bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3521: RECRUIT-TandAb AFM13: Overcoming limitations of monoclonal antibodies in Hodgkin lymphoma
Authors: Rajkovic Erich , Knackmuss Stefan , Reusch Uwe , Rothe Achim , Topp Max , Younes Anas , Ravic Miroslav , Hucke Christian , Zhukvosky Eugene , Little Melvyn 
Published: August 2012

Abstract
Introduction: AFM13 is a RECRUIT-TandAb (CD30xCD16A) for treating Hodgkin Lymphoma by recruiting NK-cells and macrophages to the specific CD30 surface antigen on Reed-Sternberg cells. This redirected immune response leads to potent tumor cell killing. RECRUIT TandAbs are tetravalent and bispecific, and address key deficiencies of monoclonal antibodies such as (i) V/F polymorphism and (ii) non-selective binding to immune effector cells vs. granulocytes via CD16B receptor. Furthermore, RECRUIT-TandAbs have significant advantages over other antibody fragment technologies such as (i) bivalent binding to the targets and, (ii) longer half-life. Methods: AFM13 binds with high affinity to both CD30 and CD16A and is able to rapidly induce the lysis of CD30+ cells at picomolar concentrations in the presence of PBMCs. Intensive in vitro characterization demonstrated that AFM13 is specific for the CD16A receptor, which becomes activated only in the presence of tumor cells: there is no systemic activation of NK-cells in the absence of target cells. A robust GMP production process in mammalian cells and a lyophilized formulation with excellent stability have been established. Toxicology testing in Cynomolgus monkeys did not reveal any toxicity. Currently, AFM13 is being investigated in a single arm phase I dose escalation trial for patients with relapsed and/or refractory Hodgkin Lymphoma (HL). Patients receive a single cycle of 4 weekly doses, which are escalated in cohorts of 3 patients at the dose levels of 0.01, 0.04, 0.15, 0.5, 1.5, 4.5 and 7.0 mg/kg. Study objectives are the assessment of safety and tolerability, PK, immunogenicity, antitumor activity, as well as the determination of the maximum tolerated dose (MTD) or the optimal biological dose (OBD). The safety of the MTD or OBD will be confirmed in further patients receiving 2 cycles of AFM13. Results and Conclusion: So far, AM13 was shown to be safe and well tolerated by highly pre-treated Hodgkin Lymphoma patients in weekly doses of up to 1.5mg/kg. Adverse events were generally mild, with the most frequent drug-related event being fever. A first objective response was achieved on the dose level 1.5mg/kg. Five cases of stable disease / minor response were observed on lower dose levels. Further patients are being treated in the ongoing dose escalation study. Preclinical and interim clinical data will be presented, showing that AFM13 may become a safe and effective targeted therapy for CD30 positive 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 3521. doi:1538-7445.AM2012-3521
Abstract 3522: Preclinical development of an anti-CD30/anti-CD16A bispecific tetravalent TandAb antibody for the treatment of Hodgkin lymphoma
Authors: Knackmuss Stefan H. , Reusch Uwe , Burkhardt Carmen , Fucek Ivica , Gall Fabrice Le , Pauels Hans-Gerd , Zhukovsky Eugene A. , Little Melvyn 
Published: August 2012

Abstract
NK cells are professional cytotoxic immune effector cells and, unlike cytotoxic T cells, exist in a constitutively activated state not requiring pre- or co-stimulation. Thus, NK cells are attractive effectors to employ for cancer immunotherapy with bispecific antibodies. To improve the recruitment and activation of NK cells for lysis of tumor cells, we isolated a human antibody that was highly specific for the A isoform of FcαRIII (CD16A) and displayed substantially lower dissociation constant than native or Fc-optimized mAbs. The variable domains of this antibody were used to construct a tetravalent bispecific antibody, termed TandAb, consisting solely of antibody variable domains, with two valencies for CD16A (on effector cells) and two for CD30 (on target cells). CD30 represents a validated tumor target which is expressed on Hodgkin's Reed-Sternberg lymphoma cells, and on some activated immune cells. The binding properties of the TandAb and its efficacy for inducing tumor cell lysis were compared to those of a native anti-CD30 mAb, a mAb with enhanced Fc receptor binding properties, and an anti-CD30 bispecific diabody, all of which comprised the same anti-CD30 variable domains as the