bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2811: Allogeneic cell cased vaccine development by shared antigen screening
Authors: Deyev Vadim V. , Schilling Neal , Schreiber Taylor H.
Published: May 2015

The fundamental premise of allogeneic vaccines for cancer relies upon the presence of common antigens that are shared between established cell lines and a large proportion of patients with histologically related tumors. Recent results from The Cancer Genome Atlas have clearly demonstrated that somatic mutations in exon region DNA, while potentially immunogenic, do not result in the translation of antigenic proteins that are similar from patient to patient. Instead, these data reinforce the concept that dysregulation of common pathways contributes to the general property of de-differentiation in tumor cells and the acquisition of immature phenotypes as compared to untransformed precursor cells. This phenomenon leads to expression of mucinous and embryonal antigens, collectively known as cancer testis antigens, that are otherwise rare in mature tissues and to which central tolerance remains incomplete. We have developed allogeneic vaccines based on parallel screening of non-small cell lung, bladder, triple-negative breast, ovarian and melanoma tumor cell lines and patient tumor samples. The baseline expression of certain antigens, including SSX2, SSX4, CT10, MAGE-A1, MAGE-A10, LAGE-1 and NY-ESO-1 was found to vary widely both between tumor samples and non-transformed tissue controls. Among all antigens screened, MAGE-A3 was most commonly upregulated across transformed tissue samples, however other antigens including BAGE-1, XAGE-1b and MAGE-A10 were found to be most dramatically upregulated. This analysis provides a screening tool with which to appropriately profile and prioritize individual cell lines for vaccine development in histologically diverse tumor types.

Citation Format: Vadim V. Deyev, Neal Schilling, Taylor H. Schreiber. Allogeneic cell cased vaccine development by shared antigen screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2811. doi:10.1158/1538-7445.AM2014-2811
Abstract 2812: The clinical effects of dendritic cell and cytokine-induced killer cell therapy for lung cancer after surgery
Authors: Gao Daiqing , Li Changyou , Zhao Peng , Wei Xiaofang , Xie Xihe , Sun Weihong , Guo Qingming , Zhu Danni , Gao Tianyi , Alexandrou Aris T. , Li Jian Jian
Published: May 2015

Objective:The aim of the study was to evaluate the safety and therapeutic efficacy of autologous dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) for the treatment of lung cancer patients.

Methods:In the present study, we recruited a group of 40 lung cancer patients after surgery registered in the Biotherapy Center during 2005-2011 and randomly divided patients into two groups: Twenty patients treated with DC-CIK therapy as the treatment group and the other twenty patients served as controls.Subjects were administrated with 1×106 units of IL-2 daily for 5 days before mononuclear cell isolation from peripheral blood. For the treatment group, after primary tumors were removed by surgery, 1-3 doses of DCs and CIKs were perfused via peripheral veins. The immunologic function,short-term therapeutic effects, 5-years overall survival rate (OS), and disease free survival rate (DFS) were compared between the two groups.In addition, the peripheral blood samples were extracted from all patients before and after DC-CIK therapy,analyzed for T cell subsets by flow cytometry,and the intracellular cytokines of T cells were detected simultaneously.

Results:OS for 1, 3, and 5 years of DC-CIK therapy group were 100%, 88%, and 88% respectively which contrasted with 78%,66%, and 25% in the control group. DFS 1, 3, and 5 years of DC-CIK therapy groups were 100%, 85%,65% respectively compared to 73%,58%, 23% in the control groups. Although there were no changes in the subsets of T cells in peripheral blood before and after DC-CIK therapy, the intrace1lular cytokines IFN-γ,IL-2,IL-4, and IL-6 of the immune cells were noticeably improved in the treatment group.

Conclusion:DC-CIK therapy is a potential effective therapeutic modality to improve OS and DFS in post-surgical lung cancer patients.

Citation Format: Daiqing Gao, Changyou Li, Peng Zhao, Xiaofang Wei, Xihe Xie, Weihong Sun, Qingming Guo, Danni Zhu, Tianyi Gao, Aris T. Alexandrou, Jian Jian Li. The clinical effects of dendritic cell and cytokine-induced killer cell therapy for lung cancer after surgery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2014-2812
Abstract 2817: DCVex(TM): A novel DC-targeted vector platform for cancer immunotherapy
Authors: Albershardt Tina C. , Tareen Semih U. , Odegard Jared M. , Campbell David J. , Flynn Patrick , Robbins Scott H. , Berglund Peter , Meulen Jan H. ter
Published: May 2015

Dendritic cells (DCs) are essential for the initiation of T cell responses and are therefore an attractive target for cancer immunotherapy. The DC vaccine, Provenge®, as well as a number of on-going clinical trials, have in principle validated this concept. However, the currently pursued strategy of ex vivo immunization of DCs is time-consuming and costly. We have developed a 3rd generation, integration-deficient lentivector platform, DCVex(TM), which is designed to deliver tumor antigen-encoding genes directly to DCs in vivo by targeting the DC-SIGN receptor. Mice immunized with DCVex(TM) vectors expressing a variety of model antigens developed strong, dose-dependent poly-functional and cytotoxic antigen-specific CD8 T cell responses, as assessed by intracellular cytokine staining and in vitro cytotoxic T lymphocyte assays. Repeated immunizations resulted in boosting of the T cell responses, indicating the absence of induction of inhibitory anti-vector immunity. Importantly, in stringent therapeutic tumor models (e.g., B16F10 footpad melanoma and CT26 lung metastasis models), immunization with tumor antigen-encoding vectors protected the majority of animals from death in a dose-dependent manner. These findings demonstrate the potential of DCVex(TM) as a novel cancer vaccine platform suitable for in vivo DC immunization.

