bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5605: Targeting cancer stem cells in squamous cell carcinoma of the head and neck with combinatorial adoptive immunotherapy
Authors: Visús Carmen , Wang YangYang , Szczepanski Miroslaw J. , Ferris Robert L. , Whiteside Theresa L. , Ferrone Soldano , Wang Xinhui , DeLeo Albert B. 
Published: February 2011

Abstract
According to current views, in order for cancer immunotherapy to be successful it must target cancer stem cells (CSC) and counteract the multiple mechanisms involved in immune escape. Guided by these concepts, we have developed a combinatorial adoptive immunotherapeutic strategy which utilizes a monoclonal antibody (mAb) and cytotoxic T lymphocytes (CTL) in combination with continuous administration of low dose cyclophosphamide (metronomic chemotherapy) to target CSC and differentiated tumor cells, as well as activated pericytes in the tumor microenvironment. The targets selected are aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and chondroitin sulfate proteoglycan 4 (CSPG4). We now report that ALDHbright cells in squamous cell carcinoma of the head and neck (SCCHN) cell lines, which express high levels of ALDH1A1, are tumorigenic at low inoculum in immunodeficient mice, and particularly sensitive to recognition by ALDH1A1-specific T cells. The ALDHbright cells express CSPG4, a cell surface antigen functional in adhesion and migration. CSPG4 is also expressed on tumor associated activated pericytes which stabilize tumor blood vessels and provide vascular endothelial cells with survival signals. Administration of CSPG4-specific mAb and metronomic chemotherapy combined with intralesional adoptive transfer of ALDH1A1 peptide-specific CTL to mice bearing human SCCHN PCI-13-derived xenografts significantly reduced tumor growth and number of tumor cells with CSC phenotype. The antitumor effects of the immunotherapy we have developed were significantly higher than those of its individual components. These results argue in favor of the possibility that this combinatorial strategy may enhance the clinical efficacy of adoptive immunotherapy in SCCHN patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5605.
Abstract 5613: Beta-mannosylceramide: a novel NKT cell agonist which synergizes with alpha-galactocylceramide to induce protection against tumors
Authors: O'Konek Jessica J. , Illarionov Petr , Khursigara Deborah Stewart , Ambrosino Elena , Castillo Bernard F. , Raju Ravinder , Khalili Maryam , Kim Hee-Yong , Howell Amy R. , Besra Gurdyal S. , Porcelli Steven A. , Berzofsky Jay A. , Terabe Masaki 
Published: February 2011

Abstract
Type I natural killer T (NKT) cells are a unique subset of T cells which express phenotypic and functional characteristics of both NK cells and T cells. NKT cells recognize glycolipid antigens presented by the non-classical MHC-like molecule CD1d. Upon stimulation with the prototypical type I NKT cell antigen α-galactosylceramide (α-GalCer), type I NKT cells promote tumor immunity through IFN-γ-dependent mechanims. In this study the ability of glycosylceramides with alterations of the sugar moiety to induce anti-tumor immune responses in an in vivo model of CT26 colon carcinoma metastasis to lungs of BALB/c mice was investigated. β-mannosylceramide (β-ManCer) induced strong tumor protection, while α-mannosylceramide and α-fucosylceramide did not. This is the first evidence of a glycosylceramide with a β-linked sugar moiety capable of inducing significant NKT cell-dependent anti-tumor immunity. We also confirmed that β-ManCer could protect at least as well as α-GalCer in a model of B16F10 melanoma lung metastasis in C57BL/6 mice. Interestingly, β-ManCer induced little cytokine production and retained protective activity in IFN-γ KO mice, unlike α-GalCer analogs which where completely dependent upon IFN-γ. The protection did not require CD8+ T cells, and was largely independent of NK cells. Blockade of nitric oxide synthase or TNF-α significantly reversed the β-ManCer-induced protection but had no effect on tumor protection for the α-GalCer analogs. Thus, contrary to α-GalCer, β-ManCer protects through a novel TNF-α and NOS-dependent, IFN-γ-independent mechanism. Consistent with the conclusion that β-ManCer and α-GalCer induce tumor immunity by distinct mechanisms, simultaneous administration of sub-therapeutic doses of these glycolipids resulted in synergistic reduction in the number of lung metastases. The distinct mechanism of action and ability to synergize with α-GalCer may suggest that β-ManCer represents a new class of NKT agonists with novel clinical applications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5613.
