bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5508: B lymphocytes are activated during the course of sipuleucel-T treatment, leading to an antigen-specific humoral response
Authors: Wesley Johnna , Kuan Ling-Yu , Chadwick Eric , Perdue Nikole , dela Rosa Corazon , Frohlich Mark , Urdal David , Sheikh Nadeem 
Published: June 2012

Abstract
Introduction: Sipuleucel-T is an autologous cellular immunotherapy FDA approved for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Previous clinical data have shown that antibodies specific for the immunizing antigen, PA2024, develop within two weeks post-end of sipuleucel-T treatment. Here, we sought to determine whether B lymphocytes were activated during the course of treatment and to evaluate their phenotypic profile in two ongoing clinical studies (NEoACT and PRoACT).
Materials and Methods: Sipuleucel-T is manufactured from peripheral blood mononuclear cells (PBMCs) isolated every two weeks by leukapheresis. The PBMCs are cultured with PA2024, an antigen composed of prostatic acid phosphatase (PAP) fused to granulocyte macrophage-colony stimulating factor (GM-CSF), washed, and then infused into the patient as sipuleucel-T. Each patient receives three infusions. The activation status of B lymphocytes was evaluated by multi-color flow cytometry during the manufacture of sipuleucel-T, before and after culture at each of the three treatment times. B lymphocyte subsets were identified by their expression of CD20, IgD and CD27: CD20+IgD+CD27− naive, CD20+IgD+CD27+ mature activated, and CD20+IgD−CD27+ memory. Activation of each of these subsets was determined by their expression of CD80 and CD96. Antigen-specific B lymphocyte function, in the form of antibody production, was evaluated in the serum of sipuleucel-T-treated subjects before and after treatment.
Summary: In the mature activated B lymphocyte subset, an increase in the proportion of lymphocytes expressing CD80+ and CD86+ was detected following culture with PA2024, with the increase in CD86+ mature B lymphocytes being the highest after the second infusion of sipuleucel-T. An increase in mature activated B lymphocytes directly ex vivo, pre-culture, was not observed prior to the second or third infusion. Additionally, CD80 and CD86 expression was upregulated on memory B lymphocytes in response to culture with PA2024 and following the first infusion. Furthermore, PA2024- and PAP-specific antibody responses were detected and maintained 2-22 weeks after the completion of sipuleucel-T treatment.Conclusions: These data demonstrate that B lymphocyte activation is a consequence of ex vivo culture with PA2024 and precedes an antigen-specific humoral response, as detected in the patients’ serum after treatment with sipuleucel-T. Collectively, these findings provide evidence of therapy-induced humoral immune activation in men with mCRPC treated with sipuleucel-T.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5508. doi:10.1158/1538-7445.AM2011-5508
Abstract 551: A potent and selective cFMS inhibitor regulates the tumor macrophage microenvironment leading to tumor growth inhibition
Authors: Wright Albion D. , Willis Brandon S. , Gomez Anna , Boys Mark L. , DeLisle Robert K. , Burgess Laurence E. , Munson Mark C. , Kennedy April L. , Topalov George T. , Zhao Qian , Rodriguez Martha E. , Rast Bryson , Rizzi James P. , DeWolf Walter E. , Lemieux Christine , Anderson Deborah , Neale Jason R. , Martinson Matthew , Gross Stefan D. , Callejo Michele , Risom Tyler , Lee Patrice A. 