Citation Format: Tina C. Albershardt, Semih U. Tareen, Jared M. Odegard, David J. Campbell, Patrick Flynn, Scott H. Robbins, Peter Berglund, Jan H. ter Meulen. DCVex(TM): A novel DC-targeted vector platform for cancer immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2817. doi:10.1158/1538-7445.AM2014-2817
Abstract 282: Smoking and increased age in hematuric patients significantly confound the accuracy of classifiers for the diagnosis of urothelial cancer
Authors: Williamson Kate E.
Published: May 2015

Smoking and increased age in hematuria patients significantly confound the accuracy of classifiers for the diagnosis of urothelial cancer

Ricardo de Matos Simoes (a), Brian Duggan(b), Mark W. Ruddock (c), Frank Emmert-Streib (a), Declan O'Rourke (d), Hugh F. O'Kane (b), Funso Abogunrin (e), Cherith N. Reid (c), Neil H Anderson (f), David Curry (b), Kate E. Williamson (a). a Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, UK. b Department of Urology, Belfast Health and Social Care Trust, Belfast, UK. c Randox Laboratories Ltd., County Antrim, UK. d Department of Pathology, Belfast City Hospital, Belfast, UK. e Department of Urology, Craigavon Area Hospital, Northern Ireland, f Department of Pathology, Royal Victoria Hospital, Belfast, UK.

There is an urgent need for evidence-based risk stratification of hematuria patients. Currently, we have insufficient understanding of the characteristics which confound the accuracy of diagnostic classifiers for urothelial cancer (UC). Between November 2006 and October 2008 156 hematuric patients were recruited to a case control study. We defined UC diagnostic classifiers for 16 stratified subpopulations. Using a random forest classification based on ∼29 biomarkers measurements in urine, serum and plasma and random sub-sampling we generated 1000 training and test patient datasets to estimate probabilities of correct, incorrect and inconsistent classification for each patient. We defined classifiers for control and UC classified subpopulations. The distribution of characteristics across classifiable and non-classifiable patient subpopulations was explored using Fisher's exact test. The non-smoking stratified subpopulation achieved the greatest accuracy AUC = 0.95 (sd = 0•1). One hundred patients (64%) were classified correctly; 46/156 (30%) were non-classifiable, and 10/156 (6%) were inconsistently classified. The 23 non-classifiable UCs comprised 21 pTa, one pT1 and one CIS; two pTa and one pT1 were inconsistently classified. Five patients with newly diagnosed cancers other than UC, seven with “no diagnosis” and 11 with benign conditions were misclassified as UC. Consideration of smoking, increased age and antihypertensive medication in addition to biomarker profiles may achieve more accurate classification of UC in hematuria patients. This novel approach to diagnostic classifiers, once fine-tuned, may have the potential to correctly classify low risk bladder tumours and to reduce false positive cases.

Citation Format: Kate E. Williamson. Smoking and increased age in hematuric patients significantly confound the accuracy of classifiers for the diagnosis of urothelial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 282. doi:10.1158/1538-7445.AM2014-282
Abstract 2821: Dual-label microdosing approach to identify chemoresistance to carboplatin and gemcitabine combination chemotherapy
Authors: Zimmermann Maike , Scharadin Tiffany M. , Zhang Hongyong , Lin Tzu-yin , White Ralph W. deVere , Pan Chong-xian , Henderson Paul T.
Published: May 2015

Gemcitabine is commonly given in combination with cisplatin or carboplatin (GC therapy) as the first-line chemotherapy regimen for several malignancies, including bladder cancer. Unfortunately, less than half of patients respond to the therapy, generating a critical need for a test that predicts tumor response to GC therapy. The goal of this project is to measure drug-DNA adducts after administration of a single non-toxic microdose of gemcitabine in combination with carboplatin and correlating the degree of modification to chemotherapy sensitivity.

We have previously shown that resistance to carboplatin may be identified by using a [14C]carboplatin microdose (1% of therapeutic dose), and subsequent measurement of the [14C]-DNA adducts via accelerator mass spectrometry (AMS), an ultrasensitive method used for detecting rare isotopes. We postulate that adduct levels induced in tumors by GC microdoses are proportional to those formed during full dose chemotherapy. Furthermore, we hypothesize that there exists a threshold level of adducts above which tumors respond to GC therapy.

