bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4764: Vaccination of tumor-bearing mice with irradiated tumor cells and depot-formulated IL-2, IL-12, IL-4, GM-CSF and IFN-a eradicates the tumor cells and induces lasting immunity to the tumor
Authors: Falkenberg Frank W. , Pendzialek Dirk 
Published: February 2011

Abstract
In order to overcome the complex tumor-host interactions equally complex biological countermeasures have to be taken. By applying several cytokines in the vaccine the cytokine network is activated more efficiently then by using a single cytokine. To render the approach mote feasible, the cytokines were applied in depot Form. This allows formulation following pharmaceutical rules, and, at the same time, leads to steady release and keeps the inflammatory process active over a long period of time. Applying this concept, vaccines were designed that contained, besides irradiated tumor cells, a bouquet of cytokines in depot formulation. Due to their different biological activities IL-2, IL-4, IL-12, GM-CSF and IFNα were chosen.
The sequential steps of vaccine action:
The release of a multiplicity of cytokines accelerates the influx of inflammatory cells of the innate immune system.
Under the influence of IL-4. GM-CSF and IL-12 released from the depot, Dendritic cells are recruited, maturated and activated under physiological conditions in situ, at the inoculation site, circumventing tedious ex vivo procedures.
Tumor cell fragments generated by cells of the innate immune system are taken up by the locally generated CD86+ mature Dendritic Cells and transported to the lymph nodes where they are presented to T cells. In addition, cytokine-loaded depot particles are carried to the lymph nodes where they become involved in activation processes that are not understood yet.
Due to its angiogenic activity, depot-released GM-CSF induces the sprouting of capillaries into the inoculum, thus opening the way for recirculation of activated CD4+ and CD8+ T cells into the inoculum.
Depot-released IL-2 and IFNα further activate cells of the NK/NK-T cell lineage.
Applying Multi-Cytokine-Depot Tumor Vaccines, we have been able to cure mice from tumors induced by injection of a lethal dose of vital tumor cells.
Although the set-up of the vaccine is complex, its preparation is easy and relies on formulation following pharmaceutical principles rather than on trial and error.
For each cytokine as well as for the tumor cells a specific Dose-Response-relations has been determined. We are currently preparing for the application of this concept in clinical trials.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 4764.
Abstract 4767: Neo-peptides from gene fusions as cancer vaccine antigens
Authors: Lee Hojoon , Rodenberry John-Charles , Day Kristen , Cano-Buendia Jose , Craciunescu Felicia , Chapuis Jean-Charles , Stafford Phillip , Sykes Kathryn , Carrigan Patricia E. , Johnston Stephen A. 
Published: February 2011

Abstract
Background: Of all possible sources of antigens for cancer vaccines, frameshift (FS) peptides are attractive in that they may represent neo-antigens. FS peptides may be induced by insertions/deletions or by chimeric transcripts that result from mis-splicing, chromosomal translocations or trans-splicing of mRNA. Aim: In order to discover FS neo-antigens, we have taken a bioinformatical approach at identifying tumor specific, neo-peptides that are generated when chimeric transcripts are translated. Specifically we have focused our attention on identifying chimeric transcripts that create a frameshift when the exons of two different genes are joined. As a result of this gene fusion, approximately 50% of the time a frameshift occurs thus creating a neo-peptide. Method: In order to quickly identify these types of transcripts that are specific to cancer and not present in normal tissue, we have developed an algorithm that can be used to screen publically available databases and high-throughput sequencing data. As proof of principle we have applied this algorithm to the NCBI Expressed Sequence Tag database that contains cDNA sequencing information for normal and cancer tissues. Results: Based on this approach, we have identified and validated 35 chimeric transcripts that are present in breast cancer cell lines and in primary breast tumors. In addition, 9 chimeric transcripts are also present in seven different pancreatic cancer cell lines. Of the 35 chimeric transcripts, 11 chimeric transcripts produce frameshift peptides that are at least nine amino acids or longer and are predicted by SYFPEITHI and Rankpep to be immunogenic and capable of being presented in the most frequent human class I MHC alleles. Moreover, our analyses also identified chimeric transcripts that have already been confirmed by 454 sequencing for breast and prostate cancer. Discussion: Defining the chimeric transcriptome in both healthy and cancer patients could be critical for the development of new therapeutic agents. Of more interest to us, is their potential contribution to a prophylactic cancer vaccine. (This work is supported by a DoD Innovator Award and a Keck Foundation grant to SAJ)
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 4767.
Abstract 4768: Investigation of frameshift peptides for cancer vaccines
Authors: Shen Luhui , Cano-Buendia Jose , Lee Hojoon , Bui Chu , Sykes Kathryn , Carrigan Patricia E. , Johnston Stephen A. 
Published: February 2011