Published: June 2012

Abstract
Increasing evidence suggests that interactions between tumor cells, stromal cells, macrophages and the extracellular matrix are pivotal to the processes of tumorigenesis, metastasis, and neovascularization. Macrophages within the tumor microenvironment are thought to facilitate cancer progression, making them intriguing targets for therapy. Colony stimulating factor 1 (CSF-1) and its receptor, cFMS, play a central role in the development of mononuclear phagocytes, recruitment of macrophages to tumors, and differentiation and function of osteoclasts. We have developed an orally active, selective small-molecule cFMS inhibitor for cFMS. This molecule inhibits cFMS cellular activity (IC50 = 9 nM) in vitro and inhibits cFMS phosphorylation in a transfected cell line grown in nude mice (ED50 = 3 mg/kg). Our compound also inhibits CSF-1-mediated osteoclast differentiation and function (IC50 values of = 4 nM and 58 nM, respectively). To further explore the potential of our selective inhibitor for the treatment of cancer, we evaluated anti-tumor activity in several preclinical models. We first explored the effect on the murine ovarian cancer cell line, ID8. ID8 cells injected intraperitoneally into nude mice form multiple peritoneal tumor deposits and abundant ascites. Macrophage infiltration in the ID8 ascites was markedly lowered in mice treated with a cFMS inhibitor. Using MCF-7, a human breast adenocarcinoma cell line that has been shown to produce M-CSF, a daily oral dose with 100 mg/kg of our inhibitor for 21 days significantly reduced tumor growth and was accompanied by a marked reduction in tumor-associated macrophages. These findings support the potential of a selective inhibitor of cFMS to favorably impact human cancers by modulating tumor-associated macrophage functions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 551. doi:10.1158/1538-7445.AM2011-551
Abstract 5510: Immunogenicity of the MUC1/Poly-ICLC vaccine in individuals with the history of advanced colorectal adenoma
Authors: Kimura Takashi , McKolanis John R. , Schoen Robert E. , Finn Olivera J. 
Published: June 2012

Abstract
Background: MUC1 is aberrantly expressed in human adenocarcinomas including colon cancer. Aberrant MUC1 is also found on colorectal adenomas where it promotes malignant transformation by interacting with beta-catenin, ras and other signaling pathways. Induction of immunity against MUC1 during premalignancy may prevent adenoma recurrence and/or their progression to colon cancer. Various MUC1 vaccines, peptide and adjuvant-based, dendritic cell-based or as various viral vectors, have been tested previously in small Phase I/II trials in patients with advanced cancer and have shown low immunogenicity and limited efficacy. In the cancer microenvironment, it is difficult to determine if low immunogenicity is due to the vaccine, to self-tolerance, to the immunosuppressive tumor microenvironement, previous treatments, age of the patient or all of the above. We are conducting a trial using MUC1 peptide and Poly-ICLC adjuvant vaccine in individuals who are cancer free but at high risk for developing cancer because of a recent history of advanced colorectal adenoma.
Method: Patients with advanced colorectal adenoma which meets at least one of following criteria, 1) ≥ 1cm in maximal diameter, 2) with villous or tubulovillous histology, 3) with high-grade dysplasia, were vaccinated with 100μg of 100aa MUC1 peptide [H2N-(GVTSAPDTRPAPGSTAPPAH)5-CONH2] admixed with 500μg of Poly-ICLC (TLR-3 agonist) as adjuvant on week 0, 2, 10 and one year later. The primary objective is to evaluate the vaccine immunogenicity (anti-MUC1 IgG and T cell responses) and safety.
Results: 43/65 patients have been enrolled. Among 31 patients studied to date, 16 developed anti-MUC1 IgG (52% response rate). This frequency of responders and the high levels of IgG (3-30 fold increase) have never been achieved in cancer patients. Antibody titers declined over time but could be boosted to previous or higher levels at 1 year, showing development of long-term memory. Confirmatory T cell assays are in progress. No adverse events above grade 1 have been identified, and no unanticipated adverse events have been observed.