We used bladder cancer cell lines and the nod scid gamma severe combined immunodeficient (NSG) mice containing patient-derived tumor xenografts (PDX) from bladder cancer patients to determine GC-DNA adduct levels using AMS. The NSG mouse is uniquely capable of accepting and propagating tumor tissue engrafted directly from patient biopsy samples. The resulting groups of mice each have identical tumors, but can be treated in a variety of ways with replicate experiments; characteristics that are impossible to achieve in normal clinical studies. We will report progress on developing protocols and preliminary GC microdosing data using the NSG-PDX mouse model of human bladder cancer.

Citation Format: Maike Zimmermann, Tiffany M. Scharadin, Hongyong Zhang, Tzu-yin Lin, Ralph W. deVere White, Chong-xian Pan, Paul T. Henderson. Dual-label microdosing approach to identify chemoresistance to carboplatin and gemcitabine combination chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2014-2821
Abstract 2823: Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition
Authors: Shah Nina R. , Tancioni Isabelle , Ward Kristy K. , Lawson Christine , Chen Xiao Lei , Miller Nichol L.G. , Sulzmaier Florian J. , Uryu Sean , Schlaepfer David D.
Published: May 2015

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that undergoes gene amplification in >20% of serous ovarian cancers. In addition to increased tumor growth and spread, ovarian cancer patients with FAK amplification have a poorer prognosis with decreased overall survival. Merlin, a product of the NF2 tumor suppressor gene, is being evaluated as a biomarker for sensitivity to FAK inhibition in human clinical trials for malignant mesothelioma. As it remains undetermined whether linkages exist between merlin and FAK in other tumor types, we evaluated nine human and two murine ovarian cancer cell lines with sub-micromolar levels of FAK inhibitor (PF-271) for effects on anchorage-independent cell growth. Cells were identified as sensitive (OVCAR3, OVCAR8, HEY, ID8-IP), intermediate (A2780, IGROV1), or resistant (OVCAR10, IGROV1-IP, SKOV3, SKOV3-IP, 5009) to FAK inhibition. Notably, merlin protein levels were high in all resistant cell lines, moderate in intermediate cell lines, and low or undetectable in sensitive cell lines. Oral FAK inhibitor administration reduced orthotopic tumor growth of sensitive (ID8-IP, low merlin) but not resistant (5009, high merlin) murine ovarian carcinoma cells. However, stable knockdown of merlin expression in resistant SKOV3-IP and OVCAR10 human ovarian carcinoma cells did not induce sensitivity to FAK inhibition in vitro. These results support the notion that high merlin expression is correlated with a FAK-inhibitor resistant phenotype, likely through an indirect mechanistic linkage. Nevertheless, merlin protein levels may serve as a biomarker to predict ovarian cancer sensitivity or resistance to FAK inhibitor treatment.

Supported by NIH CA102310

Citation Format: Nina R. Shah, Isabelle Tancioni, Kristy K. Ward, Christine Lawson, Xiao Lei Chen, Nichol L.G. Miller, Florian J. Sulzmaier, Sean Uryu, David D. Schlaepfer. Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2823. doi:10.1158/1538-7445.AM2014-2823
Abstract 2830: Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) by mining gene expression data of human breast cancer xenografts
Authors: Zhang Chun , Yeung Pete , Beviglia Lucia , Cancilla Belinda , Tang Tracy , Yen Wan-Ching , Gurney Austin , Lewicki John , Hoey Timothy , Kapoun Ann M.
Published: May 2015

The Wnt/β-catenin signaling pathway has been shown to play key roles in both normal development and tumorigenesis (Polakis, 2007; MacDonald et al., 2009).

We have developed a monoclonal antibody, vantictumab, that blocks canonical WNT/β-catenin signaling through binding of five Fzd receptors (1, 2, 5, 7, 8) at a conserved epitope within the extracellular domain. This antibody inhibits the growth of several tumor types, including breast, pancreas, colon and lung. Furthermore, studies also showed that vantictumab reduces tumor-initiating cell frequency and exhibits synergistic activity with standard-of-care chemotherapeutic agents (Gurney et al., 2012).

Predictive biomarkers are central to maximizing clinical benefit by targeting breast cancer patients most likely to respond to vantictumab. We analyzed microarray gene expression data from 8 minimally passaged breast cancer xenograft models (mostly triple-negative) with established in vivo responses to vantictumab combined with paclitaxel (4 responders, 4 non-responders). We utilized support vector machine—recursive feature elimination (SVM-RFE, Guyon et al., 2002) to identify genes that can distinguish between responder and non-responders and SVM for classification. Leave-one-out cross-validation was used to measure positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity of the models. The selected 6-gene signature achieved the best performance with PPV=NPV=sensitivity=specificity=100% in the 8 breast cancer models. In addition, we observed a strong correlation between the gene signature biomarker and the ratio of tumor volume (RTV) observed in the breast xenograft experiments.

The identified 6-gene biomarker was used to predict the response to vantictumab in combination with paclitaxel in 6 additional, HER2-negative breast cancer xenograft models. The efficacy in all 6 models was predicted successfully by the biomarker. Prevalence data for the biomarker will be presented for both HER2-negative and triple-negative breast cancers. The 6-gene biomarker is currently being evaluated in a Phase 1b study of vantictumab in combination with paclitaxel in patients with locally recurrent or metastatic HER2-negative breast cancer.