TandAb. Due to its bivalency for CD16A, the TandAb was retained longer on NK cells than the IgGs or the bispecific diabody, and relatively high concentrations of IgG were necessary to displace it from NK cells. The TandAb bound equally well to both CD16A alleles (158F, 158V) indicating a potentially broader patient response than that achieved with current therapeutic mAbs. The TandAb did not induce any systemic activation of NK cells even though it's binding was bivalent to CD16A. In a cytotoxicity assay, the TandAb displayed higher potency (EC50) and higher efficacy (maximal lysis) than the IgGs or the bispecific diabody. Cynomolgus monkeys were identified as the only relevant species for toxicity testing. Pharmacokinetics studies revealed half-lives for the TandAb up to 22.9 h after repeated dosing. No MTD was reached in a single dose escalation study to a maximum dose of 100 mg/kg. A pivotal 28 days toxicity study in which animals were dosed repeatedly up to 10 mg/kg every other day revealed an excellent safety profile. Several immunological parameters were assessed indicating no signs of immunotoxicity or systemic cytokine release. In conclusion, TandAbs may provide a more effective treatment for tumors that are refractory to treatment with IgGs and is currently being evaluated in the Phase I clinical trial.
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 3522. doi:1538-7445.AM2012-3522
Abstract 3529: A direct mass spectrometry approach for HPV T cell epitope identification
Authors: Blatnik* Renata , Hoppe* Stephanie , Wühl Martin , Grabowska Agnieszka K. , Riemer Angelika B. 
Published: August 2012

Abstract
To rationally design therapeutic cancer vaccines, it is important to know which T cell epitopes are present on cancer cells. Malignant transformation affects the cellular antigen processing machinery, thus not every epitope derived from intracellular proteins is necessarily presented by MHC molecules on the cancer cell surface. Up to now, T cell epitopes have mostly been defined by indirect methods, such as screening peptide libraries for MHC binders, and subsequent lymphocyte reactivity and cytotoxicity assays. However, all these assays with externally added peptides do not answer the question whether a candidate epitope is naturally processed and presented on the malignant cell. This can now be elucidated by using highly sensitive mass spectrometry approaches. For this study, we chose high-risk HPV-driven cancers as a model system. The induction and maintenance of the malignant phenotype in these tumors are dependent on two viral oncoproteins, E6 and E7, which are therefore present in all stages of HPV-driven cancers. We here aimed to assess the presence of T cell epitopes restricted by the major MHC class I supertypes, namely HLA-A1, A2, A3, A11, A24, B7, and B15, on HPV16-transformed cells. Prospective epitopes from the HPV16 E6 and E7 proteins for the above MHC supertypes were identified by high-throughput in silico epitope predictions, employing several web-based prediction algorithms. These peptides were tested for MHC binding in cellular binding assays on B-LCL of the respective HLA type. Finally, MHC-peptide complexes were immunoprecipitated from HPV16-transformed cells, and the presence of candidate epitopes was analyzed by nano-HPLC-MS2 and MS3 mass spectrometry. Binding of the majority of predicted peptides to the respective HLA allele was verified in the cellular assays. Several novel HPV16 MHC binders were identified. We optimized the immunoprecipitation protocol for epitope yield. Mass spectrometry analysis was successfully established and validated for HLA-A2, and is currently performed for the other supertypes. In conclusion, we show that ascertaining the actual cellular presentation of HPV T cell epitopes is feasible. As the included HLA supertypes have a cumulative population prevalence of &gt;95%, the resulting set of peptides may be used for the formulation of a widely applicable therapeutic HPV vaccine, or for immunomonitoring purposes in other HPV immunotherapy studies. * These authors contributed equally to this study.
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 3529. doi:1538-7445.AM2012-3529
Abstract 3531: Papillary thyroid carcinomas with and without lymph node metastasis show differences in tumor-infiltrating leukocytes
Authors: Angell Trevor E. , Correa Adrian J. , Kang Kate , Bass Rikki S. , Church Connor H. , Epstein Alan L. 
