longer survival than the other groups. Tumor-bearing mice treated with kinetic low dose mAb PC61could inhibit the suppressive immunologic profiles, enhance the effective immunologic profiles, and generate potent antigen-specific anti-tumor immunities and effects. We concluded that the imbalance between effective and suppressive immunities could be identified in tumor-bearing situation, especially in advanced diseases. The depletion of Treg cells could correct the immunologic profiles and generate potent antigen-specific immunity. The strategy of targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3536. doi:1538-7445.AM2012-3536
Abstract 3543: Complete regression of solid B16F1 melanoma tumors obtained by intratumoral injection of LTX-315 (Oncopore®)
Authors: Camilio Ketil A. , Rekdal Oystein , Sveinbjornsson Baldur 
Published: August 2012

Abstract
Background: Malignant melanoma is imposing an increasing threat to the world's population and new therapies are needed.Standard treatment involves surgery, chemotherapy, and radiation therapy and often leads to relapse after ended therapy. LTX-315 (Oncopore®) is a chemically modified cationic cytolytic peptide which is equally active against drug-sensitive and drug-resistant cancer cells. Earlier animal studies have demonstrated that treatment of syngeneic murine A20 B-cell lymphomas and CT26WT colon carcinomas with intratumoral (i.t.) injection with LTX-315 resulted in complete tumor regression and long-term protective effect against re-inoculated tumor cells. The present study was undertaken to investigate whether LTX-315 induced an antitumor response in vivo in a highly aggressive murine melanoma tumor model. Methods: Pre-cultured B16F1 melanoma cells (5 x 104) were subcutaneously inoculated into the abdomen of syngeneic C57BL/6N mice and established tumors treated i.t. with LTX-315. Animals were taken for analysis to elaborate the mechanism of action of LTX-315 and for potential immune modulatory effects following treatment. Blood plasma was analyzed for changes in cytokine content and tumor tissue was analyzed for infiltrating immune cells using immunohistochemistry and flow-cytometry. Results: Intratumoral treatment with LTX-315 resulted in a complete regression of tumor in the treated animals. Tumors treated with LTX-315 showed an increased infiltration of immune cells into the tumor compared to control tumors receiving vehicle. Conclusions: Our results suggest that LTX-315 treatment can induce complete regression in solid B16F1 melanoma tumors, thus leading to local tumor control. Intratumoral treatment with LTX-315 can lead to immune-modulatory effects such as an increase in the number of infiltrating immune cells, causing a shift in the balance between immune effector and immune suppressive cells in the tumor environment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3543. doi:1538-7445.AM2012-3543