Citation Format: Chun Zhang, Pete Yeung, Lucia Beviglia, Belinda Cancilla, Tracy Tang, Wan-Ching Yen, Austin Gurney, John Lewicki, Timothy Hoey, Ann M. Kapoun. Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) by mining gene expression data of human breast cancer xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2014-2830
Abstract 2832: Single nucleotide polymorphisms of DPYD and MTHFR predict adverse events associated with 5-fluorouracil in patients with gastrointestinal cancer
Authors: Toshima Masahide , Ohnuma Shinobu , Tanaka Michiiro , Miura Koh , Fujibuchi Wataru , Kajiwara Taiki , Komura Toshihiro , Musha Hiroaki , Haneda Sho , Kudoh Katsuyoshi , Kohyama Atsushi , Naitoh Takeshi , Unno Michiaki
Published: May 2015

Purpose

The aim of this study was to investigate the association between 5-fluorouracil (5-FU)-related adverse events (AEs) in Japanese patients with gastrointestinal cancer treated with 5-FU and the patient genotypes DPYD, MTHFR, OPRT, and TYMS.

Methods

Sequence analyses of 33 gene polymorphisms in four genes were performed using genomic DNA extracted from peripheral blood mononuclear cells of 103 patients with gastric (n = 34) or colorectal (n = 69) cancer. The 5-FU-related AEs of 157 regimens in these 103 patients were evaluated based on the medical records of patients in each of three groups: the intravenous administration group (i.v. group, n = 51), oral administration group (p.o. group, n = 106), and all-regimens group (both i.v. and p.o. group, n = 157). The associations between the incidence of AEs and each genotype were statistically analyzed.

Results

Six single-nucleotide polymorphisms (SNPs) were identified (three SNPs in DPYD: c.496A>G, c.1905+1G>A, and c.2303C>A; two SNPs in MTHFR: c.677C>T and c.1298A>C; and one SNP in OPRT: c.638G>C). Among them, the patients in the all-regimens group carrying any one of three DPYD SNPs showed statistically significant associations with the incidence of AEs of any type and fatigue. Furthermore, the MTHFR SNP c.1298A>C was significantly associated with the incidence of neutropenia. A similar trend was observed in the p.o. group, but not in the i.v. group.

Conclusion

These findings suggest that the DPYD SNPs c.496A>G, c.1905+1G>A, and c.2303C>A and the MTHFR SNP c.1298A>C may be predictive factors for the occurrence of severe 5-FU-related AEs.

Citation Format: Masahide Toshima, Shinobu Ohnuma, Michiiro Tanaka, Koh Miura, Wataru Fujibuchi, Taiki Kajiwara, Toshihiro Komura, Hiroaki Musha, Sho Haneda, Katsuyoshi Kudoh, Atsushi Kohyama, Takeshi Naitoh, Michiaki Unno. Single nucleotide polymorphisms of DPYD and MTHFR predict adverse events associated with 5-fluorouracil in patients with gastrointestinal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2832. doi:10.1158/1538-7445.AM2014-2832
Abstract 2833: Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers
Authors: Birkeland Einar , Blaalid Rakel , Bjørnslett Merete , Dørum Anne , Lønning Per Eystein , Knappskog Stian
Published: May 2015

Background: The mechanisms underlying resistance to chemotherapy in ovarian cancer are incompletely understood. Identifying genetic alterations associated with treatment response is decisive in the determination of which patients may benefit from adjuvant chemotherapy.

Methods: Biopsies were collected from twenty patients diagnosed with ovarian cancer who were subjected to post-operative taxane- and platinum-containing chemotherapy. Patients were selected for genetic analyses based on response to chemotherapy, determined as time to relapse (10 sensitive and 10 resistant patients). A panel of 620 genes, including known cancer driver genes, as well as genes involved in DNA repair were analysed by massively parallel sequencing. Alignment and mutation calling was performed using MiSeq Reporter, with further manual filtering of variants to exclude common SNPs. Validation of low quality mutation calls was done by Sanger sequencing.

Results: A median of 6 genes (range: 3 - 45) per patient was found to harbour non-synonymous mutations. Among previously identified driver genes in ovarian cancer, we found mutations in TP53, BRCA1, CDK12, NF1 and CSMD3. These mutations were more common among patients with more advanced disease and higher grade. For example, TP53 mutations were found in 10 out of 12 patients with high grade, stage 3c or 4 disease, and in 2 out of 5 with lower stage and/or grade. One patient was found to have a tumor potentially of a hyper-mutator phenotype with 49 mutations in 45 genes identified within our gene panel. With respect to treatment efficacy, 73 and 40 genes were found to be mutated exclusively in patients with a good and poor response to treatment, respectively.

Conclusion: We describe the profile of mutations in cancer driver genes and DNA repair genes among patients suffering from ovarian cancer according to treatment response.