Published: August 2012

Abstract
Papillary thyroid carcinoma is the most common endocrine malignancy with approximately 48,000 new cases expected in 2011. Additionally, the incidence has doubled over the last three decades. While 20-year survival rates are extremely high with usual therapy, 15% will have recurrence and 5-10% will die from their disease. If refractory to standard treatment, no sufficient adjuvant therapies are available. Cancer immunotherapy uses a patient's own immune system to recognize and eliminate malignant cells. The potential advantages of this approach over conventional treatments include the systemic trafficking of immune cells to treat primary and metastatic disease, inherent antigen-specificity of adaptive immunity to minimize collateral damage, and most importantly, the induction of immunological memory to prevent recurrent disease. The degree and type of immune response are poorly understood in thyroid cancer. In this study, papillary thyroid cancer samples, with normal tissue matched to the same specimen, from de-identified patients were obtained retrospectively from the Norris Cancer Center Tumor Bank and stained using immunohistochemistry with antibodies specific for CD8 and CD16. Sections were evaluated for tumor-infiltrating leukocyte location, intra-tumor versus invading margin, and percentage of CD8 or CD16 positive lymphocytes, respectively. The results were analyzed for correlation between immune infiltrate and clinical parameters. Nineteen cases of papillary thyroid cancer were studied. The mean patient age was 40 years (range 22-55). Seven of nineteen patients had lymph node metastasis. An organized lymphocytic infiltration was seen in seven samples and was significantly correlated with the presence with CD8+ and CD16+ cells, at the invading margin and tumor parenchyma, respectively. Age &lt;40 years was significantly associated with this pattern of CD8+ and CD16+ cells compared to those older than 40. Lymph node metastasis was significantly association with an increased level of intra-tumoral CD8+ cell infiltration and there was a non-significant trend towards a positive association between nodal metastasis and intra-tumoral CD16+ cell infiltration. The present study demonstrates an increase in cell-mediated immune infiltration in samples that have nodal metastases versus those that do not, suggesting that immune therapy may be utilized in the future treatment of aggressive thyroid carcinoma to improve disease response.
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 3531. doi:1538-7445.AM2012-3531
Abstract 3535: Lymphoma-associated macrophages benefit for tumor progress via overexpressing legumain to degrade extracellular matrix in diffuse large B-cell lymphoma
Authors: Li Honghao , Xiong Min , Zhang Yan , Tan Xiaoyue , Xiang Rong 
Published: August 2012

Abstract
Crosstalk between macrophages in the tumor microenvironment and malignant cells has been implicated during the pathogenesis of many kinds of tumors. However, role of lymphoma-associated macrophages in the progress of lymphoma as well as its underlying mechanism is far from completely clear yet. Here we evaluated the effect of lymphoma-associated macrophages on the characteristics of diffuse large B-cell lymphoma (DLBCL). Immunohistological staining demonstrated that level of CD163 positive macrophages, so called M2 type macrophage, was negatively related with the prognosis of DLBCL. In addition, M2 macrophage overexpressed asparaginyl endopeptidase legumain, as shown by double-immunofluoresence staining. Then we set up human DLBCL xenograft model. Mice were sacrificed at the different stages of tumor progress (average volume are 0.8 or 1.4 cm3. respectively. n=4). Real-time PCR results showed that mRNA expression of CD206 (M2 macrophage marker in mouse model) and legumain significantly increased with the progress of tumor. However, contents of matrix significantly decreased as indicated by sirus red and Masson's staining. Overlapping existed in immunofluorescence staining of legumain and fibronectin/ collagen I. In vitro, we cultured monocytes U937 with supernatant from primary DLBCL cells. Real-time PCR and western blot demonstrated that mRNA and protein expression of M2 markers as well as legumain significantly increased in U937 after incubation of 48 hours. Further, we cultured the legumain overexpressed stable cell line in the wells coated with fibronectin or collagen I. Western blot showed that compared to control, legumain overexpression promoted the degradation of fibronectin and collagen I. Mice in human DLBCL xenograft model were randomly received clodronate liposome; PBS liposome or legumain inhibitor via i.v. injection (n=5). The results revealed that tumor growth was significantly delayed in the clodronate liposome group compared with PBS liposome control. Similarly, injection of legumain inhibitor mimicked the effect of clodronate liposome on the tumor progress. Our data suggests that lymphoma-associated macrophages polarized by lymophoma cells promote tumor progress and this effect might be mediated by degrading the matrix via overexpressed legumain.