Conclusions: MUC1 poly-ICLC vaccine is highly immunogenic in this prophylactic setting without causing any significant adverse events. Recurrence of adenomas will be evaluated at year 3 and correlated with the immune response, however, a larger randomized trial will be needed to properly evaluate the clinical outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5510. doi:10.1158/1538-7445.AM2011-5510
Abstract 5518: Characterization of invariant natural killer T cells in patients with advanced melanoma treated with CTLA4 blockade and dendritic cell vaccination
Authors: Ibarrondo Javier -. , Comin-Anduix Begoña -. , Lee Yohan -. , Chodon Thinle -. , Sazegar Hooman -. , Jalil Jason -. , Chmielowski Bartosz -. , Koya Richard C. , Gomez-Navarro Jesus -. , Jamieson Beth D. , Ribas Antoni -. 
Published: June 2012

Abstract
Background. Invariant CD1d-restricted T cells (iNKT) are a T lymphocyte subset with a key role in the innate and adaptive immune systems and have been implicated in protection against cancer. iNKT cells are activated by lipid antigen presentation by CD1d on myeloid dendritic cells (mDC). Upon activation, iNKT produce Th1 and Th2 cytokines. CD4+ iNKT cells have a Th2 profile, while CD4- and CD4-CD8- (DN) subsets, behave as Th1 T-cells. We studied the phenotype of iNKT in patients treated with the anti-CTLA4 monoclonal antibody tremelimumab alone or combined with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC) to explore possible associations between iNKT with treatment outcomes.
Methods: Peripheral blood mononuclear cells (PBMC) were obtained before and after treatment with tremelimumab alone (n=21) or tremelimumab with MART-1/DC (n=8). There were 4 patients with an objective response in the combined therapy group and 3 patients with an objective response in the tremelimumab alone group. The number and phenotype of T cell and iNKT were characterized by multi-color flow cytometry.
Results. Approximately one month after the first dose of combined treatment the percentage of iNKT-cells increased over baseline, while the percentage of iNKT cells decreased in patients treated with tremelimumab alone. In patients receiving combined treatment, those with a clinical response had a significantly higher iNKT number than non-responders. Overall, iNKT phenotypes did not change in either treatment group during treatment. However, clinical responders receiving combined therapy exhibited a high percentage of iNKT-CD8+ cells and low percentages of iNKT-CD4+. In contrast, in the non-responders and patients treated with tremelimumab alone, the iNKT CD8 to CD4 subset ratio was inverted. The combined iNKT subsets (CD4+, DN+, and CD8+) shared a common phenotype of CCR5+, CD62L+ and CD45RA+ and the phenotype did not change over time. For the tremelimuamb cohort, a CCR7-CD45RA- phenotype appeared and increased within the iNKT-CD4+ and CD8+ subsets after dosing.
Conclusions. Treatment with the anti-CTLA4 antibody tremelimumab induced changes in the percentage of iNKT cells which were more pronounced when co-administered with dendritic cell vaccines. iNKT cells may be a new cell subset mediating in the mechanism of action of CTLA4 blocking antibodies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5518. doi:10.1158/1538-7445.AM2011-5518
Abstract 5523: Adoptive cellular immunotherapy contributes to better survival for NSCLC patients: Case-control study of 395 Japanese patients with advanced NSCLC
Authors: Soejima Kenzo , Iwai Kazuro , Umesato Yoshimasa , Goto Shigenori , Kudo Shoji 
Published: June 2012

Abstract
Adoptive cellular immunotherapy (ITx) targeting various types of carcinoma including the lung is widely used, yet the clinical effectiveness has not been evaluated in large cases of lung carcinoma. So we carried out a case-control study to investigate the effect of ITx for the treatment of advanced non-small cell lung cancer (NSCLC) patients in Japanese population.
Between 2001 and 2006, 163 patients were identified as having advanced NSCLC with ECOG performance status (PS) 0/1 who underwent ITx with or without standard chemotherapy (CTx). The controls were 232 advanced NSCLC patients with PS 0/1 who had standard CTx or BSC alone. Overall survival (OS) and 1- and 2-year survival were obtained with Kaplan-Meyer survival curves and compared using log-rank and generalized Wilcoxon analysis. Multivariate analysis with Cox proportional hazard models was also performed to analyze survival.