Citation Format: Einar Birkeland, Rakel Blaalid, Merete Bjørnslett, Anne Dørum, Per Eystein Lønning, Stian Knappskog. Mutation analysis of cancer drivers and DNA repair genes in chemosensitive versus resistant ovarian cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2014-2833
Abstract 284: Epigenome-wide study of sister study samples replicates and extends cpg sites associated with cigarette smoking
Authors: Harlid Sara Sophia , Xu Zongli , Panduri Vijayalakshmi , Sandler Dale P. , Taylor Jack A.
Published: May 2015

Smoking increases the risk of many diseases -including cancer, and is also linked to blood DNA methylation changes that may be important in disease etiology. The objective of the current study was to identify and confirm potentially novel CpG sites associated with cigarette smoking. To do this we used two epigenome-wide datasets from the Sister Study. One included 908 women with methylation measurements at 27,578 CpG sites using the Illumina HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the Illumina HumanMethylation450 BeadChip. Significant CpGs from the second dataset that were not included in the 27k assay were validated by pyrosequencing in a subset of 476 samples from the first dataset. We were able to successfully confirm smoking associations for nine previously established CpGs and identify two potentially novel CpGs: cg26764244 in GNG12 (p= 9.0×10-10) and cg22335340 in PTPN6 (p=2.9×10-05).In addition to this we provide the first independent confirmation of the association between smoking status and cg02657160 in CPOX (p=7.28x10-7). All 12 CpGs were under-methylated in current smokers and showed increasing percent methylation in former and never smokers. The CPOX CpG proved to be of particular interest as the corresponding enzyme is involved in heme biosynthesis and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation.

Citation Format: Sara Sophia Harlid, Zongli Xu, Vijayalakshmi Panduri, Dale P. Sandler, Jack A. Taylor. Epigenome-wide study of sister study samples replicates and extends cpg sites associated with cigarette smoking. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 284. doi:10.1158/1538-7445.AM2014-284
Abstract 2862: Overexpression of nuclear karyopherin alpha2 correlates with poor prognosis in patients with colorectal cancer
Authors: Baek Moo Jun , Jeong Dongjun , Kim Tae Hyun , Kim Chang-Jin , Lee Sang Han , Kim Han J. , Bae Sang Byeong , Ahn Tae Sung
Published: May 2015

Objectives: Karyopherin alpha 2 (KPNA2) is a member of the karyopherin family that moves protein molecules into the nucleus by binding to a specific recognition sequence. It has recently been reported to play an important role in carcinogenesis and cancer progression. The aim of the present study was to elucidate the clinicopathological significance of overexpression of nuclear KPNA2 expression in colorectal cancers.

Methods: KPNA2 expression was investigated by immunohistochemistry on tissue microarrays of 363 cases of colorectal cancer and the association of KPNA2 expression was examined with clinicopathologic features.

Results: Thirty percent (30%) of colorectal cancers demonstrated overexpression of KPNA2. The overexpression of KPNA2 was significantly associated with high pN stages (p=0.005), vascular invasions (p<0.001) and lymphatic invasions (p<0.001). Multivariate Cox regression analysis showed that the overexpression of PKNA2 in pN stage 1, 2 was an independent prognostic factor of decreased survival [HR=2.13 (95% CI: 1.32-3.45, p=0.002)]. The overall survival was significantly decreased in patients of KPNA2 high expression [HR=2.70 (95% CI: 1.74-4.20, p<0.001)]. The cumulative survival was significantly decreased in patients of KPNA2 high expression compared to those of KPNA2 low expression by Kaplan-Meier analysis (log rank test, p<0.001).

Conclusion: The overexpression of KPNA2 can be a valuable poor prognostic marker of colorectal cancer and the KPNA2 can be used in therapeutic strategies.

Citation Format: Moo Jun Baek, Dongjun Jeong, Tae Hyun Kim, Chang-Jin Kim, Sang Han Lee, Han Jo Kim, Sang Byeong Bae, Tae Sung Ahn. Overexpression of nuclear karyopherin alpha2 correlates with poor prognosis in patients with colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2862. doi:10.1158/1538-7445.AM2014-2862
Abstract 2873: A molecular signature predictive of indolent prostate cancer
Authors: Irshad Shazia , Bansal Mukesh , Magnen Clementine L. , Dillon Risham , Castillo-Martin Mireia , Zheng Tian , Aytes Alvaro , Wenske Sven , Guarnieri Paolo , Sumazin Pavel , Benson Mitchell , Shen Michael M. , Califano Andrea , Abate-Shen Cory
Published: May 2015

With more than 230,000 estimated new cases in 2013, prostate cancer represents the most commonly diagnosed cancer in American men. While a subgroup of patients will develop an aggressive and lethal prostate cancer, most present with a low-risk form of the disease that requires little or no treatment. It is therefore crucial to distinguish patients whose tumors are likely to progress to aggressive disease from those whose tumors will remain indolent and for whom treatment may be more detrimental than beneficial.

In our recent study, we hypothesized that low Gleason score prostate tumors can be distinguished as indolent and aggressive based on expression of genes associated with aging and senescence (1). Using gene set enrichment analyses and a decision tree learning model, we identified a 3-gene panel_FGFR1, PMP22, and CDKN1A_that is enriched in indolent prostate cancers and accurately predicts outcome of low Gleason score tumors at both the RNA and protein levels. In particular, protein expression of this 3-gene panel in biopsy samples correctly distinguished Gleason 6 patients who failed active surveillance over a 10-year period.