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 3535. doi:1538-7445.AM2012-3535
Abstract 3552: Cancer immunoediting: Profile of cytokines in a mammary adenocarcinoma tumor model
Authors: Pagura Lucas , Caceres Juan M. , Cardinale Albertina , Scharovsky Olga G. , Di Masso Ricardo J. , Rico María J. , Rozados Viviana R. 
Published: August 2012

Abstract
Cancer immunoediting is a dynamic process composed of three phases: elimination (EL), equilibrium (EQ), and escape (ES), that encompasses the potential host-protective and tumor-sculpting functions of the immune system throughout tumor development. Inbred mice models provide an interesting tool for identifying genes that control susceptibility to breast cancer. Inbred CBi/L FS mice were artificially selected by body conformation from CBi mice. The M-406 mammary adenocarcinoma appeared spontaneously in CBi female mouse and it is maintained in vivo in mice of the same line. When CBi/L FS mice are s.c. challenged with M-406 they show the three phases: 51.6% in ES, 18.5% in EQ en 29.8% in EL. The aim of this study was to evaluate in CBi/L FS mice in the three phases of M-406 tumor growth: 1) the profile of cytokines Th1(IL-2; INF-γ); Th2(IL-4; IL-10) in serum and 2) the effect of conditioned media (CM) from CBi/L FS mononuclear cells on tumor cells proliferation. The serum and CM cytokines were evaluated by ELISA. CMs were obtained after 24h incubation of mononuclear cells from CBi/L FS seeded at 4x105 cells/well, in RPMI + 10% BFS. Tumor cells (5x104 cells/well) were incubated 24h with different CMs and proliferation evaluated (WST-1). In serum we observed the presence of high levels of INF-γ in the ES condition, compared with EQ and EL (p&lt;0.0001). Also, we found that IL-10 was increased in EL (p&lt;0.049), and IL-4 presented high levels in ES followed by EQ and then EL (p&lt;0.001). On the other hand, IL-2 did not show significant variations between conditions. The percentage of proliferation of M-406 cells was significantly higher with CM prepared from naive mice than with RPMI control medium (p=0.0048). No significant differences were found in proliferation between control medium and CM prepared from EL or ES mononuclear cells. Detectable levels of IL-4 and IL-10 were found in CMs. Interestingly, CM IL-10 level correlated negatively (p=0.0016, r=−0.8252) with M-406 proliferation. In conclusion we observed that while IL-4 concentration varied as expected in the three tumor phases, IL-10 and IFN-γ did the opposite. Furthermore, both in vivo and in vitro experiments would indicate that IL-10 might act as an inhibitor of tumor growth.These results are supported by new findings that endow immune inhibitory and stimulatory functions to IFN- γ and IL-10, respectively.