The mean age of total population was 64.8 + 10.6 years. There were 251 males and 144 females and 295 adenocarcinoma (Ad) and 74 squamous cell carcinoma (Sq) patients. The mean period and frequency of ITx was 10.2 months and 8.7 times, respectively. Median OS for CTx and ITx + CTx was 15.7 and 20.8 months, respectively. Multivariate analysis with Cox proportional hazard model showed that sex (male vs female) (HR=0.33, p&lt;0.001) and histology (Ad vs Sq) (HR=0.14, p=0.045) were independent predictors of OS. It is revealed that ITx when administered as monotherapy was effective compared to BSC in male with Sq (HR=0.47, p=0.038) and female with Ad (HR=0.53, p=0.016). Additional effect of ITx on CTx was obtained in Ad histology, especially in female (p=0.039).
The present findings suggest that ITx may contribute to better survival for advanced or metastatic NSCLC patients under certain circumstances. These results should be confirmed in large prospective clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5523. doi:10.1158/1538-7445.AM2011-5523
Abstract 5534: Evaluation of clinical safety and immunogenicity of DPX-0907, a multi-epitope vaccine for the treatment of breast, ovarian and prostate cancers
Authors: Nigam Rita , Karkada Mohan , Weir Genevieve M. , MacDonald Lisa D. , Berinstein Neil , Mansour Marc 
Published: June 2012

Abstract
A successful cancer vaccine needs to overcome tumor-induced immune suppression while enhancing protective Type1-biased tumor-specific immune responses. To achieve this, enhanced vaccine delivery technologies are needed. We have developed a novel liposome-in-oil depot vaccine platform called DepoVaxTM (DPX) which increases the potency of peptide-based cancer vaccines and elicits a strong cytotoxic T cell response. DPX-0907 is a human DPX-based vaccine containing 7 HLA-A2 restricted peptides and is indicated for breast, ovarian and prostate cancer. The antigens were carefully selected with a multi-targeted approach that focuses on proteins involved in pathways that are critical for the survival of a cancer cell. This reduces the likelihood of immune escape through loss of antigen expression/presentation as a tumor responds to vaccine-induced immune pressure. We recently showed that DPX-0907 produces stronger and better sustained immune responses in HLA-A2 transgenic mice than a GM-CSF/ emulsion vaccine. A multicenter phase I clinical trial was initiated in five US clinical sites in March 2010 to evaluate the safety and immunogenicity of DPX-0907 in patients with advanced breast, ovarian or prostate cancer. The open label, dose escalation study recruited patients into one of 2 dose levels (0.25 mL and 1 mL). The vaccine was administered subcutaneously every three weeks for a total of three vaccinations. PBMC's were collected prior to each vaccination and at three time points following the last vaccination. These samples were also used to monitor the immunosuppressive MDSC population in patients receiving the vaccine treatment. In addition, immune monitoring of vaccine-induced responses is based on multi-parametric intracellular cytokine staining of multiple immune cell types and the functional analysis of peptide-MHC-multimer positive CD8 T cells. This first- in-man trial has generated important safety information that support the use of DepoVax for delivering multi-peptide based vaccines. The extensive immune monitoring will aid in the rational design of future DPX-0907 and other DepoVax-based vaccine trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5534. doi:10.1158/1538-7445.AM2011-5534
Abstract 5542: Chronic TNF-α treatment augments malignant properties of HPV-immortalized oral keratinocytes
Authors: Hong Hannah , Akhavan Jonathan , Kim Reuben , Kang Mo , Park No-Hee , Shin Ki-Hyuk 
Published: June 2012

Abstract