Abstract 5614: Interleukin-10 inhibits the induction of macrophage cytotoxicity against bladder cancer cells by Mycobacterium bovis bacillus Calmette-Guérin (BCG)
Authors: Luo Yi , Han Ruifa , Evanoff David P. , Chen Xiaohong 
Published: February 2011

Abstract
Intravesical BCG therapy has been used for the treatment of superficial bladder cancer for three decades. However, the mechanisms underlying BCG therapy currently remain elusive. We have focused on BCG induction of macrophage cytotoxicity against bladder cancer cells. Previously, we observed that macrophages are cytotoxic to bladder cancer cells upon stimulation with BCG in vitro. However, we found that macrophages from C57BL/6 mice are less potent than those from C3H/HeN mice for the killing of both bladder cancer MBT-2 cells and MB49 cells. This study was to determine whether macrophage-derived interleukin (IL)-10 is responsible for this discrepancy between these two commonly used murine bladder cancer models. Thioglycollate-elicited peritoneal exudate cells were harvested from mice 3 days after intraperitoneal injection of 2 ml 3% thioglycollate. Cells were incubated for 3 hours and non-adherent cells were removed after incubation. The remaining cells were 96% F4/80-positive cells as determined by flow cytometry. The prepared macrophages were then used for the analysis of BCG induction of cytotoxicity, cytokines, and nitric oxide (NO) in vitro. Studies demonstrated that BCG-stimulated C57BL/6 macrophages produced a substantially high level of IL-10 compared to BCG-stimulated C3H/HeN macrophages. This high IL-10 production correlated with reduced production of tumor necrosis factor (TNF)-α, IL-6 and NO in BCG-stimulated C57BL/6 macrophages. Neutralizing endogenous IL-10 during BCG stimulation increased C57BL/6 macrophage cytotoxicity against MB49 cells by 3.2-fold, along with increased production of TNF-α by 6.4-fold and NO by 3.6-fold, respectively. Macrophages from genetically modified C57BL/6 mice lacking IL-10 (IL-10−/−) also exhibited increased killing of MB49 cells and production of TNF-α and NO upon BCG stimulation. In addition, supplementation of exogenous recombinant IL-10 reduced BCG-induced C3H/HeN macrophage cytotoxicity against both MBT-2 cells and MB49 cells in a dose-dependent manner. Taken together, our results reveal the inhibitory role of IL-10 in BCG-induced macrophage cytotoxicity, suggesting that blockage of IL-10 may potentially enhance the effect of BCG in the treatment of bladder cancer patients, particularly for BCG non-responders who are often associated with high IL-10 production in response to BCG treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5614.
Abstract 5619: Natural killer cell function in multiple myeloma is impaired by dexamethasone and can not be rescued by immunomodulatory drugs
Authors: Hsu Andy , Quach Hang , Tai Tsin , Prince H M. , Smyth Mark J. , Trapani Joseph A. , Neeson Paul J. , Ritchie David S. 