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 3552. doi:1538-7445.AM2012-3552
Abstract 3554: The histone deacetylase inhibitor LBH589 augments anti-tumor immunity through direct effects on tumor and immune cells leading to impaired tumor progression in vivo
Authors: Woods David M. , Woan Karrune V. , Wang Hongwei , Cheng Fengdong , Wang Zi , Vazquez Lianet , Perez Patricio , Lienlaf Maritza , Rock-Klotz Jennifer , Sahakian Eva , Powers John , Deng Susan , Oscar Merino , Atadja Peter , Seto Ed , Pinilla-Ibarz Javier , Weber Jeffrey S. , Sotomayor Eduardo M. , Villagra Alejandro 
Published: August 2012

Abstract
Overcoming immune tolerance is critical for the development of effective immunotherapy against cancer. Tumor cells induce tolerance through a variety of modalities including the secretion of IL-10 and TGF-β, the expression of inhibitory ligands, and the generation of cells with regulatory properties. Epigenetic modifiers have gained special attention due to their ability to modify immune regulatory pathways. In this context, a group of chemical compound collectively named histone deacetylase inhibitors (HDACi) have recently been shown to modulate tumor cell immunogenicity, adding a new property to their already well-documented cytotoxic effect against transformed cells. LBH589 is a potent, pan-HDACi that has been used in clinical trials for the treatment of several hematological malignancies. Here, we provide evidence of the anti-melanoma effect of LBH589 through its direct effects upon tumor cells as well as its modulatory effects upon immune cells. Indeed, treatment of human and murine melanoma cells in vitro with LBH589 resulted in inhibition of melanoma proliferation, characterized by cell cycle arrest in G1. Moreover, we found that LBH589 enhances the expression of MHC class I and II molecules on melanoma cells, which is critical for immune recognition. In addition, LBH589 treatment inhibits the production of IL-10, while enhancing the secretion of pro-inflammatory cytokines such as IL-12 and the expression of the costimulatory molecule B7.2 on antigen-presenting cells (APCs). LBH-treated APCs also displayed an enhanced capability to activate naïve antigen-specific T-cells as evidenced by their increased production of IL-2 and IFN-γ. More importantly, LBH589-treated APCs also restored the function of anergic T-cells isolated from tumor bearing mice. Finally, in vivo treatment of B16 melanoma bearing mice with LBH589 resulted in a substantial decrease in tumor growth when compared to vehicle-control treated mice (mean 602mm3 vs. 1316mm3, respectively). In conclusion, the dual ability of the pan-HDACi LBH589 to target both melanoma cells and to enhance anti-tumor immune responses provides the rationale for evaluating this compound either alone or in combination with immune enhancing therapeutic approaches (eg, CTLA4 blockade) for melanoma treatment.
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 3554. doi:1538-7445.AM2012-3554
Abstract 3557: Reduced ovarian hormones & reduced mammographic & MRI determined breast density in BRCA carriers following a hormonal chemo-prevention regimen of gonadotropin releasing hormone agonist (GnRHA) & low-dose add-back estrogen & testosterone
Authors: Sand Sharon R. , Klifa Catherine , Press Michael F. , Pike Malcolm , Ursin Giske , Spicer Darcy , Vora Lalit , Daniels AnnaMarie , Blazer Kathleen R. , Herzog Josef , Villalobos Ivonne , Weitzel Jeffrey N. 
Published: August 2012

Abstract
Young women at high risk of breast and/or ovarian cancer due to a BRCA mutation need risk-reducing options that preserve childbearing capacity. Purpose: Correlate changes in breast tissue determined by magnetic resonance imaging (MRI) & mammography with ovarian hormone levels following GnRHA treatment. Methods: In this prospective phase 2 biomarker chemoprevention trial, 10 premenopausal high-risk women, mean age 29.4 (21-43), were treated with intranasal GnRHA (deslorelin), low-dose add-back estradiol & testosterone once daily for 10 months. MPA was given for 10 days starting Day 140. Serum hormone levels were measured pre-administration of study drugs on Day 1, 29, 169 & 300. All participants underwent mammography, breast MRI & breast biopsy before & after 300 days of treatment. Mammographic density was measured & compared to volumetric breast density from MRI at both time points for all participants & fibroglandular tissue volume was also determined. Results: Significant decreases (p &lt; .05) were shown in estradiol (-61%) and testosterone (-41%) over time. Nine out of 10 participants showed a mean reduction in MRI volumetric breast density of 17.3% (p=0.045), a mean reduction in MRI fibroglandular volume of 15.1% (p=0.041) and a mean reduction in mammographic density of 31.9% (p=0.0033). Conclusion: Changes in breast tissue composition were significant after 10 months of hormonal chemoprevention, validating the proof of principle that density as a risk biomarker can be manipulated in BRCA carriers. We documented reduction in breast density by both mammographic and MRI assessment. While greater quantitative change in density was detected by mammography, MRI yields additional qualitative structural observations. Our findings confirm that MRI can be used to measure hormonal chemoprevention effects in women at high-risk of breast 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 3557. doi:1538-7445.AM2012-3557