While acute inflammation is a part of the defense response, there have been emerging lines of evidence that suggest a strong link between chronic inflammation and cancer. Human papillomaviruses (HPV) infection is one of key factors in cervical cancer development, and possible link between HPV and oral carcinogenesis have been proposed. However, mechanisms by which HPV and chronic inflammation contribute to oral carcinogenesis have not been fully understood. The objective of this study was to determine the effect of chronic inflammation on malignant progression of HPV-associated oral carcinogenesis. We treated HPV-immortalized oral keratinocytes (HOK-16B) with a major pro-inflammatory cytokine, TNF-α for 4 months and examined the effect of chronic TNF-α treatment on malignant behavior of HOK-16B. Chronic treatment of TNF-α resulted in reduction in differentiation potential, and induction in proliferation potential and in migration ability of the HPV-immortalized oral keratinocytes. cDNA microarray analysis revealed that a subset of genes was significantly downregulated in long-term TNF-α treated cells, and the genes that were involved in differentiation, tumor suppression, and cell-cell junction functions supported the three increased malignant phenotypes, respectively. Our results indicate that chronic inflammation promotes malignant behavior of HPV-immortalized oral keratinocytes, suggesting that chronic inflammation is an important co-carcinogenic factor for HPV-associated oral carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5542. doi:10.1158/1538-7445.AM2011-5542
Abstract 5554: Margin of exposure of genotoxic and carcinogenic furan
Authors: Jestoi Marika , Järvinen Talvikki , Järvenpää Eila , Tapanainen Heli , Virtanen Suvi , Peltonen Kimmo 
Published: June 2012

Abstract
An in-house validated solid-phase microextraction followed by gas chromatography-mass spectrometric determination was used to study furan concentrations in baby-food samples purchased from the Finnish markets (LOD 1.9 ng g−1, LOQ 4.0 ng g−1 and RSTD &lt;20%). The mean levels of furan varied between 4.7 ng g−1 and 90.3 ng g−1 (n=21). The mean concentrations of similar product formulas based on their ingredients were 9.2 ng g−1, 37.0 ng g−1 and 49.6 ng g−1 for fruit-, vegetables- and meat-containing baby-foods, respectively. The consumption of industrial baby-foods in Finland is 172 g/day which results to the furan intake ranging from 0.8 to 15.5 µg/day and exposure of 0.1 to 2.1 µg kg−1 bw/day, respectively. Two extreme worst case scenarios can be deduced from our data: i) the maximum value in consumption of canned baby-foods (883 g/day) and the maximum concentration of furan detected (90.3 µg kg−1) and ii) 95 percentile consumption of canned baby-foods (384 g/day) and the maximum concentration of furan detected (90.3 µg kg−1). These two extreme worst case scenarios gave intakes of 79.7 µg and 34.7 µg, respectively. Applying the benchmark dose rate as well as safety-factor approaches a NOAEL of 0.08 mg kg−1 bw/day for furan can be deduced. If MOE is calculated by using the deduced NOAEL (600 µg/day for 7.5 kg baby) or BMDL10 (1.28 mg kg−1 bw/day) and the worst case exposure scenarios the MOE values of 7.5NOAEL/120BMDL10 and 17.3NOAEL/276BMDL10 can be derived. In the case of low exposure scenario (consumption 172 g/day; furan level 4.7 µg kg−1) the MOE values are 750NOAEL/2030BMDL10. A very low MOE exists in the extreme worst case infant exposures and particularly for such a clear rodent carcinogen (cholangiocarcinoma, hepatocellular adenoma and carcinoma). The MOEs derived clearly indicate that it is now a priority to understand the mode of action for the development of the liver tumours in the rat after exposure to furan and whether this is relevant to man. A significant reduction, however, to the exposure scenarios is provided by the fact that the use of fruit-based baby-foods with low furan content comprises a substantial proportion (mean consumption 78 g/day, maximum consumption 488 g/day and 95 percentile consumption 197 g/day) of the consumption of total industrial baby-foods.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5554. doi:10.1158/1538-7445.AM2011-5554