Following from our initial study, our current efforts are focused on exploiting this 3-gene panel to develop a robust clinical assay for distinguishing indolent and aggressive tumors. We are currently using qRT-PCR, immunofluorescence, and immunohistochemistry assays to assess the most effective way to quantify the simultaneous expression of the 3-gene panel in low Gleason score tumor biopsies/tissues. This quantitative assay will ultimately be applied to a large cohort study assessing the predictive power of the 3-gene signature in patients under active surveillance. We envision that such a prognostic test will significantly improve our ability to predict the outcome of patients with low Gleason score tumors and facilitate appropriate decisions of treatment for men under active surveillance.

1. Irshad S, et al. (2013) A molecular signature predictive of indolent prostate cancer. Science translational medicine 5(202):202ra122.

Citation Format: Shazia Irshad, Mukesh Bansal, Clementine Le Magnen, Risham Dillon, Mireia Castillo-Martin, Tian Zheng, Alvaro Aytes, Sven Wenske, Paolo Guarnieri, Pavel Sumazin, Mitchell Benson, Michael M. Shen, Andrea Califano, Cory Abate-Shen. A molecular signature predictive of indolent prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2014-2873
Abstract 2876: Genetic polymorphism in the mir-196a as a prognostic biomarker for early breast cancer
Authors: Lee Soo Jung , Chae Yee Soo , Kang Byung Woog , Kim Jong Gwang , Park Ji-Young , Jung Jin Hyang , Park Ho Yong
Published: May 2015

Background: MicroRNAs (miRNA) may play important roles in tumorigenesis by regulating the expressions of proto-oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNP) in miRNA-coding genes and miRNA binding site genes might affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located in miRNA and miRNA-binding sites of various genes and their impact on the prognosis for patients with early breast cancer (EBC) by altering miRNA binding efficiency. Methods: Four hundred and fifty-two consecutive patients with curative resection were enrolled in the present study. Three SNPs (rs11614913, rs3746444 and rs1044129 of miR-196a, miR-499a and miR-367, respectively) were selected in Silico analysis for the current study based on several miRNA database and HapMap database. The SNP genotyping was performed using the Sequenom MassARRAY. Results: The median age of all patients was 48 years, and 298 (66.7%) had ER/PR-positive EBC, 64 (14.3%) had HER2-overexpressed EBC, and 79 (17.7%) had triple-negative EBC. The pathologic stages after the surgical resection were as follows: stage I (n=174, 38.5%), stage IIA (n=168, 37.2%), stage IIB (n=54, 11.9%), and stage IIIA (n=56, 12.4%). During the median follow-up of 6.9 (range 0.37 -19.93) years, 67 (14.8%) relapses and 47 (10.4%) deaths occurred. Among the 3 polymorphisms miR-196a rs11614913T>C was significantly associated with disease-free survival (DFS) and distant DFS (DDFS) when adjusted for age, histologic grade, receptor status, and pathologic stage. In particular, the prognostic impact of rs11614913 was limited to the HR- expressed subtype, where the patients bearing the CC genotype showed worse survival in terms of DFS and DDFS compared with those with the TT or TC genotype as a recessive model (HR= 2.571 and P-value=0.031, HR= 4.263 and P-value=0.001, respectively). Meanwhile, there were no statistical differences in patient and tumor characteristics among each genotype of rs11614913. Conclusions: The current study provides evidence that the miR-196a rs11614913T>C polymorphism is a possible prognostic biomarker for patients with HR-expressed early breast cancer.

Citation Format: Soo Jung Lee, Yee Soo Chae, Byung Woog Kang, Jong Gwang Kim, Ji-Young Park, Jin Hyang Jung, Ho Yong Park. Genetic polymorphism in the mir-196a as a prognostic biomarker for early breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2014-2876
Abstract 2882: p53MVA therapy in patients with refractory gastrointestinal malignancies primes robust CD8+ T cell responses
Authors: Hardwick Nicola , Carroll Mary , Kaltcheva Teodora , Qian Dajun , Espenschied Jonathan , Leong Lucille , Chu Peiguo , Kim Joseph , Chao Joseph , Fakih Marwan , Ellenhorn Joshua , Diamond Don , Chung Vincent
Published: May 2015

PURPOSE: To conduct a Phase I safety trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in patients with refractory gastrointestinal malignancies.

EXPERIMENTAL DESIGN: Three patients were vaccinated with 108 pfu p53MVA followed by nine patients at 5.6 x 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre vaccine and post vaccination for immunophenotyping and assessment of p53MVA induced immune response.

RESULTS: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. Induction of strong T cell and antibody responses to the MVA backbone were apparent. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T cell compartment (p=0.03). However in most patients this did not expand further with the second and third immunization. Some patients exhibited a decline in myeloid-derived suppressor cells post vaccine, but this was not statistically significant. The frequency of PD-1+ T cells detectable in patients PBMC was significantly higher than healthy controls. Furthermore, the frequency of PD-1+ CD8+ T cells showed an inverse correlation with the peak CD8+ T cell response to p53 (p=0.02).