Published: February 2011

Abstract
The immunomodulatory (IMiD) drug Lenalidomide (Len) is known to stimulate natural killer (NK) cells and enhance anti-tumor responses. Len plus Dexamethasone (Dex) therapy (Len-Dex) is an effective treatment for multiple myeloma (MM). As part of a prospective clinical trial of monthly cycles of Len-Dex therapy we assessed NK cell number and function in 25 MM patients. Whilst NK numbers increased from a mean of 2×105/ml (baseline) to a mean of 3.9×105/ml (cycle 6) (p=0.05), the mean NK cell-mediated cytotoxicity in chromium assays against K562 significantly decreased from 48.9% to 27.6% respectively (p=0.0028). Further analysis showed that when NK cell cytotoxicity was assessed from MM patient peripheral blood mononuclear cells (PBMC) during therapy, no enhancement of cytotoxicity could be observed when cultured in vitro with Len. We hypothesized that Dex potently suppressed the Len-mediated enhancement of NK function. In vitro, Len increased normal donor (n=6) NK cytotoxicity from 38.5% (untreated) to 53.3%. Dex severely impaired NK cytotoxicity to &lt;10%, this failed to increase (&lt;13%) in the presence of Len. Only the addition of high dose IL-2 (500U/ml) rescued cytotoxicity of Dex-treated NK cells (28.6%). The suppressive effect of Dex on NK cytotoxicity was not permanent as NK function returned to normal levels within 3 days of drug removal. However, these dex-‘washout’ PBMCs could no longer respond to Len with increased NK function, suggesting a permanent Dex-induced NK impairment. In cell sorting and co-culture experiments we found that Len enhancement of NK cytotoxicity was only mediated by CD4+ T cells (NK alone 76.6% vs NK+CD4 85%) and the effect of CD4+ T cells was IL-2 dependent. Furthermore IL-2 production by CD4+ T cells in response to anti-CD3/CD28 was also suppressed by Dex. Following Len-Dex therapy in patients we observed less IL-2 and IFN-γ production from T cells in response to anti-CD3/CD28 at cycle 6 compared to baseline.
Therefore, Len-mediates enhanced NK function through CD4+ T cell production of IL-2. The NK impairment observed in MM patients receiving Len-Dex is due to CD4+ T cell suppression. Our findings indicate that in order to harness both the anti-tumor and immunomodulatory capacity of Len the dose and timing of Dex therapy should be carefully reconsidered.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5619.
Abstract 5625: In vitro and in vivo pharmacology of MEDI-565 (MT111), a novel CEA/CD3-bispecific single-chain BiTE antibody in development for the treatment of gastrointestinal adenocarcinomas
Authors: Fuhrmann Stacy R. , Amann Maria , Mulgrew Kathy , Lorenczewski Grit , Baffa Raffaele , Wolf Andreas , Oberst Michael , Rattel Benno , Lutterbuese Petra , Baeuerle Patrick , Jallal Bahija , Trail Pamela , Richman Laura , Coats Steven , Hammond Scott A. 
Published: February 2011

Abstract
MEDI-565 (MT111) is a novel bispecific single-chain antibody of the BiTE (Bispecific T cell engager) class that transiently links carcinoembryonic antigen (CEA) on cancer cells with human CD3 on T cells. MEDI-565 specifically binds to human CEA with an affinity of 8.5 nM but not to any other member of the CEACAM family. In targeted expression studies on cryopreserved and formalin-fixed paraffin-embedded sections, MEDI-565 demonstrated membrane-localized binding specifically to epithelial cells in human cancerous tissues. The highest prevalence of MEDI-565 binding (∼90%) was in adenocarcinomas of gastrointestinal origin.
In in vitro killing assays, MEDI-565 recruited T cells via the CD3 antigen (affinity of 310 nM) in a process that required concomitant binding to CEA positive tumor cells for T cell activation. As a consequence, T cells expanded, increased cell surface expression of the activation markers CD69 and CD25, and released perforin and granzymes. The release of cytotoxic granule content led to a Ca2+-dependent activation of pro-caspases and subsequent apoptosis of CEA-expressing tumor cells. Efficient target cell lysis by MEDI-565 was predominantly mediated by CD8+ T cells and occurred within a wide range of effector-to-target ratios (80:1 to 5:1) for T cells derived from various human donors. BiTE mediated killing was not affected by the presence of soluble CEA (≤5 µg/mL).