Abstract
Background: Our overall goal is to develop a general, preventative cancer vaccine. We are systematically applying bioinformatics, proteomics and immunological methods to achieve this vision. One of our foci is the identification of framshifted (FS) neo-peptides in tumor cells as vaccine components. FS peptides are expressed in alternate reading frames which are activated by various gene mutations and abnormal splicings in tumor cells. Aim/Method: Our hypothesis is that FS peptides are recognized as foreign antigens to the immune system thus making them potential cancer vaccine candidates. We have identified a list of FS peptides by bioinformatic analysis using the publically available human tumor and normal EST databases. To set up a systematical approach of prophylactic cancer vaccine development, we evaluated one potential FS peptide on the list as cancer vaccine candidate which is produced by a splice variant in SMC1A (Structural Maintenance of Chromosomes 1A). Results: The SMC1A FS peptide is a 17 amino acid peptide which is encoded by an abnormal alternative splicing event between exon 1 and exon 4. It was detected in mouse tumor cell lines including melanoma (n=2) and a breast tumor cell lines. It was also detected in human tumor cDNAs assayed thus far including breast (n=34), pancreas (n=4), and lung cancer (n=1) cell lines and primary breast (n=7) and pancreatic tumors (n=4). The expression levels of the SMC1 FS variant increases in most primary tumors with ranges from 2 to 70 fold. Specifically we see an increased expression in 6/7 breast and 2/4 pancreatic tumors screened. Single genetic immunization with plasmids expressing SMC1 FS, mouse GM-CSF, and CpG2216 significantly delayed tumor growth in C57BL/6 mice transplanted with the B16F10 melanoma cell line. Both antibody and IFN-γ released splenocytes to SMC1 FS were detected in immunized mice. Discussion: These findings suggest that the SMC1 FS peptide can be a potential cancer vaccine candidate to prevent various tumors. We are applying this same basic approach to accumulate sufficient antigens to constitute a broadly protective, prophylactic cancer vaccine. (This research is supported by an Innovation Award from the DoD and The Keck Foundation to SAJ.)
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 4768.
Abstract 4771: Molecular, epigenetic, and phenotypic repolarization of human T lymphocytes using 5-aza-2′-deoxycytidine increases CD8 responsiveness and induces Th1 polarity
Authors: Dubovsky Jason A. , Powers John J. , Gao Yang , Pinilla-Ibarz Javier A. , Sotomayor Eduardo M. 
Published: February 2011

Abstract
The improper polarization of helper and cytotoxic T lymphocytes is a trademark immunosuppressive strategy employed by a litany of human malignancies. Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Very recent in-vitro evidence indicates that this plasticity may be phenotypically replicated by using methylation inhibitors which are approved for clinical use in certain types of cancer, however the longevity and therapeutic potential of repolarized cells remains to be elucidated. These results beg the question: can the ineffective polarization of T lymphocytes in the context of cancer be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has focused on repolarizing helper and cytotoxic T lymphocytes using 5-aza-2′-deoxycytidine (5A2) tracking changes in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our studies relied upon intracellular staining, methylation specific PCR, and phosflow anlaysis. The data indicates that 5A2 treatment can repolarize Th2 cells to effectively secrete interferon gamma, signal via STAT4, and achieve demethylation of critical Th1 specific promoters. We also show that this repolarization can be maintained. Similar increases in cytotoxic signaling capability were obtained with CD8+ T cells after treatment with 5A2. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. Finally, we have identified a cytotoxic threshold for 5A2 treatment which is above the concentration necessary to achieve effective and sustained molecular and epigenetic repolarization. All in all our data seeks to define a modality in which improper or ineffective T cell polarization can be altered ex post facto and continued immunotherapeutic intervention may benefit from the naïve polarization of anti-cancer responses.
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 4771.
Abstract 4776: Properties of allogeneic WT1126–134-specific CD8+ T cells generated across an HLA A2 barrier
Authors: Melenhorst Jan J. , Falkenburg Willem J.J. , Gostick Emma , Quigley Máire F. , Hensel Nancy F. , Douek Daniel C. , Price David A. , Barrett Austin J. 
Published: February 2011