CONCLUSION: p53MVA was well tolerated and induced robust CD8+ T cell responses. Combination of p53MVA with immune checkpoint inhibition could improve sustained immune responses and lead to clinical benefit.

Citation Format: Nicola Hardwick, Mary Carroll, Teodora Kaltcheva, Dajun Qian, Jonathan Espenschied, Lucille Leong, Peiguo Chu, Joseph Kim, Joseph Chao, Marwan Fakih, Joshua Ellenhorn, Don Diamond, Vincent Chung. p53MVA therapy in patients with refractory gastrointestinal malignancies primes robust CD8+ T cell responses. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2882. doi:10.1158/1538-7445.AM2014-2882
Abstract 2888: Dendritic cell-targeted lentiviral vector vaccines overcome tolerance to generate a protective T-cell immune response to breast cancer antigens ERBB2 and α-lactalbumin
Authors: Bryson Paul D. , Han Xiaolu , Truong Norman , Wang Pin
Published: May 2015

Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. In contrast, active immunotherapy through therapeutic vaccination has yet to be proven clinically effective for breast cancer. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To achieve this in vivo, we have pseudotyped lentiviral vector vaccines with a modified Sindbis Virus glycoprotein that targets the C-type lectin DC-SIGN, which is expressed on DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors as a breast cancer vaccine could lead to an improved immune response against self antigens found in breast cancer tumors. Such an improved immune response may help to prevent or slow tumor growth in breast cancer models. To test these hypotheses, we have constructed lentiviral vectors encoding each of the breast cancer antigens, human Her2 (ERBB2) and mouse alpha-lactalbumin (Lalba). Single injections were able to amplify antigen-specific CD8 T cells to 1.6% of total CD8 T cells in BALB/cJ mice and 0.7% in transgenic ERBB2 mice. This compares favorably with recently published vector vaccines, which have elicited 0.9% and <0.1% antigen-specific CD8 T cells under similar conditions. In addition, DC-targeted immunization of these mice completely inhibited tumor growth in a foreign antigen environment (ERBB2 + wt BALB/cJ), while it significantly reduced the rate of tumor growth in a self-antigen environment (Lalba + BALB/cJ or ERBB2 + FVB/Tg.MMTV.f.huHER2 #5). Our data show that these vectors alone can provide an effective therapy. Future studies may be able to improve these responses by combining DC-targeted immunization with established methods of reducing cancer immunosuppression. Thus, lentivector vaccines may be an excellent component to future clinical vaccine trials, either by themselves or in combination with other chemo- and immunotherapies.

Citation Format: Paul D. Bryson, Xiaolu Han, Norman Truong, Pin Wang. Dendritic cell-targeted lentiviral vector vaccines overcome tolerance to generate a protective T-cell immune response to breast cancer antigens ERBB2 and α-lactalbumin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2888. doi:10.1158/1538-7445.AM2014-2888
Abstract 2891: Bench-to-bedside development of a novel idiotype vaccine against lymphoma
Authors: Qin Hong , Cha Soungchul , Rao Sheetal S. , Kim Kunhwa , Gwak Dongho , Kim Sung-doo , Parshottam Sapna R. , Thomas Sheeba K. , Kwak Larry W.
Published: May 2015

Available therapies for lymphoplasmacytic lymphoma (LPL) provide no survival advantage if started before symptoms of end organ damage develop. Current recommendations are to follow a program of observation while patients are in the asymptomatic phase of disease. In this clinical study we will use idiotypic determinants of B-cell lymphoma surface immunoglobulins as tumor-specific antigens (idiotype) to develop a patient-specific vaccine against LPL. By activating the host immune system through vaccination to eradicate tumor cells, we postulate that disease control of asymptomatic phase lymphoplasmacytic lymphoma can be maintained. This novel 2nd generation idiotype vaccine was initially developed by genetic fusion of idiotype antigen in single-chain format with a pro-inflammatory chemokine. The central hypothesis is that antitumor immunity can be triggered by targeting antigen delivery to antigen-presenting cells in vivo by chemokine receptor-mediated binding, uptake and processing of idiotype antigens for more efficient presentation to T cells. A large body of preclinical data demonstrated that the immunogenecity of the idiotype antigen was considerably enhanced by such a genetic modification by a mechanism of facilitating antigen presentation. As a consequence, vaccine-induced prophylactic and therapeutic antitumor effects were significantly potentiated. To translate our vaccine therapy from bench to bedside, we established a CLP laboratory for vaccine preparation. Furthermore, we developed reliable technology to differentiate lymphoma idiotype antigens from idiotypic cell-surface immunoglobulins on normal B cells. Using this technology, we successfully cloned the cDNA encoding variable regions of heavy and light chains of LPL idiotype, and generated patient-specific plasmid constructs containing LPL idiotype single chain in fusion with macrophage inflammatory protein 3 alpha (MIP3a). All three engineering rounds of down-stream GMP amplification of clinical-grade plasmid DNA have been accomplished, which eventually paves the way for us to take a lab-grown agent to a first-in-human clinical trial.