The in vivo activity of MEDI-565 was investigated in subcutaneous xenograft models using immunocompromised SCID mice inoculated with mixtures of human T cells and human cancer cell lines. The antibody was eliminated from the serum with a half-life of a few hours following a single intravenous (IV) or subcutaneous (SC) injection. Despite a relatively short serum half-life, daily IV or SC bolus treatments over 5 days provided sufficient levels of exposure to inhibit the growth of CEA-positive tumors in a dose-dependent manner. Inhibition of growth was observed for tumors of different tissue origins and was dependent on the presence of human T cells and CEA expression by tumor cells. There were no MEDI-565-related in-life observations following treatment. These studies demonstrated that MEDI-565 has potent and selective anti-cancer activity in vitro and in vivo and provides evidence that MEDI-565 may be an effective monotherapy to treat CEA-expressing malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5625.
Abstract 5633: Two-compartment pharmacokinetics model of radioimmunotherapy with 131I-3F8 directly administered into the cerebrospinal fluid
Authors: He Ping , Kramer Kim , Smith-Jones Peter , Zanzonico Pat , Humm John , Larson Steven M. , Cheung Nai-Kong V. 
Published: February 2011

Abstract
Introduction
Injection of 131I-3F8 directly into the cerebrospinal fluid (CSF) through an Ommaya reservoir is a safe form of radioimmunotherapy (RIT) treatment for leptomeningeal metastasis (JCO, 25:5465, 2007). Recently, we described a one-compartment pharmacokinetics model that showed good fitting to CSF sampling data from 6 patients (JNM 50:1324, 2009). We now describe an improved two-compartment model to take into account the ventricular reservoir before 131I-3F8 distribution into the subarachnoid space and to explore limiting factors that may significantly affect the efficacy of the therapy.
Methods
The distribution and binding of 131I-3F8 in the cerebral spinal fluid were modeled using a system of rate equations derived from the principle of mass conservation. The model was fitted to CSF sampling data from an expanded cohort of patients (39 injections in 25 patients). Three sets of criteria were used to examine the effect of each parameter on the efficacy of the treatment. These criteria were (1) the area under the radioactivity concentration curve of the bound antibody (AUC[CIAR]) (2) the unbound antibody AUC[CIA], and (3) their therapeutic ratio (AUC[CIAR]/AUC[CIA]). In addition to parameters tested in the previous model, immunoreactivity, tumor distribution, and nonspecific binding were also tested.
Results
The two-compartment model showed improved fitting to patient data when compared to the one compartment model (R=0.92±0.11 versus 0.77±0.21, p=0.005). Predictions from the one compartment model were confirmed. Furthermore, we made these new observations: (1) Increasing immunoreactivity of 131I-3F8 from 10% to 90% increased both (AUC[CIAR]) and therapeutic ratio ([AUC[CIAR]/AUC[CIA]) by 7.4 fold, (2) The presence of ≤ 5% tumor cells in the ventricles or ≤ 10% of nonspecific 131I-3F8 binding to normal tissues had no appreciable effect on the therapeutic ratio. When extrapolated to a clinical setting, the model predicted that if 131I-3F8 could be split into 4 doses of 1.4 mg each and given at ≥ 24 hours apart, an antibody affinity of KD of 4 × 10−9 and immunoreactivity of 50% were adequate in order to deliver ≥10,000 Rad to tumor cells while keeping normal CSF exposure to &lt;1,000 Rad.
Conclusion
The two compartment model of intra-ommaya radioimmunotherapy showed better fitting to patient data than the one-compartment model. This model predicted that immunoreactivity and affinity were crucial in improving therapeutic efficacy. Nevertheless, an optimal scheduling of antibody injections should permit highly favorable therapeutic ratio even with 4 nM affinities and suboptimal immunoreactivity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5633.