Abstract
T cells recognizing self-antigens overexpressed in malignant cells such as the Wilms tumor 1 protein (WT1) may contribute to anti-tumor reactivity after both allogeneic and autologous stem cell transplantation. HLA A*0201-restricted WT1-reactive CD8+ T cells recognizing peptide-loaded HLA-A2+ target cells have been isolated from both HLA-A2 negative and positive donors. HLA-A2-restricted WT1-specific CD8+ T cells generated from HLA-A2 positive donors are likely to be specific for the WT1 peptide, but may show only low reactivity against targets presenting endogenous WT1 antigen due to thymic deletion of high avidity T cells. In contrast, HLA-A2-restricted WT1-specific T cells generated from HLA-A2 negative donors may be highly reactive against these targets, but with increased risk for cross-reactivity. To explore the possibility of generating highly WT1-reactive CTL across an HLA barrier, EBV-transformed lymphoblastic B cell lines (EBV-LCL) were transduced with a retroviral HLA-A2 construct, loaded with WT1126–134, and used to stimulate autologous CD8-selected T cells. Several T cell clones and lines were generated and sorted with wildtype WT1 tetramer. All T cell clones and lines selected for functional analysis stained brightly with WT1/A2 tetramers, but not with irrelevant HLA-A2 control tetramers (PR1, PRAME300–309, CMVpp65495–503), indicating specificity for the WT1 peptide presented in HLA-A2. Four lines screened against a panel of HLA-A2+ and HLA-A2- EBV-LCL recognized HLA -A2+ and one HLA-A2-, HLA-B57+ LCL. Autologous PHA blasts were not recognized, indicating specificity for EBV-derived antigens presented in the context of both HLA-A2 and -B57. Of five clones and one line tested only two showed true WT1126–134 specificity, whereas the other clones and line recognized any HLA-A2+ target cell without exogenously loaded WT1 peptide. Sequence analysis of the T cell receptor (TCR)-α and β genes showed that the WT1-specific CD8 T cell clones differed from the pan-HLA-A2-recognizing clones at only two positions in the TCRα third complementarity determining region. In conclusion, high avidity anti-WT1126–134 CD8 T cell responses could be generated in the HLA-A2 mismatch setting; however, the response was dominated by a WT1-independent, promiscuous HLA-A2 reactivity that could be hazardous after allogeneic transplantation.
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 4776.
Abstract 4784: CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma
Authors: Yamada Noriyuki , Oizumi Satoshi , Kikuchi Eiki , Shinagawa Naofumi , Konishi Jun , Ishimine Atsushi , Aoe Keisuke , Gemba Kenichi , Kishimoto Takumi , Torigoe Toshihiko , Nishimura Masaharu 
Published: February 2011