Citation Format: Hong Qin, Soungchul Cha, Sheetal S. Rao, Kunhwa Kim, Dongho Gwak, Sung-doo Kim, Sapna R. Parshottam, Sheeba K. Thomas, Larry W. Kwak. Bench-to-bedside development of a novel idiotype vaccine against lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2891. doi:10.1158/1538-7445.AM2014-2891
Abstract 2892: Vaccination with a therapeutic cancer vaccine containing prostate specific antigen and the biological adjuvants IL-2 and GM-CSF results in reduced serum PSA in prostate cancer patients
Authors: Head Jonathan F. , Elliott Robert L.
Published: May 2015

In 1997 we initiated a phase I/II clinical trial of a therapeutic prostate cancer vaccine. We have enrolled 12 biopsy confirmed prostate cancer patients in this study and 11 finished the initial course of 6 intradermal vaccinations containing prostate specific antigen (50 μg) and biological adjuvants (IL-2, 20,000 units, and GM-CSF, 16.7 μg) at 0, 1, 2, 6, 10 and 14 weeks. During this study the prostate cancer patients received no other concurrent therapy (surgery, hormone, radiation, radioactive seeds, chemotherapy). One of the 12 patient's PSA rose from 7.6 to 13.7 after the fourth vaccination and he (patient #8) withdrew from the study to seek other therapy. In the remaining 11 prostate cancer patients serum PSA concentrations were determined before initiating vaccination and 3-4 weeks after the 6th vaccination. There was a decrease in the PSA levels in 8 of 12 of the prostate cancer patients after 6 vaccinations. One of the patients (patient #3), whose PSA had dropped from 6.8 to 6.4 and had previously received radiotherapy (the only patient previously treated), elected to withdraw from the study and underwent radical prostatectomy. Nine of the original 12 patients have received monthly 3 intradermal IL-2 injections (11 million units) alternated with 3 further vaccinations for the 6 months following the initial vaccinations, and 8 patients have been followed from 18 to 92 months. The mean PSA values for the 8 patients still being followed without additional therapy were 5.8 initially, decreasing to 4.1 after 6 vaccines, 3.7 after 12 vaccines and is 4.7 after a mean follow-up of 49 months (median follow-up of 45.5 months). These promising results have led to the creation of the U.S. Navy Cancer Vaccine Program with a Phase I clinical trial at the Veterans Administration Medical Center San Diego/UCSD Medical School.

Citation Format: Jonathan F. Head, Robert L. Elliott. Vaccination with a therapeutic cancer vaccine containing prostate specific antigen and the biological adjuvants IL-2 and GM-CSF results in reduced serum PSA in prostate cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2014-2892
Abstract 2898: HCA519/TPX2: a potential T-cell tumor-associated antigen for human hepatocellular carcinoma
Authors: Aref Ahmed M. , Hoa Neil T. , Ge Lisheng , Agrawal Anshu , Dacosta-Iyer Maria , Lambrecht Nils , Ouyang Yi , Cornforth Andrew N. , Jadus Martin R.
Published: May 2015

Immunotherapy for human hepatocellular cancer (HCC) is slowly making progress towards treating these fatal cancers. The identification of new antigens can improve this approach. We describe a possible new antigen, Hepatocellular Carcinoma-associated Antigen-519/ Targeting Protein for Xklp-2 [HCA519/Tpx2], for HCC that might be beneficial for T cell specific HCC immunotherapy. HCC was studied for the expression for 15 tumor-associated antigens considered useful for immunotherapy within three HCC cell lines (HepG2, Hep3B and PLC/PRF/5), lymphocytes, non-cancerous livers and clinical HCC. The expression of Tumor Antigenic Precursor Proteins (TAPPs) mRNA was first screened by quantitative real time PCR. Four antigens (alpha fetoprotein, aspartyl/asparaginyl β-hydroxylase, glypican-3 and HCA519/Tpx2) proved to be the best expressed TAPPs within the HCC specimens by molecular analyses. HCA519/Tpx2 was detected by intracellular cell flow cytometry within HCC cell lines by using a specific antibody towards this TAPP. This antibody also detected the protein within primary HCCs. We synthesized two HCA519/Tpx2 peptides (HCA519464-472 and HCA519351-359) which can bind to HLA-A*0201. Dendritic cells pulsed with these peptides stimulated cytolytic T lymphocytes (CTLs). These killer T cells lysed HLA-A*0201+ T2 cells exogenously loaded with the correct specific peptide. The CTLs killed HepG2 (HLA-A2+ and HCA519+), but not the Hep3B and PLC/PRF/5 cell lines, which are HCA519+ but HLA-A2-negative. In silico analysis reveals that HCA519/Tpx2 has the inherent ability to bind to a very wide variety of HLA antigens. HCA519/Tpx2 is a viable immunotarget that should be further investigated.

Citation Format: Ahmed M. Aref, Neil T. Hoa, Lisheng Ge, Anshu Agrawal, Maria Dacosta-Iyer, Nils Lambrecht, Yi Ouyang, Andrew N. Cornforth, Martin R. Jadus. HCA519/TPX2: a potential T-cell tumor-associated antigen for human hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2898. doi:10.1158/1538-7445.AM2014-2898