Abstract 564: A &gt;50KDa soluble factor from the stroma-derived conditioned media contributes to resistance towards BCR-ABL inhibitors in CML via the JAK-STAT3 pathway
Authors: Nair Rajesh R. , Tolentino Joel H. , Argilagos Raul F. , Pinilla-Ibarz Javier , Hazlehurst Lori A. 
Published: February 2011

Abstract
Soluble factors and extracellular matrices from the bone marrow stroma, provides the essential microenvironment that contributes to the persistence of minimal residual disease found in patients with Chronic Myeloid Leukemia (CML), under treatment with tyrosine kinase inhibitors. We previously showed that in CML cells, bone marrow stroma-derived conditioned medium (CM) is sufficient to cause resistance to BCR-ABL inhibitors in a STAT3-dependent manner. In this study, we show that development of resistance in CM correlated with increased STAT3 phosphorylation and increased STAT3 DNA binding in CML cells. The activation of Stat3 in the context of CM was persistent even in the presence of BCR-ABL inhibitors. Moreover, the increase in DNA binding resulted in increased transcriptional activity of STAT3 and increased expression of MCL-1, Bcl-xl and Cyclin D1 in cells exposed to CM. We also found that CM-mediated increase in STAT3 activation requires JAK activity, since use of a pan JAK inhibitor sensitized the cells to BCR-ABL inhibitor in CM. Surprisingly, neutralizing the activity of IL-6, G-CSF and VEGF in the CM did not reverse the protection afforded by CM against BCL-ABL inhibitors. Furthermore, utilizing size exclusion filter columns, we were able to show that CM retentates that were higher than 50 kDa, was sufficient to duplicate the protective effects of CM against BCR-ABL inhibitor. Finally, we could show that CD34+ cells from BCR-ABL patients when exposed to CM showed an increase in STAT3 phosphorylation and this correlated with resistance to Nilotinib-mediated cell death. In conclusion, a greater than 50 KDa factor in CM leads to JAK-STAT3 activation, which is necessary and sufficient to confer resistance to CML cells against BCR-ABL inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 564.
Abstract 5642: Investigation of effective combination of anti-cancer drugs and radiation therapy against non-small cell lung cancer using NCI-H520 cell line
Authors: Oh In-Jae , Ban Hee-Jung , Kwon Yong-Soo , Kim Kyu-Sik , Lim Sung-Chul , Kim Young-Chul , Song Sang-Yun , Na Kook-Joo , Yoon Mee-Sun , Ahn Sung-Ja , Choi Song , Kim Yun-Hyeon , Choi Yoo-Duk , Choi Chan 
Published: February 2011

Abstract
Background: Radiotherapy (RT) is used for to treat unresectable locally advanced non-small cell lung cancer (NSCLC). For better disease control, RT has recently been combined with chemotherapy (CTx) in a variety of ways. This study examined the most effective combination methods of CTX and RT against NSCLC.
Material and Methods: Human lung cancer cell line (NCI-H520) and various chemotherapeutic agents (paclitaxel, docetaxel, gemcitabine, and cisplatin) were used in this study. The radiation doses used were 0, 2, 4 and 8 Gy. After processing of various combinations according to the radiation dose and concentrations of chemotherapeutic agents, the level of cell survival was quantified by a MTT assay. The combination index was calculated using the Chou and Talalay method on Calcusyn software and used to examine the synergism between CTx and RT.
Results: Among the various combinations of chemotherapeutic agents and radiation doses, concurrent chemoradiation therapy (CCRT) led to the highest rate of apoptosis and synergism. CTx followed by RT was the most effective combination when taxane was administrated. When high-dose chemotherapeutic agents were added to CCRT, induction CTx resulted in higher rate of apoptosis rate and synergism than consolidation CTx.
Conclusions: CCRT is the most effective combination when RT is combined with CTx in the NCI-H520 cell line. Induction CTx is more effective than consolidation CTx if a high-dose chemotherapeutic agent is added to CCRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5642.