Abstract
Purpose: Defect in human leukocyte antigen (HLA) class I expression may provide tumor cell with a mechanism to escape immune recognition, while T-cell infiltration is associated with good prognosis in many cancers. However, little has been known about the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM). In this study, we investigated the immune profile and conducted outcome analyses in MPM patients.
Experimental Design: HLA class I expression and TILs (CD4+, CD8+, and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5.
Results: The expression of HLA class I was positive in 33 patients (75%) and heterogenous in 11 patients (25%). There was no case that showed negative HLA class I expression. The density of CD4+ and CD8+ TILs were strongly correlated (R = 0.76, p&lt;0.001). High density of CD8+ TILs were significantly better prognostic factor for survival of patients with extrapleural pneumonectomy (p&lt;0.05). Multivariate analysis revealed high density of CD8+ TILs to be an independent prognostic factor. Conclusion: The presence of intratumoral CD8+ T cells correlated with improved clinical outcome, raising the possibility that CD8+ T cells might play a pivotal role in anti-tumor immune response against MPMs. Thus stimulation of CD8+ lymphocytes might offer new opportunities for efficacious immunotherapy in MPM.
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 4784.
Abstract 4785: Identification of HSP105 as a novel non-Hodgkin lymphoma (NHL) restricted antigen
Authors: Pupa Serenella M. , Zappasodi Roberta , Bongarzone Italia , Cabras Antonello , Ghedini Gaia C. , Castagnoli Lorenzo , Micciché Francesca , Gianni Massimo A. , Nicola Massimo Di 
Published: February 2011

Abstract
We recently reported that vaccination using dendritic cells (DCs) loaded with killed autologous tumor cells in relapsed indolent NHL patients induced objective clinical responses that correlate with multifaceted immunological responses. In particular, since responders (R) showed tumor-restricted humoral immunity in autologous setting, we exploited antibody (Ab) repertoires from vaccinated patients to evaluate whether the observed antibody responses was directed to indolent NHL-shared antigens (ags).
Immunohistochemistry and flow-cytometric analyses of biotinylated Immunoglobulins (Igs) from vaccinated patients’ serum samples preadsorbed on normal isolated B cells in the attempt to decrease Abs cross-reacting with normal auto-ags showed that only post-vaccine serum Ig of responders specifically reacted with higher intensity on allogeneic NHL tumors (either long term cell cultures or primary tumors from the same series) compared to matched biotinylated Igs from control samples (pre-vaccine serum from responders, pre- and post-vaccine serum from non-responders and healthy donors). In addition, only Abs contained in post-vaccine serum from R significantly inhibited NHL DOHH2 cells growth strongly suggesting the presence of therapeutic Abs in their serum samples. These findings indicate that Igs from R recognize tumor cell-surface associated molecules different from patient-specific idiotypes and support the potential expression of novel NHL-restricted ags. As a step toward identifying NHL-restricted ags as potential novel therapeutic targets, we applied a properly modified serological proteome analysis (SERPA) using as target DOHH2 cells and as probes pre- and post-vaccine Ab repertoires from our series. Proteins, fractionated using an OFFGEL IPG strip (pH 3-10), were separated on SDS-PAGE and then immunoblotted with pre- and post-vaccine Igs from R and controls. Differential hybridization analyses have revealed some potential candidate tumor-associated antigens which include heat shock protein 105 (HSP105), whose immunological role has been already proved in solid tumors. Preliminary data indicate that HSP105 is also expressed on cell membrane from different tumor B cell lines and experiments are in progress to evaluate its potential implication in tumor growth control. Partially supported by AIRC.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 4785.
Abstract 4786: MiR-17-92 expression in differentiated T cells - Implications for cancer immunotherapy
Authors: Kohanbash Gary , Sasaki Kotaro , Hoji Aki , Fujita Mitsugu , Okada Hideho 
Published: February 2011

Abstract
As type-1 T cells have been shown to mediate effective anti-tumor immune response, we sought to identify microRNA (miRs) differentially regulated between type-1 and type-2 T cells, and determine how the expression of such miRs are regulated. We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used RT-PCR to confirm the differential expression levels. WST-1, ELISA, and flow cytometry were used to evaluate the survival, function and phenotype of cells, respectively. Lastly, we employed mice transgenic for the identified miRs to determine the biological impact of the miR expression in T cells. Our miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Finally Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD). Collectively, our data suggest that the type-2-skewing tumor microenvironment can induce the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor destruction. Genetic engineering of T cells to express miR-17-92 may prove to be a promising approach for cancer immunotherapy.
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 4786.